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Role of microRNAs in endocrine cancer metastasis
Accepted Manuscript Role of MicroRNAs in endocrine cancer metastasis Cilene Rebouças Lima, Cibele Crastequini Gomes, Marinilce Fagundes Santos PII:
S0303-7207(17)30184-3
DOI:
10.1016/j.mce.2017.03.015
Reference:
MCE 9888
To appear in:
Molecular and Cellular Endocrinology
Received Date: 3 October 2016 Revised Date:
12 March 2017
Accepted Date: 13 March 2017
Please cite this article as: Lima, C.R., Gomes, C.C., Santos, M.F., Role of MicroRNAs in endocrine cancer metastasis, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017.03.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Role of MicroRNAs in endocrine cancer metastasis Cilene Rebouças Lima1, Cibele Crastequini Gomes1, Marinilce Fagundes Santos1.
1
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Department of Cell and Developmental Biology, Institute of Biomedical Sciences,
University of São Paulo, Avenida Professor Lineu Prestes 1524, Prédio I, CEP
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05508-000, São Paulo, SP, Brazil.
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Cilene R. Lima: [email protected] Cibele Crastequini Gomes [email protected]
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Marinilce F. Santos: [email protected]
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*Corresponding author:
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Cilene Rebouças Lima, PhD
Running Title: MicroRNAs in Endocrine Cancer Metastasis
Keywords: Endocrine cancers, EMT, invasion, small RNA, metastasis
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ACCEPTED MANUSCRIPT Abstract The deregulation of transcription and processing of microRNAs (miRNAs), as well as their function, has been involved in the pathogenesis of several human diseases, including cancer. Despite advances in therapeutic approaches, cancer
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still represents one of the major health problems worldwide. Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment
complexity and a worse prognosis. After more than one decade of extensive
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studies of miRNAs, the fundamental role of these molecules in cancer progression and metastasis is beginning to be elucidated. Recent evidences have
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demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic. They are involved in distinct steps of metastasis including epithelial-to-mesenchymal transition, migration/invasion, anoikis survival, and distant organ colonization. Studies on the roles of miRNAs in
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cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets,
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function and regulation. Functional miRNA studies on endocrine cancers are still scarce and represent an important area of research, since some tumors, although
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not frequent, present a high mortality rate. Among the endocrine tumors, thyroid cancer is the most common and best studied. Several miRNAs show lowered expression in endocrine cancers (i.e. miR-200s, miR-126, miR-7, miR-29a, miR30a, miR-137, miR-206, miR-101, miR-613, miR-539, miR-205, miR-let7f, miR145, miR-9, miR-195), while others are commonly overexpressed (i.e. miR-21, miR-183, miR-31, miR-let7b, miR-584, miR-146b, miR-221, miR-222, miR-25, miR-595). Additionally, some miRNAs were found in serum exosomes (miR-151,
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ACCEPTED MANUSCRIPT miR-145, miR-31), potentially serving as diagnostic tools. In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory roles in endocrine cancer metastasis, which may contribute for the finding of novel therapeutic targets. The review focus on miRNAs with at least
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some identified targets, with established functions and, if possible, upstream regulation. 1. MicroRNAs
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MicroRNAs (miRNAs) are highly conserved endogenous small non-coding
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RNAs (~17-25 nucleotides), known as important negative regulators of gene expression. Most commonly, they regulate gene expression by perfect or imperfect (partial complementarity) pairing with messenger RNAs (mRNAs), promoting their degradation or blocking translation, respectively. They can regulate multiple genes, what allows them to coordinate many biological processes, increasing the
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complexity of the molecular regulatory mechanisms of gene expression (Wang et al., 2007; Lin & Gregory, 2015).
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The biogenesis of miRNAs involves several steps already well understood. Initially, miRNA is transcribed from DNA by RNA polymerase II / III as a long
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primary transcript RNA (pri-miRNAs) (Lee et al., 2004). In the nucleus, the primiRNA is initially processed by a microprocessor complex that contains the RNase III enzyme Drosha to generate pre-miRNAs with a stem loop hairpin secondary structure (60-70 nucleotides). This molecule is exported from the nucleus to the cytoplasm by exportin 5, mediated by Ran GTPase and processed into a mature miRNA duplex by another molecular complex, which contains the RNase III enzyme Dicer (Lin & Gregory, 2015). Some miRNAs may be synthesized by alternative mechanisms which do not involve Drosha and Dicer activities, i.e.
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ACCEPTED MANUSCRIPT miRNAs generated by alternative splicing, known as miRtrons (Ruby et al., 2007; Cheloufi et al., 2010; Westholm et al, 2011; Havens et al., 2012).
MiRNAs exert their function associated to a RNA-induced silencing complex (RISC) which promotes, most commonly, the pairing of 5′-seed sequences (2-7
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nucleotides) of miRNA to the 3′-UTR of the target mRNA. Some studies have
demonstrated that miRNAs can also associate at any position to a target mRNA, such as the 5’ UTR or coding region sequences and this seems to be enough to
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suppress gene expression (Lytle et al., 2007; Lee et al., 2009; Takagi et al., 2010; Jin et al., 2011; Li et al., 2016; Teplyuk et al., 2016). Furthermore, the complexity
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of these interactions has become even greater with the discovery that different regions of the same miRNA can bind to a target mRNA, generating different types of pairing: 3′-end centric ‘seedless’ pairing, centred miRNA pairing and nucleation bulges in the seed region. Additionally, a target mRNA offers different regions for
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the association of a specific miRNA. This ability may, in part, explain the large number of target mRNAs for the same miRNA (Betel et al., 2010; Chi et al., 2012; Helwak et al., 2013).
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The inaccurate cleavage of the pri-miRNA or pre-miRNA from a single gene by Dicer or Drosha respectively, can give rise to small variations of miRNAs that
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generate isoforms known as isomiRs. These nucleotide variations may occur in the 5 'end giving rise to small variations in the seed sequence (nucleotides 2–8), thus influencing the specificity of a miRNA to its target (Kawahara et al., 2007; Wu et al., 2009; Starega-Roslan et al., 2011; Ekdahl et al., 2012). Furthermore, isomiRs may also have additional nucleotides at the 3' end, which can influence the stability of the pairing between the miRNA and the target mRNA (Martin & Keller, 2007). The variations in the distribution of isomiRs among different cells
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ACCEPTED MANUSCRIPT and tissues, as well as in pathological conditions, supports the hypothesis of a refinement in the control of gene expression by miRNAs, potentially functioning together to control complex signaling pathways and greatly increasing its
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regulatory potential (Cloonan et al., 2011). Independently of the mechanisms involved, the biogenesis of miRNAs is perfectly modulated by many signaling pathways. The deregulation of transcription and processing of miRNAs, as well as their function, has been involved in the
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pathogenesis of several human diseases, including cancer. As a matter of fact,
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miRNAs have been reported as crucial molecules in the development and progression of cancer (Jansson & Lund, 2012; Zaravinos, 2015; Hata & Kashima, 2016).
Despite advances in therapeutic approaches, cancer still represents one of the major health problems worldwide. About 14.1 million new cancer cases were
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diagnosed and 8.2 million cancer-associated deaths were reported in 2012. The main leading cause of these deaths was tumor metastasis, responsible for
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approximately 90% of all cases (Ferlay et al., 2015). In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory
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roles in endocrine cancer metastasis. 2. The metastatic cascade Briefly, tumor metastasis is defined as the ability of highly aggressive
cancer cells to detach from the primary neoplasm and spread to form secondary metastatic lesions in other tissues and organs (Spano et al., 2012). The metastatic cascade in epithelial cancers involves multiple biological events in several stages: (1) epithelial to mesenchymal transition (EMT) in primary tumor cells promoting their detachment, (2) invasion and migration through the
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ACCEPTED MANUSCRIPT microenvironment (basement membrane and extracellular matrix) of the primary neoplasm and surrounding tissues, (3) intravasation and survival on blood or lymphatic circulation and (4) extravasation, mesenchymal to epithelial transition
al., 2010; Chaffer & Weinberg, 2011).
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(MET) and growth of a secondary tumor at the target receptive organ (Brooks et
It is well known that the success of a metastatic tumor cell following this cascade depends on the coordinated function of a complex molecular network
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which has been elucidated during the last decades (Brooks et al., 2010; Spano et al., 2012). Nonetheless, much remains to be studied and no effective therapeutic
al., 2012; Chan & Wang, 2015).
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treatments were found to adequately interpose the metastatic process (Spano et
Recent evidences have demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic (Tables 1, 2
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and 3 and Figure 1) (White et al., 2011; Bouyssou et al., 2014; Chan & Wang, 2015). They are involved in distinct steps of metastasis including EMT, migration/invasion, anoikis survival, intravasation/extravasation and distant organ
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colonization. Therefore, it is important to increase the knowledge about the regulatory role of miRNAs on the metastatic cascade, which may contribute to the
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discovery of new therapeutic approaches. 3. Endocrine cancers Endocrine tumors frequently lead to disturbances in the production of
hormones, sometimes causing characteristic hormonal syndromes. The endocrine glands that present malignant tumors include the thyroid, adrenal, pancreas, parathyroid and pituitary. Although some of these tumors are rare, they may have high mortality indices; in general, the presence of metastasis indicates a poor
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ACCEPTED MANUSCRIPT prognosis, with a high recurrence and poor response to treatments (Schulte et al., 2012; Wong et al., 2014; Sav et al., 2015; Xu et al., 2016; Scollo et al., 2016). The thyroid cancer is the most common endocrine cancer, affecting mostly
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women (77% of cases) (Ferlay et al., 2015). In 2016, according to the SEER (Surveillance, Epidemiology and End Results Program), about 56,000 new cases of thyroid cancer were estimated, accounting for 3.8% of all new cases of cancer (http://seer.cancer.gov/statfacts/html/thyro.html, Accessed on September 13,
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2016; SEER program, 2016). The most common type of thyroid cancer is the
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papillary thyroid carcinoma, followed by the follicular thyroid carcinoma. The anaplastic carcinoma is the most undifferentiated, aggressive and invasive form, occurring in less than 2% of cases (Aschebrook-Kilfoy et al., 2011). The incidence of thyroid cancer has increased over the past decades, mainly due to the increased number of papillary carcinomas (Smallridge et al., 2012).
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Epidemiological studies suggest that several thyroid cancers could be attributable to environmental factors, such as obesity (Kitahara et al., 2011; Pazaitou-
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Panayiotou et al., 2013; Kitahara & Sosa, 2016). The molecular pathogenesis of the thyroid cancer is frequently associated
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with the mutation of the BRAF gene, resulting in the expression of a constitutively active mutant protein. This mutation occurs in approximately 35-50% of papillary thyroid carcinomas (Fukushima et al., 2003; Kimura et al., 2003). BRAF is a serine/threonine kinase that receives a signal from RAS, and then transmits it to the MAP Kinase pathway. Besides BRAF mutation, there is also the mutation of RAS itself and the rearrangement of RET/PTC, which also leads to the activation of the MAP kinase pathway. Mutations involving one of these genes are found in 66% of papillary thyroid carcinomas, and they rarely overlap in the same tumor
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ACCEPTED MANUSCRIPT (Kimura et al., 2003). Activation of the MAP Kinase pathway is an important mechanism for the upregulation of cell proliferation. When constitutively activated, the MAP Kinase pathway leads to tumorigenesis (Shapiro, 2002; Xing, 2013).
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Parathyroid carcinoma is one of the rarest tumors, accounting for only 0.005% of all cancers (Hundahl et al., 1999). These tumors usually secrete
parathyroid hormone, thereby producing severe hyperparathyroidism. Sandelin et al. (1994), in an epidemiological study, reported that distant metastases occur in
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25% of patients with parathyroid carcinoma, mostly in the lungs, liver and bones.
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Approximately 70% of parathyroid carcinomas carry a mutation of cell division cycle 73 (CDC73, also known as HRPT2), a tumor suppressor gene that encodes a protein known as parafibromin. Parafibromin is a nuclear protein that participates of the regulatory RNA Polymerase Associated Factor-1 Complex (Paf1C), and interacts directly with β-catenin, regulating different cellular processes that are
Arndt, 2013).
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important for tumorigenesis (Howell et al., 2003; Newey et al., 2009; Tomson &
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Adrenal cancer (adrenocortical carcinoma) is a rare and usually highly aggressive malignancy, with high recurrence rates and poor response to
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chemotherapy. Epidemiological data about this tumor is scarce and out of date; with the advancement of new diagnostic methods, there is a need for further research in this area. Higher incidence is between 40 and 50 years of age, affecting mostly women (Kebebew et al., 2006). Assié et al. (2007) studied the parameters that influence the prognosis of patients with adrenocortical carcinoma with metastases. Regardless of factors such as mitotic rate and affected organs, the prognosis of these patients was poor, with low survival. Genetic alterations commonly related to the molecular pathogenesis of this tumor include the
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ACCEPTED MANUSCRIPT overexpression of the Insulin-like Growth Factor-2 (IGF-2) gene (90% of cases)
and β-catenin mutation, leading to Wnt signaling pathway activation (Gicquel et al., 1997; Tissier et al., 2005). Phan et al. (2015) studied the role of the pathway elicited by the proto-oncogene cMET and its ligand Hepatocyte Growth Factor
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(HGF) in adrenocortical carcinoma. They found that the expression of both cMET and HGF is high in this cancer, and functional genomic analysis revealed that
cMET overexpression was related to several cancer hallmarks such as sustained
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proliferation, increased tumor metabolism, resistance to cell death, chemotherapy resistance, and activation of metastasis. Indeed, cMET activation was associated
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with increased tumor cell proliferation, angiogenesis and reduced apoptosis. Moreover, cancer cells rapidly upregulated cMET expression in response to radiation and chemotherapy.
The downstream response to c-MET activation involves the classical
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Mitogen activated protein kinase (MAPK) cascades regulating cell proliferation, cell motility and cell cycle progression (Trusolino et al. 2010; Organ & Tsao, 2011).
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It also activates the PI3K/Akt signaling axis, responsible for the cell survival response to c-MET signaling, and the focal adhesion kinase (FAK), which is
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localized to cellular adhesion complexes, for the regulation of cell migration and the promotion of anchorage-independent growth (Organ & Tsao, 2011). Pancreatic cancers represent 3.1% of all new cancer cases in 2016 in the
US, and represented 3% of all cancers in the UK in 2013 (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statisticsby-cancer-type/pancreatic-cancer/incidence, Accessed on September 13, 2016; SEER program, 2016). Pancreatic neuroendocrine tumors (PNETs) arise from pancreatic islet cells and are less common, representing less than 2% of the
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pancreatic tumors (Yao et al., 2007). These tumors are classified according to the type off affected cells, and may produce hormones, such as insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP) and somatostatin. It is important to mention, however, that not all hormone-producing PNETs cause symptoms related
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to hormone overproduction. Insulinomas are the most common functional PNET, which account for 30% - 45% of the functional PNETs (McKenna & Edil, 2014). Considering different types of islet cell tumors, Yao et al. (2007) have shown that
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most of them were metastatic at the time of diagnosis, including islet cell
carcinomas (61%), insulinomas (61%), glucagonomas (56%), and gastrinomas
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(60%). A smaller percentage of VIPomas (47%) were metastatic, probably because the symptoms of this tumor lead to an early diagnosis. There is some controversy about the origin of PNETs. It has been argued that PNETs may arise from MEN-1 gene mutations into alpha and beta cells,
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suggesting an endocrine origin for this type of tumor (Bertolino et al., 2003; Lu et al., 2010; Hackeng et al., 2016). This tumor suppressor gene is related to the
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autosomal dominant multiple endocrine neoplasia type-1, an inherited syndrome that causes tumors in the endocrine pancreas, parathyroid and pituitary glands.
