Function of microRNA-143 in different signal pathways in cancer: New insights into cancer therapy

Biomedicine & Pharmacotherapy 91 (2017) 121–131

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Function of microRNA-143 in different signal pathways in cancer: New insights into cancer therapy Leila Karimia , Behzad Mansooria,b , Dariush shanebandia , Ali Mohammadia , Mahyar Aghapourc, Behzad Baradarana,* a b c

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran

A R T I C L E I N F O

Article history: Received 15 February 2017 Received in revised form 5 April 2017 Accepted 13 April 2017 Keywords: MicroRNA-143 Tumor suppressor Cancer Apoptosis Metastasis

A B S T R A C T

MicroRNAs (miRNAs) are small non-coding RNAs which participate in the post-transcriptional regulation of gene expression. They play important roles in cellular events such as growth and differentiation. Deregulation of miRNAs is frequently evident in human cancers where their aberrant expression is associated with uncontrolled proliferation, metastasis, impaired cell cycle and DNA damage response. The miRNAs are important in cancer as
50% of miRNA genes are located in cancer-associated regions such as fragile sites of genome. MiRNA-143 is defined as an important tumor suppressor in a variety of neoplasms including solid tumors and B-cell malignancies. MiRNA-143 is involved in the pathogenesis of cancers by directly targeting several mRNAs such as Bcl-2, KRAS, HK2, DNMT3A, TP53 and MMP-13. In this study, an overview of the miRNA-143 function in different signaling pathways in cancer will be provided. © 2017 Elsevier Masson SAS. All rights reserved.

Contents 1. 2.

3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of miR-143 expression . . . . . . . . . . . . . . . . . . . . . . . . . Effects of epigenetic modificationson miR-143 expression 2.1. Regulation of miR-143 expression by p53 and HIF-1 . . . . 2.2. Aberrant miRNA expression in human cancers . . . . . . . . . . . . . . Proliferative target genes of miR-143 in cancer . . . . . . . . . . . . . . Metastatic genes as targets for miR-143 in cancer . . . . . . . . . . . . Apoptotic target genes of miR-143 in cancer . . . . . . . . . . . . . . . . Conclusions and future prospective . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The miRNAs are a class of small non-coding endogenously expressed RNAs, comprising of about 19–25 nucleotides, that contribute to post-transcriptional regulation of genes involved in cell cycle, proliferation and differentiation by directly binding to the 30 -UTR of the target messenger RNAs (mRNAs) [1,2].

* Corresponding author at: Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran. E-mail address: [email protected] (B. Baradaran). http://dx.doi.org/10.1016/j.biopha.2017.04.060 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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Approximately, 50% of miRNA genes are located in common breakpoint regions of chromosomal amplifications and deletions, highlighting the significance of miRNAs in human cancers. The advent of miRNAs has become one of the promising advances in cancer biology over the past decade.Due to the biological characteristics of miRNAs, more attention has been attracted to these moleculesin recent years [3]. Deregulation of miRNA expression in cancer was first reported in 2002 [4,5]. The miRNAs play a central role in tumorigenesis, immune evasion, invasion and angiogenesis by controlling the expression of their target mRNAs [4,6,7]. MiRNAs can impact critical steps such as epithelial

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mesenchymal transition (EMT), angiogenesis, apoptosis, survival, proliferation, migration and metastatic progression [8,9]. In cancer, there is an imbalance between cell division and cell death which results in reduced apoptosis, enhanced tumor growth and development [10,11]. Escape from apoptosis is one of the characteristics of cancerous cells which results in tumorigenesis and drug resistance. This reinforces the basic concept that inducing efficient apoptosis is essential for therapeutic response and clinical outcomes. MiR-143 is shown to be the upstream regulator of metastasis-related genes such as MMPs, CD44 and PKC. MiR-143 geneis located at chromosome 5q32 andits transcription is performed by RNA polymerase II [12]. It is found to be downregulated in primary tumor samples. MiR-143 seems to be involved in anti-oncogenic processes, because its decreased expression has been shown in most of the cancer cell lines. Some of the target genes of miR-143 are correlated withcell proliferation and metastasis [13]. There are two isoforms of miR-143 including miR-143-3p and miR-143-5p; miR-143-3p is among the most common miRNAs in normal tissues [14]. Consequently, miR-143 can be utilized as a prognostic biomarker of cancer. Furthermore, restored expression of this miRNA canbe considered as a possible therapeutic approach [15,16]. Moreover, the success of miRNA therapy has been impeded by the fact that one miRNA targets multiple genes involved in cell growth, survival, differentiation and apoptosis, for instance, KRAS, DNMT3A, ELK1, MYO6, Bcl2 and ERK5 genes are being by miR-143[7,17,18] (Table 1). In this review, the correlations between the expression level of miR-143 and the prognostic and clinicopathological features of different epithelial carcinomas are investigated. 2. Regulation of miR-143 expression 2.1. Effects of epigenetic modificationson miR-143 expression MiRNAs as endogenous families of gene regulators are found in animals, plants and humans. In cancer, miRNAs are divided into two groups: tumor suppressor and oncomiRs. The tumor suppressor miRNAs negatively regulate their targets through interfering with mRNA translation or direct degradation [13,19,20]. Epigenetic changes in regulatory elements of miRNA coding genes can lead to their transcriptional silencing [21,22]. Aberrant epigenetic variations occur at the primary stages of neoplastic transformation. Consequently, epigenetics can play an essential role in initiation and progression of cancer [23]. For example, when the miRNA gene is located near CpG islands in the 50 -UTR of a host gene, the target miRNA is susceptible to hypermethylation changes. About 50 percent of the miRNA genes are related with CpG islands and it can be influenced by the DNA methylation machinery [21,22,24,25]. CpG hypermethylation of promoter

regions occurs in genes which areassociated with invasion, cell adhesionand angiogenesis, such as cadherin family and tissue inhibitors of metalloproteinases (TIMPs). Similarly, methylation status has been associated with altered levels of miRNAsexpression [26]. For example, epigenetic variation of miR-143 in colorectal cancer (CRC) can interfere with KRAS expression and prompt cell growth [27]. Cytosine DNA methylation is catalyzed by a small family of DNA methyltransferase (Dnmt) enzymes, including Dnmt1, Dnmt3a and Dnmt3b [28] Several mechanisms seem to account for the overexpression of Dnmt, including aberrant cell cycle control and epigenetic variations such as CpG island hypermethylation [29,30]. MiR-143 promoter is actively hypermethylated in mesothelioma cancer cell lines, leading to a progressive downregulation of miR-143 in brain metastases from lung tumors and other epithelial tumors. Moreover, treatment with histone deacetylase inhibitors, demethylating agents or ectopic re-establishment of the miRNA levels is associatedwith a decrease in tumorigenicity in vivo [31]. 2.2. Regulation of miR-143 expression by p53 and HIF-1 Expression of miR-143 is mainly regulated by p53 protein. However, the functioning of p53 is influenced by its interaction with mouse double minute 2 homolog (MDM2) andhypoxia inducible factor-1a (HIF-1a). P53 was reported to promote MDM2 mediated degradation and ubiquitination of HIF-1a. Nevertheless, it is not clear whether HIF-1a interacts directly with p53. Studiesindicate a strong interaction between MDM2 and HIF-1a protein since MDM2 is a ubiquitin ligase that regulates the p53 level and can interact with HIF-1a [32]. High level of p53 reduces HIF-1a expression but induces MDM2, while loss of p53 can lead to an increase in the HIF response [33,34]. HIF-1 exerts its function on tumor progression bybinding it to target genes with hypoxia response elements (HREs) [35]. HIF-1a has been reported to prompt p53-dependent apoptosis which is mediated by APAF-1 and caspase-9. Induction of particular miRNAs through p53dependent pathway is believed to be important for apoptosis and p53-mediated cell cycle arrest [36]. Several miRNA aberrations are related with the deregulation of p53. A number of investigations recommend that p53 deregulation may be important in miRNA expression machinery. P53 tumor suppressor protein is a key regulator of cell-cycle and apoptosis. It can affect the activity of miRNA by at least two mechanisms. First, it functions as an RNAbinding protein which involves miRNAs inactively translated mRNA complexes. Second, it acts as a transcription factor that increases the expression of miRNAs to modulate the levels of downstream mRNAs [26]. In other words, p53 can enhance the expression of specific pri-miRNA genes at the transcriptional level. Furthermore, it can act as a processing stimulator of specific