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Some researchers, however, consider the possibility that PNETs may originate from pluripotent cells within the exocrine pancreas (Vortmeyer et al., 2004). Tumors in the pituitary gland account for 9% of all brain tumors, with
carcinomas accounting for only 0.1 to 0.2 % of pituitary tumors (Surawicz et al, 1999; Scheithauer et al., 2005). They may present craniospinal or distant metastases, with poor prognosis (Pernicone et al., 1997, Hansen et al., 2014). These tumors can produce prolactin (PRL), adrenocorticotrophic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropin,
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ACCEPTED MANUSCRIPT or may also be nonfunctional tumors. The pathogenesis of these tumors is complex and not very well understood; factors such as stimulation by growth factors, alterations in hormone regulation, cell-cell interactions and alterations in the cell cycle control were reported (Ezzat & Asa, 2006), as well as epigenetic
expression of non-coding RNAs (Sapochnik et al., 2016).
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alterations of tumor suppressor genes and oncogenes and the differential
4.1. EMT and detachment
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4. Role of miRNAs in the metastatic cascade in endocrine cancers
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The early phase of a glandular tumor metastasis is characterized by a loss of the epithelial tumor cell properties and acquisition of a mesenchymal phenotype, known as EMT. Its activation involves both genetic and epigenetic alterations of tumor cells as well as the presence of EMT-inducing signals secreted by stromal and inflammatory cells, the latter being previously recruited to
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the tumor microenvironment (Chaffer & Weinberg, 2011, Ye et al., 2015). MiRNAs have been described as important regulators of this process by modulating the
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expression of many genes involved in EMT. Examples of genes regulated by miRNAs are some coding adherens junctions proteins, transcription factors,
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cytoskeletal and signaling proteins from different pathways among others, which in general promote the ability of cells to migrate, to invade surrounding tissues, to survive and to disseminate to other organs (Zhang et al., 2012; Lamouille et al., 2013, 2014; Abba et al., 2016). During the initial stages of the EMT, specialized protein complexes on the surface of epithelial cells lose their integrity, promoting disaggregation. Additionally, downregulation of the expression of junctional epithelial proteins destabilizes those structures, reducing cell-cell adhesiveness. Cell junctions are
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deconstructed and the junction proteins are relocated and/or degraded (Huang et al., 2012; Lamouille et al., 2013; 2014). Cadherins, a large family of intercellular adhesion proteins, have important
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features in EMT, especially E-cadherin (cadherin-1 or CDH1). The repression of Ecadherin has been strongly associated with the metastatic phenotype in many cancers, including endocrine cancers (Chetty et al., 2008; Fendrich et al., 2009). MiRNAs may act directly by inhibiting the expression of E-cadherin or indirectly,
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through the regulation of transcription factors (Braun et al., 2010, Zhang et al.,
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2012; Abba et al., 2016). The transcription factors ZEBs (Zinc Finger Ebox Binding Homeobox), Snails and Twists, in example, are master negative regulators of Ecadherin expression, also modulating other molecules involved in EMT (Lamouille et al., 2013; 2014). The family of miR-200 (miR-200a, miR-200b, miR-200c, miR141 and miR-429), in example, frequently targets ZEBs and has been studied in
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cancer (Korpal et al., 2008; Díaz-López et al., 2014). The ZEB family comprises two members, ZEB1 and ZEB2 (Vandewalle et
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al., 2009). In general, miR-200s play an anti-metastatic role and their expression is reduced in metastatic cancers. Consequently, ZEB factors are augmented,
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promoting the downregulation of E-cadherin expression and favoring EMT, migratory capacity and invasiveness (Lamouille et al., 2013; 2014). The analysis of miR-200s expression in samples of different thyroid
carcinomas has shown that miR-200a, miR-200b and miR-200c were significantly reduced only in Anaplastic Thyroid Carcinoma, the most aggressive type (Braun et al., 2010). In those cells, the expression of miR-200s was correlated with the EGF/EGFR signaling. The EGFR is overexpressed in anaplastic carcinoma and its
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ACCEPTED MANUSCRIPT activation by EGF downregulates miR-200 expression (Bergstrom et al, 2000; Zhang et al., 2012). Members of the miR-200 family were also downregulated in
metastatic medullary thyroid cancer, being functionally involved in EMT and tumor
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invasion through the targeting of ZEB1 and ZEB2 (Santarpia et al., 2013). In a recent study, a signature of miRNAs was obtained in multistep tumorigenesis using the RT2 transgenic mouse model of Pancreatic
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Neuroendocrine Tumors. The miR-200s family showed a notable reduction.
In addition to target ZEBs, miR-200s also suppress the expression of the
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zinc finger transcription factors from the Snail family, which lead to EMT activation in some cancers (Lamouille et al., 2013; 2014; Abba et al, 2016). The Snail family comprises three members: Snail1, Snail2 (Slug), and Snail3 (SMUC) (Baulida et al., 2015). The relationship between miR-200s/Snail/E-cadherin is still unknown in
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endocrine tumors, although Snails and E-cadherin expression have been studied. Besides miR-200s, other miRNAs have been described as EMT regulators in endocrine cancers. In anaplastic thyroid carcinomas, the expression of miR-29a
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and miR-30a is reduced. Both miRNAs directly target lysyl oxidase, which is able
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to promote EMT (Hebrant et al., 2014; Boufraqech et al., 2015). Boufraqech et al. (2016) showed that lysyl oxidase binds and transactivates the Snail2 promoter, increasing Snail2 expression. In papillary thyroid carcinoma with lymph node metastasis, miR-146b-5p is
overexpressed and induces EMT, increasing invasiveness targeting the Zinc Ring Finger 3 protein (ZNRF3), which is a cell surface transmembrane E3 ubiquitin ligase that negatively regulates the Wnt/β-catenin signaling (Deng et al., 2015).
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ACCEPTED MANUSCRIPT The role of miRNAs in the regulation of genes linked to EMT in endocrine cancers is still poorly known, but these findings suggest an important modulation of the early phases of EMT by miRNAs.
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4.2. Invasion and Migration Cell invasion and migration are crucial processes for the metastatic
dissemination of tumor cells. Under EMT, epithelial cancer cells remodel their cellcell and cell-extracellular matrix adhesions, acquire a fusiform morphology and
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increase their directional motility to escape the primary tumor and move on to
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another organ (Brooks et al., 2010). During this process, the cortical actin cytoskeleton is reorganized and new actin-rich membrane projections that facilitate cell movement are constructed: the sheet-like membrane protrusions called lamellipodia, spike-like extensions called filopodia and small projections with matrix proteolytic activity involved in cell invasion, known as invadopodia (Ridley,
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2011; McNiven, 2013). Most filopodia are exploratory of the microenvironment, and precede lamellipodia. Cells extend lamellipodia in the direction of migration,
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establishing new immature adhesions to the extracellular matrix. Some of these adhesions mature into focal adhesions, serving as anchorage sites for actin-
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myosin II contractile bundles named stress fibers. The contraction of stress fibers helps the pulling of the cell body forward; finally, the cells retract the rear end. This movement is cyclic during cell migration, being mostly regulated by small GTPases from the Rho family (Ridley, 2015). The ability to degrade the extracellular matrix and move to penetrate tissue barriers is a hallmark of tumor aggressiveness. MiRNAs regulate both processes, targeting molecules involved in many signaling pathways in different cancers, including endocrine cancers. One of the first studies to investigate the role of
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ACCEPTED MANUSCRIPT miRNAs in thyroid cancer aggressiveness was published by Chou et al. (2010).
After previous studies that showed a high expression of miR-146b-5p, miR-221-3p and miR-222-3p in papillary thyroid carcinomas (He et al., 2005; Pallante et al., 2006; Nikiforova et al., 2008), they analyzed 100 cases of papillary thyroid
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carcinomas with distinct characteristics and demonstrated that these miRNAs were significantly higher in tumors with extrathyroidal invasion. Other studies
followed through, establishing similar correlations. A higher expression of the
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same miRNAs was found in papillary thyroid carcinoma patients that presented capsule invasion, vascular invasion or lymph node metastasis, as well as distant
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metastases (Zhou et al., 2012; Saiselet et al., 2015; Mutalib et al., 2016). Concerning all the miRNAs differentially expressed in papillary thyroid carcinomas until now, miR-146b-5p is regarded as the best correlated with tumor aggressiveness and has been considered as a potential prognostic marker for this
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cancer (Chou et al., 2013; Peng et al., 2014; Lee et al., 2015; Mutalib et al., 2016). The mechanisms involved in miR-146b-5p-stimulated migration and invasion in
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papillary thyroid carcinomas are still poorly understood. Chou et al. (2013) transiently overexpressed this miRNA in papillary thyroid carcinoma cell lines in
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vitro, showing increased migration, invasion and increased resistance to chemotherapy-induced apoptosis. Recently, Lima et al. (2016) demonstrated that miR-146b-5p positively regulates migration and invasion of papillary thyroid carcinoma cell lines in vitro targeting Smad4, a member of the TGF-β signaling pathway. Downregulation of Smad4 has been widely associated with TGF-β resistance in thyroid tumor cells, contributing to accelerate the malignant progression (Mincione et al., 2011; Geraldo et al., 2012). The overexpression of
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ACCEPTED MANUSCRIPT miR-146-5p was also detected in follicular thyroid carcinomas, accelerating cell migration (Dettmer et al., 2013). Similarly to miR-146b, miR-221 and miR-222 were also associated with
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papillary thyroid carcinoma aggressiveness and are overexpressed in metastatic follicular thyroid carcinomas (Jikuzono et al., 2013). Visone et al. (2007) have shown that miR-221 and miR-222 directly repress p27Kip1 expression in
anaplastic thyroid carcinoma. The protein p27Kip1 negatively controls cell cycle
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progression, and decreased p27Kip1 levels have been correlated with poor patient
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survival (Slingerland & Pagano, 2000; Acibucu et al., 2012). Acibucu et al. (2012), studying a potential correlation between miR-146b, miR-221/222, p27Kip1 and clinicopathologic parameters in papillary thyroid cancers, showed that the expression of these miRNAs was elevated in patients with distant metastases and
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lower levels of p27Kip1.
The identification of differentially expressed miRNAs in parathyroid cancers by miRNA array showed the upregulation of three miRNAs (including miR-222 and
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miR-503) and the downregulation of fourteen miRNAs, including miR-296 and miR-139. Although the functional role of miR-222 in this tumor has not been
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elucidated, its overexpression seems to contribute to tumorigenesis (Corbetta et al., 2010).
The role of miR-221 and miR-222 in tumorigenesis and invasiveness,
however, is far from clear. For some types of cancer, these miRs are considered oncomiRs, whereas in others they are considered tumor-suppressor miRs; basically, they are capable of regulating EMT, migration, invasion, angiogenesis, proliferation and apoptosis (Garofalo et al., 2012; Xu et al., 2015; Li et al., 2016).
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ACCEPTED MANUSCRIPT Other miRNAs involved in thyroid cancer progression and aggressiveness
are miR-126 and miR-7 (Kitano et al., 2011; Yue et al, 2016). Kitano et al. (2011) suggested that these miRNAs might be used as markers to distinguish thyroid carcinomas from benign thyroid lesions, being downregulated in both papillary and
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follicular thyroid carcinomas. More recent studies tried to clarify the role of miR126 in thyroid cancer (Rahman et al., 2015; Xiong et al., 2015; Wen et al., 2015; Qian et al., 2016; Salajegheh et al., 2016). Its tumor suppressor role was first
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demonstrated by Xiong et al. (2015), who showed that lowered levels of miR-126 expression were correlated with more aggressive thyroid cancers. The
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overexpression of miR-126-3p inhibited thyroid cancer cell proliferation, colony formation, tumor spheroid formation, migration and VEGF secretion, and significantly reduced tumor growth and metastasis in vivo (Xiong et al., 2015). The effects on growth and migration were at least partially attributed to two direct target
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genes: SLC7A5 and ADAM9, respectively. SLC7A5 codes a neutral amino acid transporter also known as LAT1, which is overexpressed in a variety of tumor cells, associated with poor prognosis (Fan et al., 2010; Oda et al., 2010). The
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other target, ADAM9, is a member of the disintegrin and metalloprotease domain family and plays an important role in ectodomain shedding of membrane-bound
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molecules.
The tumor suppressor role of miR-126 in papillary thyroid carcinomas was
also studied by Wen et al. (2015) using miRNA in vitro and in vivo functional assays. MiR-126 overexpression in papillary thyroid carcinoma cell lines significantly reduced cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and cell cycle arrest at G1 in vitro, also inhibiting tumor growth and decreasing tumor size in vivo (Wen et al., 2015). A potential target of
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ACCEPTED MANUSCRIPT this miRNA was the low-density lipoprotein receptor related protein 6 (LRP6),
which acts as a co-receptor for Wnt ligands to activate the Wnt/β-catenin signaling pathway (Liu et al., 2003; MacDonald & He, 2012). More recently, Qian et al. (2016) confirmed the downregulation of miR-126 in thyroid cancer tissues and
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established the C-X-C chemokine receptor type 4 (CXCR4), which binds
chemokine CXCL12, as another target of miR-126 that contributes to the regulation of proliferation, migration and invasion.
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MiR-126 is deregulated in other endocrine cancers, with not very clear
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roles. Olson et al. (2009) suggested a miRNA signature for each step of tumorigenesis in pancreatic neuroendocrine tumors, and miR-126 was overexpressed during angiogenesis, one of the early steps of tumorigenesis. Its expression decreased substantially in more advanced stages, however, when cells presented a metastatic profile and the tumors became more aggressive. Patterson
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et al. (2011), using miRNA microarray, found 23 deregulated miRNAs in adrenocortical carcinomas; among them, miR-126 was significantly decreased.
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Rahbari et al. (2011) found 167 deregulated miRNAs in parathyroid carcinomas when compared to normal parathyroid glands, and found three (miR-126, miR-26b
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and miR-30b) compared to parathyroid adenomas. MiR-126 was considered the best diagnostic marker for carcinomas. As already mentioned, in the last few years miR-7 has also been
investigated as a potential marker to distinguish malignant from benign thyroid tumors (Santarpia et al., 2013; Stokowy et al., 2014). More recently it has been associated with tumor aggressiveness and metastasis (Saiselet et al., 2015; Mutalib et al., 2016; Yue et al., 2016). Kitano et al. (2012) developed a diagnostic technique for thyroid fine-needle aspiration biopsies based on miRNA expression
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ACCEPTED MANUSCRIPT levels. Among four miRNAs previously reported as differentially expressed between benign and malignant tumors (miR-7, miR-126, miR-374a, and let-7g) (Kitano et al., 2011), miR-7 was the most accurate miRNA for the diagnosis of
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carcinomas (Kitano et al., 2012). Using next-generation deep sequencing to analyze miRNA length
heterogeneity and expression profiles in papillary thyroid cancers, subsequently validated by miRNA microarray, Swierniak et al. (2013) found 43 differentially
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expressed miRNAs. The expression of miRNAs was not correlated to BRAF
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mutation, and almost all miRNAs exhibited isoforms of variable length (isomiRs), possibly with distinctive functions in thyroid tumorigenesis. Corroborating other studies, miR-7-3p, among the top six deregulated miRNAs, was significantly downregulated in thyroid carcinomas. More recently, however, Mancikova et al. (2015) reported that papillary thyroid carcinomas with BRAF mutation displayed
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extreme downregulation of miR-7 and miR-204. In a similar study aiming the establishment of better miRNA markers to distinguish follicular thyroid carcinomas
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from follicular adenomas, Stokowy et al. (2014) evaluated publicly available miRNA expression profiling data sets and found 27 miRNAs differentially
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expressed; miR-7-5p was among the top four significantly deregulated. The downregulation of miR-7 was also correlated with tumor
aggressiveness, since it was among the ten miRNAs most aberrantly deregulated in metastatic medullary thyroid carcinoma samples (Santarpia et al., 2013). Saiselet et al. (2015) found that miR-7 and miR-30c were among the most downregulated miRNAs in lymph node metastases of invasive papillary thyroid carcinomas. In that study the authors employed small RNA deep sequencing followed by qPCR and in silico analysis using the dataset from The Cancer
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ACCEPTED MANUSCRIPT Genome Atlas. Besides confirming the identity of the major deregulated miRNAs already described in the literature, they selected the 14 most downregulated miRNAs as potential biomarkers of papillary thyroid carcinoma, some of them
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related to invasiveness. More recent studies have employed integrated analysis of miRNAs and gene expression profiles to improve the identification of functional miRNA-target gene relationships, providing a more complete view of molecular events underlying
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metastasis. Mutalib et al. (2016) reviewed datasets from the Cancer Genome Atlas
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(TCGA) on papillary thyroid carcinoma to identify differentially expressed miRNAs/genes in tumors with lymph node metastasis. MiR-7-2, miR-146b, miR375, miR-31 and miR-204 were the five top deregulated miRNAs among the 181 differentially expressed miRNAs in metastatic tumors. Four pathways potentially involved in metastasis to the lymph nodes were significantly enriched: oxidative
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phosphorylation, cell adhesion molecules, leukocyte transendothelial migration and cytokine-cytokine receptor interactions.
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Although several studies have shown that miR-7 is an important miRNA involved in thyroid tumorigenesis, its tumor suppression function began to be
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elucidated only recently. Yue et al. (2016) showed that miR-7 overexpression in thyroid cell lines significantly suppressed proliferation, migration and invasion. They also demonstrated that the serine/threonine kinase p21-activated kinase-1 (PAK1), overexpressed in this cancer is a direct target of this miRNA (McCarty et al., 2010). Hua et al. (2016) showed that the overexpression of miR-7 in thyroid carcinoma cell lines not only inhibited proliferation, suppressed migration and invasion, but also caused a G0/G1 arrest through the targeting of the cyclindependent kinases regulatory subunit 2 (CKS2).
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In addition to thyroid tumors, decreased expression of miR-7 has also been described in adrenal cancers. Soon et al. (2009) found that miR-7 expression was reduced in adrenocortical carcinoma samples compared to both adrenocortical adenomas and normal adrenal cortices. Recently, Glover et al. (2015) reported
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that miR-7 reduced adrenocortical carcinoma cell proliferation in vitro, inducing G1 cell cycle arrest. They also demonstrated that the systemic administration of miR-7 using a targeted, clinically safe delivery vesicle (EGFREDVTM nanocells) reduced
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adrenocortical carcinoma xenograft growth originated from both adrenocortical carcinoma cell lines and primary adrenocortical carcinoma cells. The mTOR and
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MAPK signaling pathways were affected by miR-7 through the targeting of Raf-1 proto-oncogene and Epidermal Growth Factor Receptor (EGFR). In vivo, miR-7 therapy also leaded to the inhibition of CDK1. These studies suggest that miR-7 might be a potential target for replacement therapy in adrenocortical carcinomas.
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The expression and function of miR-137 has been investigated in different tumors but only recently endocrine tumors were included in these studies. Luo et
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al. (2016) showed that miR-137 exerts a tumor suppressor role in papillary thyroid carcinoma inhibiting cell proliferation, colony formation and invasion, directly
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targeting the epidermal growth factor receptor (EGFR) and indirectly reducing the levels of cyclin E, MMP2, p-ERK, and p-AKT. Dong et al. (2016) not only confirmed miR-137 suppression on those tumors but also reported a correlation between miR-137 lowered expression, tumor-node-metastasis (TNM) stage and lymph node metastasis. Through functional assays in vitro, they demonstrated the inhibitory role of miR-137 on proliferation, colony formation, migration and invasion targeting directly the chemokine CXCL12. Some authors suggested CXCL12 as
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an effective biomarker for papillary thyroid carcinomas (Chung et al., 2014; Zhu et al., 2016). MiR-206 was also investigated in different types of thyroid cancers and
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associated to aggressiveness. This miRNA is significantly downregulated in papillary thyroid carcinomas (Liu et al., 2013) and upregulated in follicular thyroid carcinomas (Stokowy et al., 2014). Interestingly, in anaplastic thyroid carcinomas miR-206 expression may be downregulated (metastatic tumors) or upregulated
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(non-metastatic tumors) (Zhang et al., 2015). MiR-206 overexpression in
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anaplastic thyroid cancer cells inhibited invasion and metastasis, directly targeting MRTF-A (myocardin-related transcription factor A), also known as MKL1. This protein belongs to the myocardin family, which regulates the expression of different signaling molecules, transcription factors and cytoskeletal components,
al., 2009).
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including actin, non-muscle myosins and vinculin (Cen et al., 2003; Medjkane et
MiR-101 has been described as an important tumor suppressor miRNA,
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and its decrease was associated with malignancy in some types of cancer, including thyroid carcinomas (Liu et al., 2013) A correlation between the
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expression of miR-101, inhibition of cell proliferation (Lin et al., 2014), colony formation, migration, invasion and lymph node metastasis was established (Wang et al., 2014). MiR-101 inhibits migration and invasion targeting the small GTPase Rac1 (Wang et al., 2014). Besides its well-known role promoting cell adhesion and migration, Rac1 is also involved in the cell cycle progression, gene transcription and the release of pro-angiogenic factors, thereby promoting cancer initiation, progression and metastasis (Benitah et al., 2004; Parri et al., 2010).
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MiR-613 is another downregulated miRNA with potential importance for the aggressiveness of papillary thyroid carcinomas (Yang et al., 2013; Qiu et al., 2016). It is one of the top five miRNAs differentially expressed in aggressive papillary thyroid carcinoma targeting the sphingosine kinase 2 (SphK2) (Qiu et al.,
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2016).
Among the tumor suppressor miRNAs recently described as potential markers for thyroid tumors is miR-539 (Gu & Sun, 2015). Its expression is
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downregulated in tumors and further reduced in lymph node metastasis, distant
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metastasis as well as TNM stage, suggesting an inversed correlation with aggressiveness. In a thyroid cell line, the overexpression of miR-539 inhibited migration and invasion targeting CARMA1 (CARD domain and MAGUK domaincontaining protein-1), also known as CARD11 or Bimp3.
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Although much is known about the differential expression of several miRNAs in endocrine cancers (especially thyroid cancers) and a little is known about their targets, much less is known today about the regulation of miRNAs
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expression in these cancers. The deregulation of miRNAs in cancer initiation and progression may be modulated by the immune system, in example, through the
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secretion of factors that stimulate cell proliferation, survival, angiogenesis, etc. (Galdiero et al., 2016). In different cancers interleukin–23 (IL–23), a conventional proinflammatory cytokine, has been detected in high levels and may be related to metastasis. IL-23 is overexpressed both in papillary and follicular thyroid carcinomas (Mei et al., 2015) and regulates miR-25 expression, which, in turn, promotes migration and invasion directly targeting SOCS4 (cytokine-inducible SH2-containing protein).
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ACCEPTED MANUSCRIPT A similar pathway was reported for interleukin-22 (IL-22), synthesized by different immune cells and elevated in many types of cancer. Recently, Mei et al. (2016) reported that IL-22 induces miR-595 expression in papillary thyroid
carcinoma, which, in turn, promotes migration and invasion by targeting Sox17, a
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member of the SRY-related high-mobility group (HMG)-box transcription factor
cancers (Ye et al., 2011; Yang et al., 2014). 4.3. Other roles in metastasis in general
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superfamily that modulates proliferation, differentiation, migration and invasion in
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The roles of specific miRNAs in EMT, cell migration and invasion in endocrine cancers are much better understood than their roles in other steps of metastasis, such as intravasation, extravasation and colonization at distant sites. It is known, however, that cell proliferation, scape from anoikis and survival, among
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other features, are important during these stages. For this reason, studies related to the role of miRNAs in the final steps of the metastatic cascade in endocrine cancers are compiled below. The roles of some specific miRNAs are not clear-cut,
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however, as they simultaneously affect different processes.
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MiR-21 is one of the most studied miRNAs in many cancers, including endocrine cancers. As an oncomiR, it affects all the major hallmarks of tumordeveloping pathways (Yang et al., 2015; Li et al., 2016). Its expression was meaningfully increased in different thyroid carcinoma types (Braun et al., 2010; Frezzetti et al., 2011; Huang et al., 2013; Zhang et al., 2014; Guo et al., 2015; Pennelli et al., 2015). Talotta et al. (2009) showed that miR-21 was induced by the transcription factor AP-1 and mediated the RAS-dependent downregulation of PTEN (phosphatase and tensin homolog) and Pdcd4 (programmed cell death
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ACCEPTED MANUSCRIPT protein 4). The downregulation of Pdcd4, in turn, would be necessary for the
maximal stimulation of AP-1 activity in response to the RAS oncoprotein, pointing to miR-21 as both target and regulator of AP-1. This study suggested a novel autoregulatory loop, mediated by miR-21 and Pdcd4 in the control of AP-1 activity in
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RAS-transformed cells. Pdcd4 is directly targeted by miR-21 in other endocrine cancers as well, such as pancreatic neuroendocrine cancer and adrenocortical carcinoma (Roldo et al., 2006; Talotta et al., 2009; Ozata et al., 2011; Mian et al.,
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2012; Zhang et al., 2014; Pennelli et al., 2015). Interestingly, Frezzetti et al. (2011) showed that among many mRNAs downregulated by miR-21, there were some
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encoding cell cycle checkpoint regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.
Considering that miR-21 plays important roles in different cell processes, Haghpanah et al. (2016) employed off-miR-21 (antagomir) to sequester this
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miRNA in anaplastic thyroid carcinoma cell lines. They found that miR-21 antagomiR decreased the stemness state and cell cycle progression, increasing
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differentiation and apoptosis, being potentially interesting for therapeutic purposes. In other endocrine cancers, miR-21 has also been described as a potential
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marker, but still with unknown functions. In example, in insulinomas, miR-21 was upregulated and strongly associated with the proliferation index and the presence of liver metastasis (Roldo et al., 2006). Ozata et al. (2011) demonstrated that miR21 was significantly increased in adrenocortical carcinoma samples compared to adenomas and normal tissues. In adrenocortical carcinomas, many studies developed up to now aimed to detect differentially expressed miRNAs in comparison to adrenocortical adenomas or normal tissues. Some overexpressed miRNAs were meaningfully correlated to
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aggressiveness, such as miR-483-5p, miR-483-3p, miR-210, miR-503, miR-181b, miR-1202, miR-1275, miR-139-5p and miR-376a. Other downregulated miRNAs associated to poor prognosis were miR-195, miR-497, miR-1974, and miR-214 (Ozata et al, 2011; Patterson et al, 2011; Singh et al, 2012; Chabre et al, 2013;
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Patel et al, 2013; Szabó et al, 2014, Jain et al, 2014; Bezerra et al, 2014;
Feinmesser et al, 2015; Igaz et al, 2015; Yu et al, 2016). The functional roles of most of these miRNAs remain unknown, as well as the molecular mechanisms
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involved.
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Interestingly, Ozata et al (2011) demonstrated that both miR-483-5p and miR-483-3p act as oncogenes in adrenocortical carcinomas stimulating proliferation, but only miR-483-3p inhibited apoptosis. The expression of PUMA (p53 upregulated modulator of apoptosis), a potential target of miR-483-3p, was inversely correlated with miR-483-3p expression in carcinomas. In contrast, both
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miR-497 and miR-195 are tumor suppressors in adrenocortical carcinomas, regulating cell proliferation and death (Ozata et al 2011). Jain et al (2014)
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demonstrated that miR-195 also negatively regulates adrenocortical carcinoma cells adhesion, migration and invasion through a direct target, ZNF367 (zinc finger
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protein 367).
Among many miRNAs overexpressed and associated to the metastatic
profile in different thyroid carcinomas are miR-183 and miR-375 (Abraham et al., 2011; Mian et al., 2012. Gundara et al., 2014; Wojtas et al., 2014; Wei et al., 2015). Wei et al. (2015) identified the protein Pdcd4 as a direct target of miR-183. As mentioned above, miR-375 is also overexpressed in thyroid cancer samples and has been associated to metastasis, tumor aggressiveness and poor
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ACCEPTED MANUSCRIPT prognosis (Abraham et al., 2011; Mian et al., 2012; Hudson et al, 2013; Reddi et al, 2013; Dettmer et al, 2013; Gundara et al, 2014; Mutalib et al., 2016). Many studies have driven their efforts to characterize this miRNA as a potential marker in thyroid cancer, but only few have focused on the role of this miRNA in the
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disease. Hudson et al. (2013) were the first to show, using miRNA array and qPCR, that miR-375 was significantly overexpressed in medullary thyroid
carcinoma samples. Although not validated as targets at the time, the proteins
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YAP1 (Yes-associated protein 1) and SLC16a2 (a transporter of thyroid hormone) were downregulated. Contrary to Hudson et al. (2013), however, Lee et al. (2013)
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showed that YAP1 was overexpressed in thyroid cancers. They also demonstrated that YAP1 knockdown resulted in marked decrease of tumor volume, invasion and distant metastasis in orthotopic tumor xenograft mouse models using the 8505C thyroid cancer cell line, suggesting that YAP1 acts as an oncogene in thyroid
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cancer.