Table 1 The effect of miR-143 on signaling pathway and proliferative target genes in cancers. Target gene

Involved pathway

Cancer types

References

PKCe, AKT, PKB K-RAS, ERK5 HK2 K-RAS,MAPK7, ERK5 DNMT3A RAS/RAF/MAPK Syn-1 ErbB family MAPK, PI3K IGFBP5 Cox2 TLR2, TLR4 ATG2B

Proliferation Proliferation Glycolyse, proliferation Proliferation, cell growth Proliferation, cell growth Proliferation Proliferation, angiogenesis Proliferation, metastasis Proliferation, survival Proliferation Proliferation Proliferation Proliferation

Lung cancer, bladder cancer Bladder cancer CRC, Breast cancer Colon cancer Gastric cancer, colon cancer, breast cancer Melanoma, prostate cancer Melanoma Breast cancer Colorectal cancer, bladder cancer Colon cancer Gastric cancer Colorectal cancer NSCLC

[78,79] [80] [43,81] [17,82] [76,83–85] [60] [86] [59,87] [59,79] [45,46] [88] [66–68] [70]

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miRNAs without a constant increase in the pri-miRNAs synthesis such as miR-143 [37]. On the one hand, p53 has been described by Suzuki et al. to enhance the maturation of several miRNAs including miR-143 at the post-transcriptional level. It also cooperates with Drosha processing complex through correlating with DEAD-box RNA helicase p68 [38]. P53 facilitates the processing of primary miRNAs to precursor miRNAs through DEAD box [39]. DNA binding domain of p53 interacts with the Drosha complexin response to DNA damage [40]. Thus, in mutant p53, due to a decreased interaction between Drosha complex and p68, an attenuated miRNA processing is evident. On the other hand, the mutant p53 lowers the mature miR-143 levels in tumor cells in comparison with normal cells [41]. The HIF DNA binding complex is composed of O2-regulated HIF-1a and HIF-1b subunits [33]. HIF can induce apoptosis through binding and stabilizing p53 or through transactivating BCL2 interacting protein 3 (BNIP3) which encodes a pro-apoptotic B-Cell lymphoma 2 (BCL2) family member [34,42]. Hypoxia occurs in the early stages of tumor progression. It is usually identified in non-invasive tumors like some types of breast cancer [43]. In cells under hypoxic conditions, p53 is organized to a form that blocks transchromosomal deletion at 5q32 location. This situation, which is detected in a number of malignancies such as colon and breast cancers, accounts for the downregulated expression of miR-143 [44]. The HIF-1a has different functions based on its phosphorylation status so that the dephosphorylated HIF-1a might facilitate apoptosis by binding and stabilizing p53. On the contrary, p53 might inhibit HIF-1a by the transcription of anti-apoptotic genes. Increased level of HIF-1a expression is associatedwith resistance totreatment and poor prognosis in some cancers such as gastric, ovarian, prostate cancer andrenalcarcinomas [45]. Several investigations have recently confirmed that, genes targeted by HIF-1a are basically involved in the regulation of tumor metastasis, angiogenesis, cell survival, resistance to therapy, apoptosis and metabolic reprogramming [46]. 3. Aberrant miRNA expression in human cancers It has been described that a reduced expression of tumor suppressor miRNA is caused by chromosomal deletions, epigenetic changes, aberrant transcription and disturbances in miRNA processing. Abnormalities can be identified both in miRNAs and proteincoding genes in a specific tumor. Aberrant expression of miRNA in human cancers was first designated in B-Cell chronic lymphocytic leukemia (B-CLL). In this malignancy, decreased expression of miR-16 and miR-15 occurs due to chromosomal deletion at the 13q14 locus [26,47]. In general, aberrant expression of miR-143 can potentially deregulate RAS-Raf-MEK-ERK, mitogenactivated protein kinase (MAPK cascade), and other proliferative signaling networks such as PI3K-Akt and transforming growth factor beta (TGF-b) pathways. Since ERK5 belongs to the MAPK superfamily, it can cause transcriptional activation of c-Myc that results in cell growth inhibition [14,48]. P53 inactivation may be caused by a variety of mutations or binding to proteins such as MDM2. Overexpression of MDM2 is often found in certain types of cancers, indicating that MDM2 has an important role in tumorigenesis [49]. MiR-143 is found to directly regulate MDM2 expression. Low levels of miR-143 triggers cellular proliferation and apoptosis inhibition in human epithelial cancers through attenuating the feedback loop of miRNAs-MDM2-p53 [50,51]. CCAAT/enhancer-binding protein beta (C/EBPb), transcriptionally activates the miR-143. Some oncogene miRNAs such as miR-155 in breast cancer cellsare shown to downregulate miR-143 expression through targeting C/EBPb and promoting hexokinase 2 (HK2) expression at the post-transcriptional level [43].]. In cancer, disruption of miRNA-mediated regulatory feedback loops

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contributes to cell transformation, EMT, migration and metastasis. Inhibition of miRNA biogenesis enhances the tumor progression and metastasisby knocking down the DICER1 gene [44]. 4. Proliferative target genes of miR-143 in cancer The miR-143, as a tumor suppressor miRNA, interferes with the genes that are involved in cell proliferation. HIF-1a is one of the important factors that affects the expression of proliferation pathway genes. HIF-1a activation in human cancers occurs due to mutations which result in loss of function in tumor suppressor proteins (such as phosphatase and tensin homologue (PTEN) and p53) or gain of function in some oncogenes (e.g. ERBB2) [33,42]. The phosphoinositide 3-kinase PI3K/Akt signaling pathway upregulates the expression of vascular endothelial growth factor (VEGF) in tumor cells, and in turn HIF-1 promotes VEGF expression. SincePI3K/Akt pathway is negativelyregulated by PTEN, both HIF-1 expression and PI3K/Akt functioning are increased in differentcancers with PTEN inactivation [52,53]. Since the HIF-1a protein synthesis is regulated by the activation of the PI3K and MAPK pathway, the role of this pathway in cell proliferation has been recognized [52]. HIF-1a is a transcription factor for VEGF which links angiogenesis with glycolyticmetabolism. PI3K/Akt signaling can lead to translocation of HK2 to the mitochondrial membrane and the subsequent binding to the voltage-dependent anion channel (VDAC), and hence negatively modulates truncated BH3-interacting domain death agonist (tBID) and perhaps BCL2 antagonist of cell death (BAD) to inhibit apoptosis. HK2 expression is regulated by p53 and HIF-1 [34,39]. Hexokinase is the first enzyme of the glycolytic pathway. HIF-1 activates the transcription of HK1 and HK2 genes [39]. Systemic method of screening in a number of breast cancer cell lines showed that the overexpression of miR-143 results in reduced HK2 protein expression, suggesting a possible approach for the treatment of cancer (Table 1). Studies show that the lowest expression of miR-143 is associated with the highest level of HK2 expression in MDA-MB-231 breast cancer cells. In addition, HK2 expression is inversely associated with miR143 [45] (Fig. 1). Moreover, stimulation of VEGF by various oncogenic growth stimuli such as ERBB family, is reduced in cells without signal transducer and activator of transcription (STAT3) signaling [52]. STAT3 is the dominant moderator of the recognized JAK/STAT pathway which plays a vital role in oncogenic signaling in the progression and carcinogenesis of some cancers including melanoma, breast, head and neck, pancreas and prostate [54,55]. The JAK/STAT and PI3K/Akt are two parallel pathways mediating the functions of many receptor and non-receptor tyrosine kinases, including epithelial growth factor receptor (EGFR), HER-2 or ERBB2 and c-Src. Moreover, STAT3 is sufficient for Akt expression [52]. STAT3 promotes cell division control (cdc2) expression of Cyclin B1 and prevents the p27Kip1 and p21Cip1 expressions [56]. STAT3 considerably promotes tumor growth in vivo, for example the subcutaneous tumors derived from cells with overexpression of STAT3 were noticeablylarger in size compared with the cells transfected with empty vector [57]. The ErbB family of receptor tyrosine kinases (RTKs) is found to be overexpressed in breast cancer. ErbB family activation results in the recruitment of downstream effector proteins. The PI3K/Akt pathways are main signaling routes for the ErbB family [58,59] (Fig. 1). Through these molecular mechanisms, the ErbB family regulates the differentiation, proliferation, survival and apoptosis of human breast epithelial cells (Table 1). RAS/RAF/MAPK signaling pathways regulate essentially all features of the tumor cell phenotypeand play central roles in carcinogenesis, tumor migration and proliferation [60] (Fig. 1). It was described that miR-143 prevents the RAS and ERK5 expression in esophageal cancer [61]. ERK5 belongs to the MAPK family activated by MEK5. It regulates gene