Also differently from the results obtained by Hudson et al. (2013), Wang et
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al. (2016) reported a meaningful decrease of miR-375 expression in 60 pairs of papillary thyroid carcinomas and noncancerous normal tissue samples, as well as
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in papillary thyroid carcinoma cell lines, analyzed by qRT-PCR. The overexpression of miR-375 in cell lines reduced proliferation and increased apoptosis, whereas in vivo it decreased metastatic nodules in mice, suggesting a decreased migration and invasion capacity. Further study demonstrated that ERBB2 (also known as HER2, neu or NGL), which is a member of EGFR family, is a direct target of miR-375 in human papillary thyroid cells. Regarding the upstream regulation of miR-375, a study developed by Reddi et al. (2013) in anaplastic thyroid cancer investigated the role of PAX8/PPARγ
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ACCEPTED MANUSCRIPT fusion protein (PPFP) as a potent modulatory factor. PPFP was constitutively
expressed in five anaplastic thyroid carcinoma cell lines, inhibiting cell growth and xenograft tumor growth through pathways involving the upregulation of miR-375 and decreased AKT pathway activation. Furthermore, PPFP expression resulted in
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marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters.
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Another miRNA differently expressed in thyroid carcinomas is miR-9.
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Although it has been shown to be significantly downregulated in several studies through miRNA signatures, both in medullary thyroid carcinoma (Abraham et al., 2011; Mian et al., 2012; Gundara et al., 2014) and in papillary thyroid carcinoma (Sondermann et al., 2015; Cong et al., 2016), suggesting an important role in
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these tumors, no functional assay was performed to better understand this role. Recently, miR-151 expression has been detected in exosomes isolated from plasma of patients with papillary thyroid carcinoma and has been suggested
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as a marker for diagnosis before and after the surgery (Yoruker et al., 2016). The overexpression of miR-151 in the serum of those patients compared to patients
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with thyroid benign tumors was previously demonstrated (Yu et al., 2012). Nonetheless, little is known about its function in thyroid cancer. Also identified as a potential marker for thyroid cancer clinical diagnosis,
miR-126 was downregulated in all thyroid carcinomas with aggressive behavior (Ebrahimi et al., 2014; Rahman et al., 2015; Xiong et al., 2015; Wen et al., 2015; Qian et al., 2016; Salajegheh et al., 2016); apparently, this miRNA regulates cell survival. Rahman et al. (2015) showed reduced levels of p85β (a regulatory
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ACCEPTED MANUSCRIPT subunit of PI3K) and p-AKT in miR-126 mimic transfected cells, decreasing cell survival. More recently, Salajegheh et al. (2016) confirmed the low levels of miR126 in thyroid carcinomas and demonstrated that high exogenous miRNA levels could reduce cell proliferation, promote cell cycle arrest in G0-G1, and promote
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apoptosis. Additionally, a significant reduction of VEGF-A protein was observed after miR-126 overexpression in different thyroid cell lines, suggesting a. A
potential correlation between miR-126 levels, VEGF-A expression, the regulation
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of angiogenesis, cell proliferation and apoptosis.
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MiR-145 was also suggested as a potential marker for the diagnosis of papillary thyroid carcinomas (Samsonov et al., 2016). It is suppressed in different thyroid cancers (Boufraqech et al., 2014; Gu et al., 2015), although there were high miR-145 circulating levels in patients. The overexpression of miR-145 in thyroid cancer cell lines inhibited proliferation, migration, and invasion, with the
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reduction of VEGF secretion. It also induced apoptosis and the expression of stem cell markers, as well as follicular thyroid cell differentiation markers. In vivo, miR-
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145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. The PI3K/Akt survival pathway was also inhibited,
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with the direct targeting of AKT3 (Boufraqech et al., 2014). MiR-31 also belongs to the group of miRNAs that showed high levels in
exosomes before surgery for papillary thyroid carcinoma and significantly reduced levels after tumor removal (Samsonov et al., 2016). Actually, Yip et al. (2011) had previously shown miR-31 expression in papillary thyroid cancer, possibly correlated with an aggressive profile. More recently, Mutalib et al. (2016), reanalyzing the Cancer Genome Atlas (TCGA) datasets on papillary thyroid
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carcinomas to compare cases with and without lymph node metastasis, positioned miR-31 among the top five most deregulated (overexpressed) miRNAs. A few miRNAs are also deregulated in serum samples of adrenocortical
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carcinoma patients. High circulating levels of miR-483-5p and miR-34a and low circulating levels of miR-195 were associated with highly aggressive
adrenocortical carcinomas and poor prognosis (Chabre et al., 2013; Patel et al,
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2013; Szabó et al, 2014).
The Let-7 family of miRNAs has been confirmed as key regulators of gene
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expression in many organisms, and as important tumor suppressors in many cancers. The Let-7 family includes let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g and let-7i. In different thyroid cancers, different members of the let-7 family are deregulated, some of them related to invasion and metastatic capacity (Visone et
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al., 2007; Ricarte-Filho et al., 2009; Braun et al., 2010; Gao et al., 2010; Braun & Hüttelmaier, 2011; Swierniak et al., 2013; Hebrant et al., 2014; Mancikova et al., 2015; Damanakis et al., 2016; Perdas et al., 2016). Ricarte-Filho et al. (2009)
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firstly reported that the RET/PTC3 oncogenic activation in rat thyroid cells led to a great reduction of let-7f expression. They also demonstrated that let-7f regulates
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cell growth and differentiation. The overexpression of let-7f in a papillary thyroid carcinoma cell line harboring RET/PTC1 rearrangement inhibited MAPK activation and cell growth by decreasing cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increasing the p21 cell cycle inhibitor mRNA. Concomitantly, the high levels of let-7 enhanced the transcriptional expression of molecular markers of thyroid differentiation such as TITF1 and TG.
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ACCEPTED MANUSCRIPT During the last few years, the role of some members of the let-7 family on tumor aggressiveness and metastasis has been investigated. Up to now, in endocrine cancers, let-7 family members were investigated only in thyroid and endocrine pancreatic cancers. Studies focused mostly on the differential
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expression of these miRNAs between cancer and normal tissues (Visone et al., 2007; Rahman et al., 2009; Braun & Hüttelmaier, 2011; Swierniak et al., 2013; Damanakis et al., 2016) or between different types of carcinomas of the same
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gland (Schwertheim et al., 2009; Damanakis et al., 2016). Gao et al. (2010)
selected the more invasive cancer cell populations from a clonal cell line of human
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papillary thyroid carcinoma with cervical lymph node metastasis and performed miRNA microarray. Let-7b was the most differentially overexpressed miRNA among eleven miRNAs identified, suggesting an important role in metastasis. Another upregulated miRNA in thyroid cancers is miR-584 (Xiang et al.,
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2015; Orlandella et al., 2016). MiR-584 did not affect the proliferation of thyroid cell lines but protected them from apoptosis directly suppressing TUSC2 (tumor
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suppressor candidate 2, also known as Fus-1). Regarding migration, Xiang et al. (2015) demonstrated that miR-584 could inhibit the migration of cell lines by
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directly suppressing Rock-1 (Rho-kinase-1). In contrast, Orlandella et al. (2016) showed that miR-584 did not affect migration and invasion, concluding that it only affects cell survival.
MiR-205 has been widely reported as a regulator of different processes such as cell survival, apoptosis, angiogenesis and metastasis in several cancers, but few studies have investigated the role of this miRNA in endocrine cancers Salajegheh et al. (2015) have recently shown a downregulation of this miRNA in thyroid carcinomas with and without lymph node metastasis, compared to normal
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ACCEPTED MANUSCRIPT thyroid tissues. MiR-205 overexpression in thyroid cell lines inhibited cell proliferation, causing a cell cycle arrest in G0-G1, promoted apoptosis and
reduced VEGFA secretion, demonstrating a tumor suppressive role for this miRNA in thyroid cancer. Recently, Wu et al. (2015) demonstrated that miR-205 was
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significantly suppressed in adrenocortical carcinoma when compared to
adrenocortical adenomas, suggesting this miRNA as a potential marker for this cancer. Additionally, they showed that high levels of miR-205 induced apoptosis
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and impaired the proliferation of adrenocortical carcinoma cells in vitro, inhibiting tumor growth in vivo. The anti-apoptotic protein Bcl-2 was validated as a target of
prognostic marker for this cancer.
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miR-205. These data suggest that miR-205 may serve as a diagnostic and
MiRNAs represent an important field of research in cancer treatment. After more than one decade of extensive studies of miRNAs, the fundamental role of
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miRNAs in cancer progression and metastasis is being elucidated. Most studies on endocrine cancers is related to the thyroid gland, and much less in known
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about other cancers. MiRNA screenings generated much data, available in different databases. Functional studies about the role of miRNAs in endocrine
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cancers, however, are still scarce. MiRNAs that are meaningfully deregulated in aggressive endocrine tumors remain with their functions unclear and, therefore, need to be better investigated. 5. Concluding remarks and future perspectives Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment complexity and a worse prognosis. Considering that cancer is a complex group of diseases involving specific changes in gene expression,
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ACCEPTED MANUSCRIPT knowledge about the role of miRNAs presents a high potential for novel therapeutic approaches. MiRNAs specifically involved in the metastatic process, especially, represent an important field of research in cancer treatment.
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Efforts in the study of miRNAs in cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in
early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets, function and regulation. For the study of
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specific cellular processes such as those involved in the metastatic cascade,
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functional analyses are very important because they clearly establish the molecular interactions of each miRNA. From these studies, it is possible to understand that a therapeutic strategy must always consider the complexity of the processes involved, to determine how important is the miRNA, or a group of
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miRNAs, for tumor progression and metastasis.
Endocrine cancers account for a large group of diseases to be better characterized and understood. Functional miRNA studies are still scarce and
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represent an important area of research, since some tumors, although not frequent, present a high mortality rate. Among the endocrine tumors, thyroid
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cancer is the most common and best studied, at least partially due to early detection of small cancers in the preclinical stage. At any stage of tumor progression, however, an altered miRNA expression (either upregulated or downregulated), may constitute important information for the elucidation of the molecular pathways involved. In the future, we expect that the rapidly growing knowledge about miRNAs generate the opportunity to develop novel therapeutic approaches for the
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treatment of endocrine cancers, especially those with high metastatic potential and poor prognosis for the patients. 6. Acknowledgements
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This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Grants # 2011/18936-7, #2012/03990-9 and
2015/19645-7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
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(CAPES, PNPD), Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq grants #307452/2012-3 and #448052/2014-8) and Pró-
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Reitoria de Pesquisa da Universidade de São Paulo (NAPMiR).
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endocrine cancers. The figure summarizes the miRNAs involved in the control of
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molecular pathways associated to cancer progression and the metastatic process. Showed in green, the anti-metastatic miRNAs and in red, the pro-metastatic miRNAs.
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Table 1. Role of miRNAs with identified targets on metastasis of endocrine
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Table 2. Role of miRNAs with potential targets on metastasis of endocrine cancers.
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Table 3. Altered miRNAs on metastatic endocrine cancers.
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ACCEPTED MANUSCRIPT MiRNA
Target
Cancer
miR-145
AKT3 ZNRF3 Smad4
Thyroid carcinoma
p27Kip1
miR-25
SOCS4
miR-595
Sox17 PTEN, Pdcd4
miR-21
Pdcd4
miR-483-3p
PUMA
miR-183
Pdcd4 ZEB1 and ZEB2
miR-200 family ZEB1
miR-30a miR-126 Anti-metastatic miR-7 miR-137
SLC7A5 and ADAM9 LRP6 CXCR4 PAK1; CKS2 Raf-1; EGFR EGFR; CXCL12 MRTF-A
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miR-206
Lysyl Oxidase
Anaplastic Thyroid carcinoma
Papillary Thyroid carcinoma Thyroid Carcinoma
Adrenocortical Carcinoma Papillary Thyroid carcinoma Papillary Thyroid carcinoma Anaplatic Thyroid carcinoma Papillary Thyroid carcinoma
miR-539
CARMA1
Papillary Thyroid carcinoma Follicular Thyroid carcinoma
miR-195
ZNF367
miR-205
Bcl-2
MiRNA
miR-584 miR-375 miR-7 miR-205
miR-126
Table 2
Pancreatic Neuroendocrine Tumor
Rac1 SphK2
pro-metastatic
Anti-metastatic
Anaplastic Thyroid carcinoma Medullary Thyroid carcinoma
miR-101 miR-613
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Table 1
Papillary Thyroid carcinoma Follicular Thyroid carcinoma Papillary Thyroid carcinoma Thyroid carcinoma Pancreatic Neuroendocrine Tumor Adrenocortical carcinoma Adrenocortical carcinoma Follicular Thyroid carcinoma Papillary thyroid carcinoma
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miR-29a
Anaplastic Thyroid carcinoma
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Pro-metastatic
miR-221 miR-222
Papillary Thyroid carcinoma
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miR-146b-5p
Target TUSC2 Rock1 YAP1 SLC16a2 ERBB2 Cdk1 VEGF-A p85β VEGF-A
adrenocortical carcinoma
Cancer Papillary Thyroid Carcinoma Medullary Thyroid Carcinoma Papillary Thyroid Carcinoma Adrenocortical carcinoma Papillary Thyroid Carcinoma Anaplastic Thyroid carcinoma
Thyroid carcinoma
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ACCEPTED MANUSCRIPT MiRNA miR-222 miR-503 miR-126 miR-21
Cancer Parathyroid cancer Pancreatic neuroendocrine tumor Adrenocortical carcinoma Pancreatic Neuroendocrine tumor
miR-151 miR-31 let-7 family
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Thyroid cancer
miR-146b
Follicular Thyroid carcinoma
miR-375
Anaplastic Thyroid carcinoma
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Pro-metastatic
Papillary thyroid carcinoma
miR-210 miR-503 miR-181b miR-1202 miR-1275 miR-139
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miR-376a miR-183 miR-139
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miR-483
miR-296
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miR-126
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Anti-metastatic
Table 3
miR-7 miR-9 miR-30c miR-7-2 miR-204 miR-497 miR-1974 miR-214
adrenocortical carcinoma
medullary thyroid carcinoma
Parathyroid cancer Follicular Thyroid carcinoma adrenocortical carcinoma parathyroid carcinoma Thyroid carcinoma Medullary thyroid carcinoma Papillary Thyroid carcinoma
adrenocortical carcinoma
ACCEPTED MANUSCRIPT Deregulation of microRNAs expression and function is involved in cancer metastasis MicroRNAs may act as pro-metastatic or anti-metastatic. Studies have focused on microRNA signatures and functions in specific cancers
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MicroRNAs may be present in serum exosomes, potentially serving as diagnostic tools
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MicroRNAs may aid in the identification of therapeutic targets in endocrine cancers
S0303-7207(17)30184-3
DOI:
10.1016/j.mce.2017.03.015
Reference:
MCE 9888
To appear in:
Molecular and Cellular Endocrinology
Received Date: 3 October 2016 Revised Date:
12 March 2017
Accepted Date: 13 March 2017
Please cite this article as: Lima, C.R., Gomes, C.C., Santos, M.F., Role of MicroRNAs in endocrine cancer metastasis, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017.03.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Role of MicroRNAs in endocrine cancer metastasis Cilene Rebouças Lima1, Cibele Crastequini Gomes1, Marinilce Fagundes Santos1.
1
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Department of Cell and Developmental Biology, Institute of Biomedical Sciences,
University of São Paulo, Avenida Professor Lineu Prestes 1524, Prédio I, CEP
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05508-000, São Paulo, SP, Brazil.
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Cilene R. Lima: [email protected] Cibele Crastequini Gomes [email protected]
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Marinilce F. Santos: [email protected]
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*Corresponding author:
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Cilene Rebouças Lima, PhD
Running Title: MicroRNAs in Endocrine Cancer Metastasis
Keywords: Endocrine cancers, EMT, invasion, small RNA, metastasis
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ACCEPTED MANUSCRIPT Abstract The deregulation of transcription and processing of microRNAs (miRNAs), as well as their function, has been involved in the pathogenesis of several human diseases, including cancer. Despite advances in therapeutic approaches, cancer
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still represents one of the major health problems worldwide. Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment
complexity and a worse prognosis. After more than one decade of extensive
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studies of miRNAs, the fundamental role of these molecules in cancer progression and metastasis is beginning to be elucidated. Recent evidences have
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demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic. They are involved in distinct steps of metastasis including epithelial-to-mesenchymal transition, migration/invasion, anoikis survival, and distant organ colonization. Studies on the roles of miRNAs in
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cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets,
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function and regulation. Functional miRNA studies on endocrine cancers are still scarce and represent an important area of research, since some tumors, although
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not frequent, present a high mortality rate. Among the endocrine tumors, thyroid cancer is the most common and best studied. Several miRNAs show lowered expression in endocrine cancers (i.e. miR-200s, miR-126, miR-7, miR-29a, miR30a, miR-137, miR-206, miR-101, miR-613, miR-539, miR-205, miR-let7f, miR145, miR-9, miR-195), while others are commonly overexpressed (i.e. miR-21, miR-183, miR-31, miR-let7b, miR-584, miR-146b, miR-221, miR-222, miR-25, miR-595). Additionally, some miRNAs were found in serum exosomes (miR-151,
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ACCEPTED MANUSCRIPT miR-145, miR-31), potentially serving as diagnostic tools. In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory roles in endocrine cancer metastasis, which may contribute for the finding of novel therapeutic targets. The review focus on miRNAs with at least
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some identified targets, with established functions and, if possible, upstream regulation. 1. MicroRNAs
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MicroRNAs (miRNAs) are highly conserved endogenous small non-coding
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RNAs (~17-25 nucleotides), known as important negative regulators of gene expression. Most commonly, they regulate gene expression by perfect or imperfect (partial complementarity) pairing with messenger RNAs (mRNAs), promoting their degradation or blocking translation, respectively. They can regulate multiple genes, what allows them to coordinate many biological processes, increasing the
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complexity of the molecular regulatory mechanisms of gene expression (Wang et al., 2007; Lin & Gregory, 2015).
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The biogenesis of miRNAs involves several steps already well understood. Initially, miRNA is transcribed from DNA by RNA polymerase II / III as a long
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primary transcript RNA (pri-miRNAs) (Lee et al., 2004). In the nucleus, the primiRNA is initially processed by a microprocessor complex that contains the RNase III enzyme Drosha to generate pre-miRNAs with a stem loop hairpin secondary structure (60-70 nucleotides). This molecule is exported from the nucleus to the cytoplasm by exportin 5, mediated by Ran GTPase and processed into a mature miRNA duplex by another molecular complex, which contains the RNase III enzyme Dicer (Lin & Gregory, 2015). Some miRNAs may be synthesized by alternative mechanisms which do not involve Drosha and Dicer activities, i.e.
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ACCEPTED MANUSCRIPT miRNAs generated by alternative splicing, known as miRtrons (Ruby et al., 2007; Cheloufi et al., 2010; Westholm et al, 2011; Havens et al., 2012).
MiRNAs exert their function associated to a RNA-induced silencing complex (RISC) which promotes, most commonly, the pairing of 5′-seed sequences (2-7
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nucleotides) of miRNA to the 3′-UTR of the target mRNA. Some studies have
demonstrated that miRNAs can also associate at any position to a target mRNA, such as the 5’ UTR or coding region sequences and this seems to be enough to
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suppress gene expression (Lytle et al., 2007; Lee et al., 2009; Takagi et al., 2010; Jin et al., 2011; Li et al., 2016; Teplyuk et al., 2016). Furthermore, the complexity
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of these interactions has become even greater with the discovery that different regions of the same miRNA can bind to a target mRNA, generating different types of pairing: 3′-end centric ‘seedless’ pairing, centred miRNA pairing and nucleation bulges in the seed region. Additionally, a target mRNA offers different regions for
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the association of a specific miRNA. This ability may, in part, explain the large number of target mRNAs for the same miRNA (Betel et al., 2010; Chi et al., 2012; Helwak et al., 2013).
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The inaccurate cleavage of the pri-miRNA or pre-miRNA from a single gene by Dicer or Drosha respectively, can give rise to small variations of miRNAs that
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generate isoforms known as isomiRs. These nucleotide variations may occur in the 5 'end giving rise to small variations in the seed sequence (nucleotides 2–8), thus influencing the specificity of a miRNA to its target (Kawahara et al., 2007; Wu et al., 2009; Starega-Roslan et al., 2011; Ekdahl et al., 2012). Furthermore, isomiRs may also have additional nucleotides at the 3' end, which can influence the stability of the pairing between the miRNA and the target mRNA (Martin & Keller, 2007). The variations in the distribution of isomiRs among different cells
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ACCEPTED MANUSCRIPT and tissues, as well as in pathological conditions, supports the hypothesis of a refinement in the control of gene expression by miRNAs, potentially functioning together to control complex signaling pathways and greatly increasing its
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regulatory potential (Cloonan et al., 2011). Independently of the mechanisms involved, the biogenesis of miRNAs is perfectly modulated by many signaling pathways. The deregulation of transcription and processing of miRNAs, as well as their function, has been involved in the
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pathogenesis of several human diseases, including cancer. As a matter of fact,
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miRNAs have been reported as crucial molecules in the development and progression of cancer (Jansson & Lund, 2012; Zaravinos, 2015; Hata & Kashima, 2016).
Despite advances in therapeutic approaches, cancer still represents one of the major health problems worldwide. About 14.1 million new cancer cases were
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diagnosed and 8.2 million cancer-associated deaths were reported in 2012. The main leading cause of these deaths was tumor metastasis, responsible for
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approximately 90% of all cases (Ferlay et al., 2015). In this review, we summarize studies concerning the discovery and functions of miRNAs and their regulatory
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roles in endocrine cancer metastasis. 2. The metastatic cascade Briefly, tumor metastasis is defined as the ability of highly aggressive
cancer cells to detach from the primary neoplasm and spread to form secondary metastatic lesions in other tissues and organs (Spano et al., 2012). The metastatic cascade in epithelial cancers involves multiple biological events in several stages: (1) epithelial to mesenchymal transition (EMT) in primary tumor cells promoting their detachment, (2) invasion and migration through the
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ACCEPTED MANUSCRIPT microenvironment (basement membrane and extracellular matrix) of the primary neoplasm and surrounding tissues, (3) intravasation and survival on blood or lymphatic circulation and (4) extravasation, mesenchymal to epithelial transition
al., 2010; Chaffer & Weinberg, 2011).
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(MET) and growth of a secondary tumor at the target receptive organ (Brooks et
It is well known that the success of a metastatic tumor cell following this cascade depends on the coordinated function of a complex molecular network
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which has been elucidated during the last decades (Brooks et al., 2010; Spano et al., 2012). Nonetheless, much remains to be studied and no effective therapeutic
al., 2012; Chan & Wang, 2015).
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treatments were found to adequately interpose the metastatic process (Spano et
Recent evidences have demonstrated a significant role of miRNAs on the metastatic cascade, acting either as pro-metastatic or anti-metastatic (Tables 1, 2
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and 3 and Figure 1) (White et al., 2011; Bouyssou et al., 2014; Chan & Wang, 2015). They are involved in distinct steps of metastasis including EMT, migration/invasion, anoikis survival, intravasation/extravasation and distant organ
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colonization. Therefore, it is important to increase the knowledge about the regulatory role of miRNAs on the metastatic cascade, which may contribute to the
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discovery of new therapeutic approaches. 3. Endocrine cancers Endocrine tumors frequently lead to disturbances in the production of
hormones, sometimes causing characteristic hormonal syndromes. The endocrine glands that present malignant tumors include the thyroid, adrenal, pancreas, parathyroid and pituitary. Although some of these tumors are rare, they may have high mortality indices; in general, the presence of metastasis indicates a poor
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ACCEPTED MANUSCRIPT prognosis, with a high recurrence and poor response to treatments (Schulte et al., 2012; Wong et al., 2014; Sav et al., 2015; Xu et al., 2016; Scollo et al., 2016). The thyroid cancer is the most common endocrine cancer, affecting mostly
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women (77% of cases) (Ferlay et al., 2015). In 2016, according to the SEER (Surveillance, Epidemiology and End Results Program), about 56,000 new cases of thyroid cancer were estimated, accounting for 3.8% of all new cases of cancer (http://seer.cancer.gov/statfacts/html/thyro.html, Accessed on September 13,
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2016; SEER program, 2016). The most common type of thyroid cancer is the
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papillary thyroid carcinoma, followed by the follicular thyroid carcinoma. The anaplastic carcinoma is the most undifferentiated, aggressive and invasive form, occurring in less than 2% of cases (Aschebrook-Kilfoy et al., 2011). The incidence of thyroid cancer has increased over the past decades, mainly due to the increased number of papillary carcinomas (Smallridge et al., 2012).
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Epidemiological studies suggest that several thyroid cancers could be attributable to environmental factors, such as obesity (Kitahara et al., 2011; Pazaitou-
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Panayiotou et al., 2013; Kitahara & Sosa, 2016). The molecular pathogenesis of the thyroid cancer is frequently associated
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with the mutation of the BRAF gene, resulting in the expression of a constitutively active mutant protein. This mutation occurs in approximately 35-50% of papillary thyroid carcinomas (Fukushima et al., 2003; Kimura et al., 2003). BRAF is a serine/threonine kinase that receives a signal from RAS, and then transmits it to the MAP Kinase pathway. Besides BRAF mutation, there is also the mutation of RAS itself and the rearrangement of RET/PTC, which also leads to the activation of the MAP kinase pathway. Mutations involving one of these genes are found in 66% of papillary thyroid carcinomas, and they rarely overlap in the same tumor
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ACCEPTED MANUSCRIPT (Kimura et al., 2003). Activation of the MAP Kinase pathway is an important mechanism for the upregulation of cell proliferation. When constitutively activated, the MAP Kinase pathway leads to tumorigenesis (Shapiro, 2002; Xing, 2013).
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Parathyroid carcinoma is one of the rarest tumors, accounting for only 0.005% of all cancers (Hundahl et al., 1999). These tumors usually secrete
parathyroid hormone, thereby producing severe hyperparathyroidism. Sandelin et al. (1994), in an epidemiological study, reported that distant metastases occur in
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25% of patients with parathyroid carcinoma, mostly in the lungs, liver and bones.
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Approximately 70% of parathyroid carcinomas carry a mutation of cell division cycle 73 (CDC73, also known as HRPT2), a tumor suppressor gene that encodes a protein known as parafibromin. Parafibromin is a nuclear protein that participates of the regulatory RNA Polymerase Associated Factor-1 Complex (Paf1C), and interacts directly with β-catenin, regulating different cellular processes that are
Arndt, 2013).
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important for tumorigenesis (Howell et al., 2003; Newey et al., 2009; Tomson &
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Adrenal cancer (adrenocortical carcinoma) is a rare and usually highly aggressive malignancy, with high recurrence rates and poor response to
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chemotherapy. Epidemiological data about this tumor is scarce and out of date; with the advancement of new diagnostic methods, there is a need for further research in this area. Higher incidence is between 40 and 50 years of age, affecting mostly women (Kebebew et al., 2006). Assié et al. (2007) studied the parameters that influence the prognosis of patients with adrenocortical carcinoma with metastases. Regardless of factors such as mitotic rate and affected organs, the prognosis of these patients was poor, with low survival. Genetic alterations commonly related to the molecular pathogenesis of this tumor include the
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ACCEPTED MANUSCRIPT overexpression of the Insulin-like Growth Factor-2 (IGF-2) gene (90% of cases)
and β-catenin mutation, leading to Wnt signaling pathway activation (Gicquel et al., 1997; Tissier et al., 2005). Phan et al. (2015) studied the role of the pathway elicited by the proto-oncogene cMET and its ligand Hepatocyte Growth Factor
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(HGF) in adrenocortical carcinoma. They found that the expression of both cMET and HGF is high in this cancer, and functional genomic analysis revealed that
cMET overexpression was related to several cancer hallmarks such as sustained
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proliferation, increased tumor metabolism, resistance to cell death, chemotherapy resistance, and activation of metastasis. Indeed, cMET activation was associated
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with increased tumor cell proliferation, angiogenesis and reduced apoptosis. Moreover, cancer cells rapidly upregulated cMET expression in response to radiation and chemotherapy.
The downstream response to c-MET activation involves the classical
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Mitogen activated protein kinase (MAPK) cascades regulating cell proliferation, cell motility and cell cycle progression (Trusolino et al. 2010; Organ & Tsao, 2011).
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It also activates the PI3K/Akt signaling axis, responsible for the cell survival response to c-MET signaling, and the focal adhesion kinase (FAK), which is
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localized to cellular adhesion complexes, for the regulation of cell migration and the promotion of anchorage-independent growth (Organ & Tsao, 2011). Pancreatic cancers represent 3.1% of all new cancer cases in 2016 in the
US, and represented 3% of all cancers in the UK in 2013 (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statisticsby-cancer-type/pancreatic-cancer/incidence, Accessed on September 13, 2016; SEER program, 2016). Pancreatic neuroendocrine tumors (PNETs) arise from pancreatic islet cells and are less common, representing less than 2% of the
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pancreatic tumors (Yao et al., 2007). These tumors are classified according to the type off affected cells, and may produce hormones, such as insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP) and somatostatin. It is important to mention, however, that not all hormone-producing PNETs cause symptoms related
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to hormone overproduction. Insulinomas are the most common functional PNET, which account for 30% - 45% of the functional PNETs (McKenna & Edil, 2014). Considering different types of islet cell tumors, Yao et al. (2007) have shown that
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most of them were metastatic at the time of diagnosis, including islet cell
carcinomas (61%), insulinomas (61%), glucagonomas (56%), and gastrinomas
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(60%). A smaller percentage of VIPomas (47%) were metastatic, probably because the symptoms of this tumor lead to an early diagnosis. There is some controversy about the origin of PNETs. It has been argued that PNETs may arise from MEN-1 gene mutations into alpha and beta cells,
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suggesting an endocrine origin for this type of tumor (Bertolino et al., 2003; Lu et al., 2010; Hackeng et al., 2016). This tumor suppressor gene is related to the
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autosomal dominant multiple endocrine neoplasia type-1, an inherited syndrome that causes tumors in the endocrine pancreas, parathyroid and pituitary glands.