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Fig. 1. Schematic drawing of miR-143 in cancer prolifration. a: MiR-143 inhibits cell growth by inhibiting RAS protein in EGF/EGFR signaling pathway. b: aberrant HK2 expression through p53 or PTEN mutations in AKT/PI3K pathway leads to tumor cell growth. MiR-143 can target HK2 and suppress cell proliferation. c: MiR-143 can prevent cell growth by suppressing c-Myc and its upstream signaling pathways.

expression by phosphorylating a wide range of cellular mitogens and is involved in the regulation of cellular proliferation and differentiation. Also, miR-143 directly targets ERK5 in prostate cancer. The expression of miR-143 is negatively correlated with ERK5 protein expression in human prostate cancer [62]. MiR-143 may function as a tumor suppressor by preventing ERK5 protein

expression in esophageal cancer [63]. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is known as an oncogene that modulates vital cellular processes including proliferation and differentiation. KRAS is a direct target of miR-143, so blocking the KRAS gene is associatedwith repressed cell viability and proliferation. The KRAS/miR-143 pathway helped to clarify the significance

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[29,30,72]. Thus, Dnmt gene overexpression can contribute to uncontrolled cell growth in some tumors [75]. While this gene is a direct target of miR-143, poor prognosis in some cancers such as colorectal cancer and breast canceris associated with underexpression of miR-143 and overexpression of DNMT3B [76,77].