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Some researchers, however, consider the possibility that PNETs may originate from pluripotent cells within the exocrine pancreas (Vortmeyer et al., 2004). Tumors in the pituitary gland account for 9% of all brain tumors, with
carcinomas accounting for only 0.1 to 0.2 % of pituitary tumors (Surawicz et al, 1999; Scheithauer et al., 2005). They may present craniospinal or distant metastases, with poor prognosis (Pernicone et al., 1997, Hansen et al., 2014). These tumors can produce prolactin (PRL), adrenocorticotrophic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropin,
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ACCEPTED MANUSCRIPT or may also be nonfunctional tumors. The pathogenesis of these tumors is complex and not very well understood; factors such as stimulation by growth factors, alterations in hormone regulation, cell-cell interactions and alterations in the cell cycle control were reported (Ezzat & Asa, 2006), as well as epigenetic
expression of non-coding RNAs (Sapochnik et al., 2016).
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alterations of tumor suppressor genes and oncogenes and the differential
4.1. EMT and detachment
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4. Role of miRNAs in the metastatic cascade in endocrine cancers
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The early phase of a glandular tumor metastasis is characterized by a loss of the epithelial tumor cell properties and acquisition of a mesenchymal phenotype, known as EMT. Its activation involves both genetic and epigenetic alterations of tumor cells as well as the presence of EMT-inducing signals secreted by stromal and inflammatory cells, the latter being previously recruited to
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the tumor microenvironment (Chaffer & Weinberg, 2011, Ye et al., 2015). MiRNAs have been described as important regulators of this process by modulating the
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expression of many genes involved in EMT. Examples of genes regulated by miRNAs are some coding adherens junctions proteins, transcription factors,
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cytoskeletal and signaling proteins from different pathways among others, which in general promote the ability of cells to migrate, to invade surrounding tissues, to survive and to disseminate to other organs (Zhang et al., 2012; Lamouille et al., 2013, 2014; Abba et al., 2016). During the initial stages of the EMT, specialized protein complexes on the surface of epithelial cells lose their integrity, promoting disaggregation. Additionally, downregulation of the expression of junctional epithelial proteins destabilizes those structures, reducing cell-cell adhesiveness. Cell junctions are
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deconstructed and the junction proteins are relocated and/or degraded (Huang et al., 2012; Lamouille et al., 2013; 2014). Cadherins, a large family of intercellular adhesion proteins, have important
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features in EMT, especially E-cadherin (cadherin-1 or CDH1). The repression of Ecadherin has been strongly associated with the metastatic phenotype in many cancers, including endocrine cancers (Chetty et al., 2008; Fendrich et al., 2009). MiRNAs may act directly by inhibiting the expression of E-cadherin or indirectly,
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through the regulation of transcription factors (Braun et al., 2010, Zhang et al.,
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2012; Abba et al., 2016). The transcription factors ZEBs (Zinc Finger Ebox Binding Homeobox), Snails and Twists, in example, are master negative regulators of Ecadherin expression, also modulating other molecules involved in EMT (Lamouille et al., 2013; 2014). The family of miR-200 (miR-200a, miR-200b, miR-200c, miR141 and miR-429), in example, frequently targets ZEBs and has been studied in
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cancer (Korpal et al., 2008; Díaz-López et al., 2014). The ZEB family comprises two members, ZEB1 and ZEB2 (Vandewalle et
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al., 2009). In general, miR-200s play an anti-metastatic role and their expression is reduced in metastatic cancers. Consequently, ZEB factors are augmented,
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promoting the downregulation of E-cadherin expression and favoring EMT, migratory capacity and invasiveness (Lamouille et al., 2013; 2014). The analysis of miR-200s expression in samples of different thyroid
carcinomas has shown that miR-200a, miR-200b and miR-200c were significantly reduced only in Anaplastic Thyroid Carcinoma, the most aggressive type (Braun et al., 2010). In those cells, the expression of miR-200s was correlated with the EGF/EGFR signaling. The EGFR is overexpressed in anaplastic carcinoma and its
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ACCEPTED MANUSCRIPT activation by EGF downregulates miR-200 expression (Bergstrom et al, 2000; Zhang et al., 2012). Members of the miR-200 family were also downregulated in
metastatic medullary thyroid cancer, being functionally involved in EMT and tumor
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invasion through the targeting of ZEB1 and ZEB2 (Santarpia et al., 2013). In a recent study, a signature of miRNAs was obtained in multistep tumorigenesis using the RT2 transgenic mouse model of Pancreatic
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Neuroendocrine Tumors. The miR-200s family showed a notable reduction.
In addition to target ZEBs, miR-200s also suppress the expression of the
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zinc finger transcription factors from the Snail family, which lead to EMT activation in some cancers (Lamouille et al., 2013; 2014; Abba et al, 2016). The Snail family comprises three members: Snail1, Snail2 (Slug), and Snail3 (SMUC) (Baulida et al., 2015). The relationship between miR-200s/Snail/E-cadherin is still unknown in
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endocrine tumors, although Snails and E-cadherin expression have been studied. Besides miR-200s, other miRNAs have been described as EMT regulators in endocrine cancers. In anaplastic thyroid carcinomas, the expression of miR-29a
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and miR-30a is reduced. Both miRNAs directly target lysyl oxidase, which is able
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to promote EMT (Hebrant et al., 2014; Boufraqech et al., 2015). Boufraqech et al. (2016) showed that lysyl oxidase binds and transactivates the Snail2 promoter, increasing Snail2 expression. In papillary thyroid carcinoma with lymph node metastasis, miR-146b-5p is
overexpressed and induces EMT, increasing invasiveness targeting the Zinc Ring Finger 3 protein (ZNRF3), which is a cell surface transmembrane E3 ubiquitin ligase that negatively regulates the Wnt/β-catenin signaling (Deng et al., 2015).
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ACCEPTED MANUSCRIPT The role of miRNAs in the regulation of genes linked to EMT in endocrine cancers is still poorly known, but these findings suggest an important modulation of the early phases of EMT by miRNAs.
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4.2. Invasion and Migration Cell invasion and migration are crucial processes for the metastatic
dissemination of tumor cells. Under EMT, epithelial cancer cells remodel their cellcell and cell-extracellular matrix adhesions, acquire a fusiform morphology and
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increase their directional motility to escape the primary tumor and move on to
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another organ (Brooks et al., 2010). During this process, the cortical actin cytoskeleton is reorganized and new actin-rich membrane projections that facilitate cell movement are constructed: the sheet-like membrane protrusions called lamellipodia, spike-like extensions called filopodia and small projections with matrix proteolytic activity involved in cell invasion, known as invadopodia (Ridley,
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2011; McNiven, 2013). Most filopodia are exploratory of the microenvironment, and precede lamellipodia. Cells extend lamellipodia in the direction of migration,
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establishing new immature adhesions to the extracellular matrix. Some of these adhesions mature into focal adhesions, serving as anchorage sites for actin-
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myosin II contractile bundles named stress fibers. The contraction of stress fibers helps the pulling of the cell body forward; finally, the cells retract the rear end. This movement is cyclic during cell migration, being mostly regulated by small GTPases from the Rho family (Ridley, 2015). The ability to degrade the extracellular matrix and move to penetrate tissue barriers is a hallmark of tumor aggressiveness. MiRNAs regulate both processes, targeting molecules involved in many signaling pathways in different cancers, including endocrine cancers. One of the first studies to investigate the role of
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ACCEPTED MANUSCRIPT miRNAs in thyroid cancer aggressiveness was published by Chou et al. (2010).
After previous studies that showed a high expression of miR-146b-5p, miR-221-3p and miR-222-3p in papillary thyroid carcinomas (He et al., 2005; Pallante et al., 2006; Nikiforova et al., 2008), they analyzed 100 cases of papillary thyroid
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carcinomas with distinct characteristics and demonstrated that these miRNAs were significantly higher in tumors with extrathyroidal invasion. Other studies
followed through, establishing similar correlations. A higher expression of the
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same miRNAs was found in papillary thyroid carcinoma patients that presented capsule invasion, vascular invasion or lymph node metastasis, as well as distant
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metastases (Zhou et al., 2012; Saiselet et al., 2015; Mutalib et al., 2016). Concerning all the miRNAs differentially expressed in papillary thyroid carcinomas until now, miR-146b-5p is regarded as the best correlated with tumor aggressiveness and has been considered as a potential prognostic marker for this
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cancer (Chou et al., 2013; Peng et al., 2014; Lee et al., 2015; Mutalib et al., 2016). The mechanisms involved in miR-146b-5p-stimulated migration and invasion in
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papillary thyroid carcinomas are still poorly understood. Chou et al. (2013) transiently overexpressed this miRNA in papillary thyroid carcinoma cell lines in
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vitro, showing increased migration, invasion and increased resistance to chemotherapy-induced apoptosis. Recently, Lima et al. (2016) demonstrated that miR-146b-5p positively regulates migration and invasion of papillary thyroid carcinoma cell lines in vitro targeting Smad4, a member of the TGF-β signaling pathway. Downregulation of Smad4 has been widely associated with TGF-β resistance in thyroid tumor cells, contributing to accelerate the malignant progression (Mincione et al., 2011; Geraldo et al., 2012). The overexpression of
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ACCEPTED MANUSCRIPT miR-146-5p was also detected in follicular thyroid carcinomas, accelerating cell migration (Dettmer et al., 2013). Similarly to miR-146b, miR-221 and miR-222 were also associated with
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papillary thyroid carcinoma aggressiveness and are overexpressed in metastatic follicular thyroid carcinomas (Jikuzono et al., 2013). Visone et al. (2007) have shown that miR-221 and miR-222 directly repress p27Kip1 expression in
anaplastic thyroid carcinoma. The protein p27Kip1 negatively controls cell cycle
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progression, and decreased p27Kip1 levels have been correlated with poor patient
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survival (Slingerland & Pagano, 2000; Acibucu et al., 2012). Acibucu et al. (2012), studying a potential correlation between miR-146b, miR-221/222, p27Kip1 and clinicopathologic parameters in papillary thyroid cancers, showed that the expression of these miRNAs was elevated in patients with distant metastases and
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lower levels of p27Kip1.
The identification of differentially expressed miRNAs in parathyroid cancers by miRNA array showed the upregulation of three miRNAs (including miR-222 and
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miR-503) and the downregulation of fourteen miRNAs, including miR-296 and miR-139. Although the functional role of miR-222 in this tumor has not been
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elucidated, its overexpression seems to contribute to tumorigenesis (Corbetta et al., 2010).
The role of miR-221 and miR-222 in tumorigenesis and invasiveness,
however, is far from clear. For some types of cancer, these miRs are considered oncomiRs, whereas in others they are considered tumor-suppressor miRs; basically, they are capable of regulating EMT, migration, invasion, angiogenesis, proliferation and apoptosis (Garofalo et al., 2012; Xu et al., 2015; Li et al., 2016).
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ACCEPTED MANUSCRIPT Other miRNAs involved in thyroid cancer progression and aggressiveness
are miR-126 and miR-7 (Kitano et al., 2011; Yue et al, 2016). Kitano et al. (2011) suggested that these miRNAs might be used as markers to distinguish thyroid carcinomas from benign thyroid lesions, being downregulated in both papillary and
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follicular thyroid carcinomas. More recent studies tried to clarify the role of miR126 in thyroid cancer (Rahman et al., 2015; Xiong et al., 2015; Wen et al., 2015; Qian et al., 2016; Salajegheh et al., 2016). Its tumor suppressor role was first
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demonstrated by Xiong et al. (2015), who showed that lowered levels of miR-126 expression were correlated with more aggressive thyroid cancers. The
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overexpression of miR-126-3p inhibited thyroid cancer cell proliferation, colony formation, tumor spheroid formation, migration and VEGF secretion, and significantly reduced tumor growth and metastasis in vivo (Xiong et al., 2015). The effects on growth and migration were at least partially attributed to two direct target
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genes: SLC7A5 and ADAM9, respectively. SLC7A5 codes a neutral amino acid transporter also known as LAT1, which is overexpressed in a variety of tumor cells, associated with poor prognosis (Fan et al., 2010; Oda et al., 2010). The
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other target, ADAM9, is a member of the disintegrin and metalloprotease domain family and plays an important role in ectodomain shedding of membrane-bound
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molecules.
The tumor suppressor role of miR-126 in papillary thyroid carcinomas was
also studied by Wen et al. (2015) using miRNA in vitro and in vivo functional assays. MiR-126 overexpression in papillary thyroid carcinoma cell lines significantly reduced cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and cell cycle arrest at G1 in vitro, also inhibiting tumor growth and decreasing tumor size in vivo (Wen et al., 2015). A potential target of
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ACCEPTED MANUSCRIPT this miRNA was the low-density lipoprotein receptor related protein 6 (LRP6),
which acts as a co-receptor for Wnt ligands to activate the Wnt/β-catenin signaling pathway (Liu et al., 2003; MacDonald & He, 2012). More recently, Qian et al. (2016) confirmed the downregulation of miR-126 in thyroid cancer tissues and
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established the C-X-C chemokine receptor type 4 (CXCR4), which binds
chemokine CXCL12, as another target of miR-126 that contributes to the regulation of proliferation, migration and invasion.
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MiR-126 is deregulated in other endocrine cancers, with not very clear
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roles. Olson et al. (2009) suggested a miRNA signature for each step of tumorigenesis in pancreatic neuroendocrine tumors, and miR-126 was overexpressed during angiogenesis, one of the early steps of tumorigenesis. Its expression decreased substantially in more advanced stages, however, when cells presented a metastatic profile and the tumors became more aggressive. Patterson
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et al. (2011), using miRNA microarray, found 23 deregulated miRNAs in adrenocortical carcinomas; among them, miR-126 was significantly decreased.
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Rahbari et al. (2011) found 167 deregulated miRNAs in parathyroid carcinomas when compared to normal parathyroid glands, and found three (miR-126, miR-26b
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and miR-30b) compared to parathyroid adenomas. MiR-126 was considered the best diagnostic marker for carcinomas. As already mentioned, in the last few years miR-7 has also been
investigated as a potential marker to distinguish malignant from benign thyroid tumors (Santarpia et al., 2013; Stokowy et al., 2014). More recently it has been associated with tumor aggressiveness and metastasis (Saiselet et al., 2015; Mutalib et al., 2016; Yue et al., 2016). Kitano et al. (2012) developed a diagnostic technique for thyroid fine-needle aspiration biopsies based on miRNA expression
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ACCEPTED MANUSCRIPT levels. Among four miRNAs previously reported as differentially expressed between benign and malignant tumors (miR-7, miR-126, miR-374a, and let-7g) (Kitano et al., 2011), miR-7 was the most accurate miRNA for the diagnosis of
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carcinomas (Kitano et al., 2012). Using next-generation deep sequencing to analyze miRNA length
heterogeneity and expression profiles in papillary thyroid cancers, subsequently validated by miRNA microarray, Swierniak et al. (2013) found 43 differentially
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expressed miRNAs. The expression of miRNAs was not correlated to BRAF
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mutation, and almost all miRNAs exhibited isoforms of variable length (isomiRs), possibly with distinctive functions in thyroid tumorigenesis. Corroborating other studies, miR-7-3p, among the top six deregulated miRNAs, was significantly downregulated in thyroid carcinomas. More recently, however, Mancikova et al. (2015) reported that papillary thyroid carcinomas with BRAF mutation displayed
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extreme downregulation of miR-7 and miR-204. In a similar study aiming the establishment of better miRNA markers to distinguish follicular thyroid carcinomas
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from follicular adenomas, Stokowy et al. (2014) evaluated publicly available miRNA expression profiling data sets and found 27 miRNAs differentially
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expressed; miR-7-5p was among the top four significantly deregulated. The downregulation of miR-7 was also correlated with tumor
aggressiveness, since it was among the ten miRNAs most aberrantly deregulated in metastatic medullary thyroid carcinoma samples (Santarpia et al., 2013). Saiselet et al. (2015) found that miR-7 and miR-30c were among the most downregulated miRNAs in lymph node metastases of invasive papillary thyroid carcinomas. In that study the authors employed small RNA deep sequencing followed by qPCR and in silico analysis using the dataset from The Cancer
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ACCEPTED MANUSCRIPT Genome Atlas. Besides confirming the identity of the major deregulated miRNAs already described in the literature, they selected the 14 most downregulated miRNAs as potential biomarkers of papillary thyroid carcinoma, some of them
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related to invasiveness. More recent studies have employed integrated analysis of miRNAs and gene expression profiles to improve the identification of functional miRNA-target gene relationships, providing a more complete view of molecular events underlying
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metastasis. Mutalib et al. (2016) reviewed datasets from the Cancer Genome Atlas
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(TCGA) on papillary thyroid carcinoma to identify differentially expressed miRNAs/genes in tumors with lymph node metastasis. MiR-7-2, miR-146b, miR375, miR-31 and miR-204 were the five top deregulated miRNAs among the 181 differentially expressed miRNAs in metastatic tumors. Four pathways potentially involved in metastasis to the lymph nodes were significantly enriched: oxidative
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phosphorylation, cell adhesion molecules, leukocyte transendothelial migration and cytokine-cytokine receptor interactions.
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Although several studies have shown that miR-7 is an important miRNA involved in thyroid tumorigenesis, its tumor suppression function began to be
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elucidated only recently. Yue et al. (2016) showed that miR-7 overexpression in thyroid cell lines significantly suppressed proliferation, migration and invasion. They also demonstrated that the serine/threonine kinase p21-activated kinase-1 (PAK1), overexpressed in this cancer is a direct target of this miRNA (McCarty et al., 2010). Hua et al. (2016) showed that the overexpression of miR-7 in thyroid carcinoma cell lines not only inhibited proliferation, suppressed migration and invasion, but also caused a G0/G1 arrest through the targeting of the cyclindependent kinases regulatory subunit 2 (CKS2).
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In addition to thyroid tumors, decreased expression of miR-7 has also been described in adrenal cancers. Soon et al. (2009) found that miR-7 expression was reduced in adrenocortical carcinoma samples compared to both adrenocortical adenomas and normal adrenal cortices. Recently, Glover et al. (2015) reported
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that miR-7 reduced adrenocortical carcinoma cell proliferation in vitro, inducing G1 cell cycle arrest. They also demonstrated that the systemic administration of miR-7 using a targeted, clinically safe delivery vesicle (EGFREDVTM nanocells) reduced
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adrenocortical carcinoma xenograft growth originated from both adrenocortical carcinoma cell lines and primary adrenocortical carcinoma cells. The mTOR and
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MAPK signaling pathways were affected by miR-7 through the targeting of Raf-1 proto-oncogene and Epidermal Growth Factor Receptor (EGFR). In vivo, miR-7 therapy also leaded to the inhibition of CDK1. These studies suggest that miR-7 might be a potential target for replacement therapy in adrenocortical carcinomas.
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The expression and function of miR-137 has been investigated in different tumors but only recently endocrine tumors were included in these studies. Luo et
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al. (2016) showed that miR-137 exerts a tumor suppressor role in papillary thyroid carcinoma inhibiting cell proliferation, colony formation and invasion, directly
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targeting the epidermal growth factor receptor (EGFR) and indirectly reducing the levels of cyclin E, MMP2, p-ERK, and p-AKT. Dong et al. (2016) not only confirmed miR-137 suppression on those tumors but also reported a correlation between miR-137 lowered expression, tumor-node-metastasis (TNM) stage and lymph node metastasis. Through functional assays in vitro, they demonstrated the inhibitory role of miR-137 on proliferation, colony formation, migration and invasion targeting directly the chemokine CXCL12. Some authors suggested CXCL12 as
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an effective biomarker for papillary thyroid carcinomas (Chung et al., 2014; Zhu et al., 2016). MiR-206 was also investigated in different types of thyroid cancers and
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associated to aggressiveness. This miRNA is significantly downregulated in papillary thyroid carcinomas (Liu et al., 2013) and upregulated in follicular thyroid carcinomas (Stokowy et al., 2014). Interestingly, in anaplastic thyroid carcinomas miR-206 expression may be downregulated (metastatic tumors) or upregulated
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(non-metastatic tumors) (Zhang et al., 2015). MiR-206 overexpression in
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anaplastic thyroid cancer cells inhibited invasion and metastasis, directly targeting MRTF-A (myocardin-related transcription factor A), also known as MKL1. This protein belongs to the myocardin family, which regulates the expression of different signaling molecules, transcription factors and cytoskeletal components,
al., 2009).
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including actin, non-muscle myosins and vinculin (Cen et al., 2003; Medjkane et
MiR-101 has been described as an important tumor suppressor miRNA,
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and its decrease was associated with malignancy in some types of cancer, including thyroid carcinomas (Liu et al., 2013) A correlation between the
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expression of miR-101, inhibition of cell proliferation (Lin et al., 2014), colony formation, migration, invasion and lymph node metastasis was established (Wang et al., 2014). MiR-101 inhibits migration and invasion targeting the small GTPase Rac1 (Wang et al., 2014). Besides its well-known role promoting cell adhesion and migration, Rac1 is also involved in the cell cycle progression, gene transcription and the release of pro-angiogenic factors, thereby promoting cancer initiation, progression and metastasis (Benitah et al., 2004; Parri et al., 2010).
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MiR-613 is another downregulated miRNA with potential importance for the aggressiveness of papillary thyroid carcinomas (Yang et al., 2013; Qiu et al., 2016). It is one of the top five miRNAs differentially expressed in aggressive papillary thyroid carcinoma targeting the sphingosine kinase 2 (SphK2) (Qiu et al.,
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2016).
Among the tumor suppressor miRNAs recently described as potential markers for thyroid tumors is miR-539 (Gu & Sun, 2015). Its expression is
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downregulated in tumors and further reduced in lymph node metastasis, distant
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metastasis as well as TNM stage, suggesting an inversed correlation with aggressiveness. In a thyroid cell line, the overexpression of miR-539 inhibited migration and invasion targeting CARMA1 (CARD domain and MAGUK domaincontaining protein-1), also known as CARD11 or Bimp3.
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Although much is known about the differential expression of several miRNAs in endocrine cancers (especially thyroid cancers) and a little is known about their targets, much less is known today about the regulation of miRNAs
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expression in these cancers. The deregulation of miRNAs in cancer initiation and progression may be modulated by the immune system, in example, through the
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secretion of factors that stimulate cell proliferation, survival, angiogenesis, etc. (Galdiero et al., 2016). In different cancers interleukin–23 (IL–23), a conventional proinflammatory cytokine, has been detected in high levels and may be related to metastasis. IL-23 is overexpressed both in papillary and follicular thyroid carcinomas (Mei et al., 2015) and regulates miR-25 expression, which, in turn, promotes migration and invasion directly targeting SOCS4 (cytokine-inducible SH2-containing protein).
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ACCEPTED MANUSCRIPT A similar pathway was reported for interleukin-22 (IL-22), synthesized by different immune cells and elevated in many types of cancer. Recently, Mei et al. (2016) reported that IL-22 induces miR-595 expression in papillary thyroid
carcinoma, which, in turn, promotes migration and invasion by targeting Sox17, a
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member of the SRY-related high-mobility group (HMG)-box transcription factor
cancers (Ye et al., 2011; Yang et al., 2014). 4.3. Other roles in metastasis in general
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superfamily that modulates proliferation, differentiation, migration and invasion in
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The roles of specific miRNAs in EMT, cell migration and invasion in endocrine cancers are much better understood than their roles in other steps of metastasis, such as intravasation, extravasation and colonization at distant sites. It is known, however, that cell proliferation, scape from anoikis and survival, among
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other features, are important during these stages. For this reason, studies related to the role of miRNAs in the final steps of the metastatic cascade in endocrine cancers are compiled below. The roles of some specific miRNAs are not clear-cut,
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however, as they simultaneously affect different processes.
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MiR-21 is one of the most studied miRNAs in many cancers, including endocrine cancers. As an oncomiR, it affects all the major hallmarks of tumordeveloping pathways (Yang et al., 2015; Li et al., 2016). Its expression was meaningfully increased in different thyroid carcinoma types (Braun et al., 2010; Frezzetti et al., 2011; Huang et al., 2013; Zhang et al., 2014; Guo et al., 2015; Pennelli et al., 2015). Talotta et al. (2009) showed that miR-21 was induced by the transcription factor AP-1 and mediated the RAS-dependent downregulation of PTEN (phosphatase and tensin homolog) and Pdcd4 (programmed cell death
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ACCEPTED MANUSCRIPT protein 4). The downregulation of Pdcd4, in turn, would be necessary for the
maximal stimulation of AP-1 activity in response to the RAS oncoprotein, pointing to miR-21 as both target and regulator of AP-1. This study suggested a novel autoregulatory loop, mediated by miR-21 and Pdcd4 in the control of AP-1 activity in
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RAS-transformed cells. Pdcd4 is directly targeted by miR-21 in other endocrine cancers as well, such as pancreatic neuroendocrine cancer and adrenocortical carcinoma (Roldo et al., 2006; Talotta et al., 2009; Ozata et al., 2011; Mian et al.,
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2012; Zhang et al., 2014; Pennelli et al., 2015). Interestingly, Frezzetti et al. (2011) showed that among many mRNAs downregulated by miR-21, there were some
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encoding cell cycle checkpoint regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.
Considering that miR-21 plays important roles in different cell processes, Haghpanah et al. (2016) employed off-miR-21 (antagomir) to sequester this
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miRNA in anaplastic thyroid carcinoma cell lines. They found that miR-21 antagomiR decreased the stemness state and cell cycle progression, increasing
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differentiation and apoptosis, being potentially interesting for therapeutic purposes. In other endocrine cancers, miR-21 has also been described as a potential
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marker, but still with unknown functions. In example, in insulinomas, miR-21 was upregulated and strongly associated with the proliferation index and the presence of liver metastasis (Roldo et al., 2006). Ozata et al. (2011) demonstrated that miR21 was significantly increased in adrenocortical carcinoma samples compared to adenomas and normal tissues. In adrenocortical carcinomas, many studies developed up to now aimed to detect differentially expressed miRNAs in comparison to adrenocortical adenomas or normal tissues. Some overexpressed miRNAs were meaningfully correlated to
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aggressiveness, such as miR-483-5p, miR-483-3p, miR-210, miR-503, miR-181b, miR-1202, miR-1275, miR-139-5p and miR-376a. Other downregulated miRNAs associated to poor prognosis were miR-195, miR-497, miR-1974, and miR-214 (Ozata et al, 2011; Patterson et al, 2011; Singh et al, 2012; Chabre et al, 2013;
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Patel et al, 2013; Szabó et al, 2014, Jain et al, 2014; Bezerra et al, 2014;
Feinmesser et al, 2015; Igaz et al, 2015; Yu et al, 2016). The functional roles of most of these miRNAs remain unknown, as well as the molecular mechanisms
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involved.
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Interestingly, Ozata et al (2011) demonstrated that both miR-483-5p and miR-483-3p act as oncogenes in adrenocortical carcinomas stimulating proliferation, but only miR-483-3p inhibited apoptosis. The expression of PUMA (p53 upregulated modulator of apoptosis), a potential target of miR-483-3p, was inversely correlated with miR-483-3p expression in carcinomas. In contrast, both
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miR-497 and miR-195 are tumor suppressors in adrenocortical carcinomas, regulating cell proliferation and death (Ozata et al 2011). Jain et al (2014)
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demonstrated that miR-195 also negatively regulates adrenocortical carcinoma cells adhesion, migration and invasion through a direct target, ZNF367 (zinc finger
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protein 367).
Among many miRNAs overexpressed and associated to the metastatic
profile in different thyroid carcinomas are miR-183 and miR-375 (Abraham et al., 2011; Mian et al., 2012. Gundara et al., 2014; Wojtas et al., 2014; Wei et al., 2015). Wei et al. (2015) identified the protein Pdcd4 as a direct target of miR-183. As mentioned above, miR-375 is also overexpressed in thyroid cancer samples and has been associated to metastasis, tumor aggressiveness and poor
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ACCEPTED MANUSCRIPT prognosis (Abraham et al., 2011; Mian et al., 2012; Hudson et al, 2013; Reddi et al, 2013; Dettmer et al, 2013; Gundara et al, 2014; Mutalib et al., 2016). Many studies have driven their efforts to characterize this miRNA as a potential marker in thyroid cancer, but only few have focused on the role of this miRNA in the
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disease. Hudson et al. (2013) were the first to show, using miRNA array and qPCR, that miR-375 was significantly overexpressed in medullary thyroid
carcinoma samples. Although not validated as targets at the time, the proteins
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YAP1 (Yes-associated protein 1) and SLC16a2 (a transporter of thyroid hormone) were downregulated. Contrary to Hudson et al. (2013), however, Lee et al. (2013)
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showed that YAP1 was overexpressed in thyroid cancers. They also demonstrated that YAP1 knockdown resulted in marked decrease of tumor volume, invasion and distant metastasis in orthotopic tumor xenograft mouse models using the 8505C thyroid cancer cell line, suggesting that YAP1 acts as an oncogene in thyroid
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cancer.
Also differently from the results obtained by Hudson et al. (2013), Wang et
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al. (2016) reported a meaningful decrease of miR-375 expression in 60 pairs of papillary thyroid carcinomas and noncancerous normal tissue samples, as well as
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in papillary thyroid carcinoma cell lines, analyzed by qRT-PCR. The overexpression of miR-375 in cell lines reduced proliferation and increased apoptosis, whereas in vivo it decreased metastatic nodules in mice, suggesting a decreased migration and invasion capacity. Further study demonstrated that ERBB2 (also known as HER2, neu or NGL), which is a member of EGFR family, is a direct target of miR-375 in human papillary thyroid cells. Regarding the upstream regulation of miR-375, a study developed by Reddi et al. (2013) in anaplastic thyroid cancer investigated the role of PAX8/PPARγ
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ACCEPTED MANUSCRIPT fusion protein (PPFP) as a potent modulatory factor. PPFP was constitutively
expressed in five anaplastic thyroid carcinoma cell lines, inhibiting cell growth and xenograft tumor growth through pathways involving the upregulation of miR-375 and decreased AKT pathway activation. Furthermore, PPFP expression resulted in
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marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters.
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Another miRNA differently expressed in thyroid carcinomas is miR-9.
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Although it has been shown to be significantly downregulated in several studies through miRNA signatures, both in medullary thyroid carcinoma (Abraham et al., 2011; Mian et al., 2012; Gundara et al., 2014) and in papillary thyroid carcinoma (Sondermann et al., 2015; Cong et al., 2016), suggesting an important role in
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these tumors, no functional assay was performed to better understand this role. Recently, miR-151 expression has been detected in exosomes isolated from plasma of patients with papillary thyroid carcinoma and has been suggested
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as a marker for diagnosis before and after the surgery (Yoruker et al., 2016). The overexpression of miR-151 in the serum of those patients compared to patients
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with thyroid benign tumors was previously demonstrated (Yu et al., 2012). Nonetheless, little is known about its function in thyroid cancer. Also identified as a potential marker for thyroid cancer clinical diagnosis,
miR-126 was downregulated in all thyroid carcinomas with aggressive behavior (Ebrahimi et al., 2014; Rahman et al., 2015; Xiong et al., 2015; Wen et al., 2015; Qian et al., 2016; Salajegheh et al., 2016); apparently, this miRNA regulates cell survival. Rahman et al. (2015) showed reduced levels of p85β (a regulatory
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ACCEPTED MANUSCRIPT subunit of PI3K) and p-AKT in miR-126 mimic transfected cells, decreasing cell survival. More recently, Salajegheh et al. (2016) confirmed the low levels of miR126 in thyroid carcinomas and demonstrated that high exogenous miRNA levels could reduce cell proliferation, promote cell cycle arrest in G0-G1, and promote
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apoptosis. Additionally, a significant reduction of VEGF-A protein was observed after miR-126 overexpression in different thyroid cell lines, suggesting a. A
potential correlation between miR-126 levels, VEGF-A expression, the regulation
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of angiogenesis, cell proliferation and apoptosis.
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MiR-145 was also suggested as a potential marker for the diagnosis of papillary thyroid carcinomas (Samsonov et al., 2016). It is suppressed in different thyroid cancers (Boufraqech et al., 2014; Gu et al., 2015), although there were high miR-145 circulating levels in patients. The overexpression of miR-145 in thyroid cancer cell lines inhibited proliferation, migration, and invasion, with the
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reduction of VEGF secretion. It also induced apoptosis and the expression of stem cell markers, as well as follicular thyroid cell differentiation markers. In vivo, miR-
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145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. The PI3K/Akt survival pathway was also inhibited,
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with the direct targeting of AKT3 (Boufraqech et al., 2014). MiR-31 also belongs to the group of miRNAs that showed high levels in
exosomes before surgery for papillary thyroid carcinoma and significantly reduced levels after tumor removal (Samsonov et al., 2016). Actually, Yip et al. (2011) had previously shown miR-31 expression in papillary thyroid cancer, possibly correlated with an aggressive profile. More recently, Mutalib et al. (2016), reanalyzing the Cancer Genome Atlas (TCGA) datasets on papillary thyroid
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carcinomas to compare cases with and without lymph node metastasis, positioned miR-31 among the top five most deregulated (overexpressed) miRNAs. A few miRNAs are also deregulated in serum samples of adrenocortical
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carcinoma patients. High circulating levels of miR-483-5p and miR-34a and low circulating levels of miR-195 were associated with highly aggressive
adrenocortical carcinomas and poor prognosis (Chabre et al., 2013; Patel et al,
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2013; Szabó et al, 2014).
The Let-7 family of miRNAs has been confirmed as key regulators of gene
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expression in many organisms, and as important tumor suppressors in many cancers. The Let-7 family includes let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g and let-7i. In different thyroid cancers, different members of the let-7 family are deregulated, some of them related to invasion and metastatic capacity (Visone et
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al., 2007; Ricarte-Filho et al., 2009; Braun et al., 2010; Gao et al., 2010; Braun & Hüttelmaier, 2011; Swierniak et al., 2013; Hebrant et al., 2014; Mancikova et al., 2015; Damanakis et al., 2016; Perdas et al., 2016). Ricarte-Filho et al. (2009)
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firstly reported that the RET/PTC3 oncogenic activation in rat thyroid cells led to a great reduction of let-7f expression. They also demonstrated that let-7f regulates
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cell growth and differentiation. The overexpression of let-7f in a papillary thyroid carcinoma cell line harboring RET/PTC1 rearrangement inhibited MAPK activation and cell growth by decreasing cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increasing the p21 cell cycle inhibitor mRNA. Concomitantly, the high levels of let-7 enhanced the transcriptional expression of molecular markers of thyroid differentiation such as TITF1 and TG.
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ACCEPTED MANUSCRIPT During the last few years, the role of some members of the let-7 family on tumor aggressiveness and metastasis has been investigated. Up to now, in endocrine cancers, let-7 family members were investigated only in thyroid and endocrine pancreatic cancers. Studies focused mostly on the differential
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expression of these miRNAs between cancer and normal tissues (Visone et al., 2007; Rahman et al., 2009; Braun & Hüttelmaier, 2011; Swierniak et al., 2013; Damanakis et al., 2016) or between different types of carcinomas of the same
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gland (Schwertheim et al., 2009; Damanakis et al., 2016). Gao et al. (2010)
selected the more invasive cancer cell populations from a clonal cell line of human
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papillary thyroid carcinoma with cervical lymph node metastasis and performed miRNA microarray. Let-7b was the most differentially overexpressed miRNA among eleven miRNAs identified, suggesting an important role in metastasis. Another upregulated miRNA in thyroid cancers is miR-584 (Xiang et al.,
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2015; Orlandella et al., 2016). MiR-584 did not affect the proliferation of thyroid cell lines but protected them from apoptosis directly suppressing TUSC2 (tumor
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suppressor candidate 2, also known as Fus-1). Regarding migration, Xiang et al. (2015) demonstrated that miR-584 could inhibit the migration of cell lines by
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directly suppressing Rock-1 (Rho-kinase-1). In contrast, Orlandella et al. (2016) showed that miR-584 did not affect migration and invasion, concluding that it only affects cell survival.
MiR-205 has been widely reported as a regulator of different processes such as cell survival, apoptosis, angiogenesis and metastasis in several cancers, but few studies have investigated the role of this miRNA in endocrine cancers Salajegheh et al. (2015) have recently shown a downregulation of this miRNA in thyroid carcinomas with and without lymph node metastasis, compared to normal
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ACCEPTED MANUSCRIPT thyroid tissues. MiR-205 overexpression in thyroid cell lines inhibited cell proliferation, causing a cell cycle arrest in G0-G1, promoted apoptosis and
reduced VEGFA secretion, demonstrating a tumor suppressive role for this miRNA in thyroid cancer. Recently, Wu et al. (2015) demonstrated that miR-205 was
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significantly suppressed in adrenocortical carcinoma when compared to
adrenocortical adenomas, suggesting this miRNA as a potential marker for this cancer. Additionally, they showed that high levels of miR-205 induced apoptosis
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and impaired the proliferation of adrenocortical carcinoma cells in vitro, inhibiting tumor growth in vivo. The anti-apoptotic protein Bcl-2 was validated as a target of
prognostic marker for this cancer.
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miR-205. These data suggest that miR-205 may serve as a diagnostic and
MiRNAs represent an important field of research in cancer treatment. After more than one decade of extensive studies of miRNAs, the fundamental role of
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miRNAs in cancer progression and metastasis is being elucidated. Most studies on endocrine cancers is related to the thyroid gland, and much less in known
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about other cancers. MiRNA screenings generated much data, available in different databases. Functional studies about the role of miRNAs in endocrine
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cancers, however, are still scarce. MiRNAs that are meaningfully deregulated in aggressive endocrine tumors remain with their functions unclear and, therefore, need to be better investigated. 5. Concluding remarks and future perspectives Cancer metastasis is an aggravating factor in tumor progression, related to increased treatment complexity and a worse prognosis. Considering that cancer is a complex group of diseases involving specific changes in gene expression,
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ACCEPTED MANUSCRIPT knowledge about the role of miRNAs presents a high potential for novel therapeutic approaches. MiRNAs specifically involved in the metastatic process, especially, represent an important field of research in cancer treatment.
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Efforts in the study of miRNAs in cancer have focused mainly on two fronts: the establishment of a miRNA signature for different tumors, which may aid in
early diagnosis using these miRNAs as markers, and functional studies of specific miRNAs, determining their targets, function and regulation. For the study of
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specific cellular processes such as those involved in the metastatic cascade,
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functional analyses are very important because they clearly establish the molecular interactions of each miRNA. From these studies, it is possible to understand that a therapeutic strategy must always consider the complexity of the processes involved, to determine how important is the miRNA, or a group of
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miRNAs, for tumor progression and metastasis.
Endocrine cancers account for a large group of diseases to be better characterized and understood. Functional miRNA studies are still scarce and
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represent an important area of research, since some tumors, although not frequent, present a high mortality rate. Among the endocrine tumors, thyroid
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cancer is the most common and best studied, at least partially due to early detection of small cancers in the preclinical stage. At any stage of tumor progression, however, an altered miRNA expression (either upregulated or downregulated), may constitute important information for the elucidation of the molecular pathways involved. In the future, we expect that the rapidly growing knowledge about miRNAs generate the opportunity to develop novel therapeutic approaches for the
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treatment of endocrine cancers, especially those with high metastatic potential and poor prognosis for the patients. 6. Acknowledgements
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This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Grants # 2011/18936-7, #2012/03990-9 and
2015/19645-7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
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(CAPES, PNPD), Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq grants #307452/2012-3 and #448052/2014-8) and Pró-
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Reitoria de Pesquisa da Universidade de São Paulo (NAPMiR).
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4.Aschebrook-Kilfoy, B.; Ward, M.H.; Sabra, M.M.; Devesa, S.S. Thyroid cancer incidence patterns in the United States by histologic type, 1992-2006. Thyroid. 2011; 21(2):125-134.
5.Assié, G.; Antoni, G.; Tissier, F.; Caillou, B.; Abiven, G.; Gicquel, C.; Leboulleux, S.; Travagli, J.P.; Dromain, C.; Bertagna, X.; Bertherat, J.; Schlumberger, M.; Baudin, E. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab. 2007; 92 (1):148-54.
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ACCEPTED MANUSCRIPT Legends of the Figure and Tables Figure 1. Role of miRNAs on different stages of the metastatic cascade in
endocrine cancers. The figure summarizes the miRNAs involved in the control of
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molecular pathways associated to cancer progression and the metastatic process. Showed in green, the anti-metastatic miRNAs and in red, the pro-metastatic miRNAs.
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Table 1. Role of miRNAs with identified targets on metastasis of endocrine
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cancers.
Table 2. Role of miRNAs with potential targets on metastasis of endocrine cancers.
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Table 3. Altered miRNAs on metastatic endocrine cancers.
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Figure 1
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ACCEPTED MANUSCRIPT MiRNA
Target
Cancer
miR-145
AKT3 ZNRF3 Smad4
Thyroid carcinoma
p27Kip1
miR-25
SOCS4
miR-595
Sox17 PTEN, Pdcd4
miR-21
Pdcd4
miR-483-3p
PUMA
miR-183
Pdcd4 ZEB1 and ZEB2
miR-200 family ZEB1
miR-30a miR-126 Anti-metastatic miR-7 miR-137
SLC7A5 and ADAM9 LRP6 CXCR4 PAK1; CKS2 Raf-1; EGFR EGFR; CXCL12 MRTF-A
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miR-206
Lysyl Oxidase
Anaplastic Thyroid carcinoma
Papillary Thyroid carcinoma Thyroid Carcinoma
Adrenocortical Carcinoma Papillary Thyroid carcinoma Papillary Thyroid carcinoma Anaplatic Thyroid carcinoma Papillary Thyroid carcinoma
miR-539
CARMA1
Papillary Thyroid carcinoma Follicular Thyroid carcinoma
miR-195
ZNF367
miR-205
Bcl-2
MiRNA
miR-584 miR-375 miR-7 miR-205
miR-126
Table 2
Pancreatic Neuroendocrine Tumor
Rac1 SphK2
pro-metastatic
Anti-metastatic
Anaplastic Thyroid carcinoma Medullary Thyroid carcinoma
miR-101 miR-613
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Table 1
Papillary Thyroid carcinoma Follicular Thyroid carcinoma Papillary Thyroid carcinoma Thyroid carcinoma Pancreatic Neuroendocrine Tumor Adrenocortical carcinoma Adrenocortical carcinoma Follicular Thyroid carcinoma Papillary thyroid carcinoma
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miR-29a
Anaplastic Thyroid carcinoma
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Pro-metastatic
miR-221 miR-222
Papillary Thyroid carcinoma
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miR-146b-5p
Target TUSC2 Rock1 YAP1 SLC16a2 ERBB2 Cdk1 VEGF-A p85β VEGF-A
adrenocortical carcinoma
Cancer Papillary Thyroid Carcinoma Medullary Thyroid Carcinoma Papillary Thyroid Carcinoma Adrenocortical carcinoma Papillary Thyroid Carcinoma Anaplastic Thyroid carcinoma
Thyroid carcinoma
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ACCEPTED MANUSCRIPT MiRNA miR-222 miR-503 miR-126 miR-21
Cancer Parathyroid cancer Pancreatic neuroendocrine tumor Adrenocortical carcinoma Pancreatic Neuroendocrine tumor
miR-151 miR-31 let-7 family
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Thyroid cancer
miR-146b
Follicular Thyroid carcinoma
miR-375
Anaplastic Thyroid carcinoma
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Pro-metastatic
Papillary thyroid carcinoma
miR-210 miR-503 miR-181b miR-1202 miR-1275 miR-139
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miR-376a miR-183 miR-139
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miR-483
miR-296
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miR-126
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Anti-metastatic
Table 3
miR-7 miR-9 miR-30c miR-7-2 miR-204 miR-497 miR-1974 miR-214
adrenocortical carcinoma
medullary thyroid carcinoma
Parathyroid cancer Follicular Thyroid carcinoma adrenocortical carcinoma parathyroid carcinoma Thyroid carcinoma Medullary thyroid carcinoma Papillary Thyroid carcinoma
adrenocortical carcinoma
ACCEPTED MANUSCRIPT Deregulation of microRNAs expression and function is involved in cancer metastasis MicroRNAs may act as pro-metastatic or anti-metastatic. Studies have focused on microRNA signatures and functions in specific cancers
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MicroRNAs may be present in serum exosomes, potentially serving as diagnostic tools
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MicroRNAs may aid in the identification of therapeutic targets in endocrine cancers