of this miRNA in the progression of nasopharensial cancer (NPC), osteosarcoma and CRC and may offer a new beneficial therapeutic approach [61,64]. ERK5 targets well-known regulators of some proliferative genes such as c-Myc, cyclin D1 and nuclear factor NFkB [17,65]. An example of this pathway is toll-like receptor (TLR) signaling. Many observations indicated that miR-143 can regulate TLR expression in colorectal cancer cells. Overexpression of miR143 has been shown to impede tumor proliferation in vitro and in vivo by TLR2 and TLR4 downregulation [66–68]. Moreover, TLR4 signaling can intensifythe colitis-related cancer through some mechanisms likeNF-kb activation, increased cyclooxygenase 2 (COX-2) expression and promoted EGFR signaling. Investigations have reported that downstream signals of TLR4 pathway such as NF-kb and COX-2 play central roles in cancer cell proliferation [68]. Insulin and insulin-like growth factor-1 (IGF-1) induced transcription of their target genes through activation of HIF-1 transcription activity and the effect of insulin/IGF-1 on HIF-1 is mediated through the PI3K/Akt/mTOR pathway [34]. Insulin-like growth factor binding protein (IGFBP5) is a target of miR-143. IGFBP5 plays an important role in intestinal epithelial proliferation by negatively regulating insulin-like growth factor signaling pathway. Also, IGFBP5 usually functions to competitively prevent IGF signaling. Consequently, a reduced phosphorylation of epithelial IGF1R is observed in miR-143 deficient mice (Table 1). Therefore, a decrease in miR-143 expression can be directly associated with colon cancer [46]. The serine/threonine kinase mTOR has a central role in the activity of a variety of oncogenes, as well as the autophagy control. Many regulators of mTOR signaling, in particular the PI3K/Akt/PTEN pathway, are commonly dysregulated in human tumors; also, PTEN improves the inhibitory effects of mTOR on autophagy via negative regulation of PI3K-I. Subsequently, PTEN inactivation inhibits autophagy. One of the main mechanism of PI3K-I activation is loss of PTEN which is the second most commonly mutated tumor suppressor in human cancer [69]. Recently, the autophagy related 2 B (ATG2B) gene, has been recognized as a target for miR 143. An increase in the miR 143 expression is shown to negatively regulate the expression of ATG2B at the level of translation or transcription through direct binding to its 30 -UTR region [70]. Cell proliferation was considerably inhibited by restoring the miR-143 expression to a normal level. Downregulation of the ATG2B gene, as a result of miR 143 overexpression, leads to a similar phenotype in non-small cell lung cancer cells (NSCLC). Furthermore, knocking down the HK2 (a key enzyme in glycolysis) and ATG2B inhibitsthe growth of NSCLCs cells [28,71]. Upregulation of DNMT genes is associated with an increased expression of cyclin A target gene. A number of studies recommend that the expression levels of Dnmt genes increase during cellular transformation in human cancers [72–74]. DNMT3A is a DNA methyltransferase that catalyzes the transfer of a methyl group onto the 50 -position of cytosine in CpG dinucleotides.

5. Metastatic genes as targets for miR-143 in cancer Metastasis is one of the main causes of poor prognosis and invasive behavior of some cancers such as esophageal squamous cell carcinoma (ESCC). According to the literature, several molecular mechanisms are involved in metastasis induction in cancers such as ESCC. EMT, upregulation of genes such as matrix metalloproteinase (MMP), VEGF and decreased expression of TIMPs can be listed in this category [89–91]. The involvement of the tumor microenvironment in progression and metastasis induction has long been proven [92]. The cells of tumor milieu provoke cell migration and invasion by secreting different tumor stimulating elements containing cytokines, chemokines, extracellular vesicles and anti-inflammatory factors. Alterations in the extracellular matrix (ECM) at the molecular and biological levels support the migration and progression of tumor cells. Hence, stromal cells and the composition of the cells in tumor microenvironment should be considered when reviewing the therapeutic strategies for epithelial tumors [45]. MiR-143 is one of the miRNAs that suppresses metastasis [93]. MiR-143 downregulation is associated with human osteosarcoma cancer with lung metastasis. MMP-13 upregulation may be responsible for this type of invasion, proposing that miR-143 can be considered as an innovative molecular target for metastasis and invasion of osteosarcoma. MMP-13 is a proteolytic enzyme which structurally has a zincbinding motif and plays a role in the degradation and alteration of extracellular matrix in physiological and pathological processes. Overexpression of MMP-13 has been observed in squamous cell carcinoma of malignant melanoma, as well as colorectal, lung, head and neck cancers [94–97] (Table 2). These data suggest that upregulation of MMP-13 expression has led to reduced miR-143 expression in human osteosarcomas and lung metastasis. Consequently, delivering miR-143 into cancer cells can inhibit lung metastasis of osteosarcoma by suppressing MMP-13 expression [98]. TLR signaling pathway is one of the routes that regulates the MMP-13 expression. TLR activation can increase the invasion and metastasis of tumor cells by increasing the MMP-13 expression. Thus, silencing TLR4 by inducing miR-143 expression in cancer cells can decrease the metastasis [68]. The upregulation of other genes such as Golgi membrane protein1 (GOLM1) and plasminogen activator inhibitor-1 (PAI-1) is positively associated with the MMP13 expression. GOLM1 gene, which encodes the GOLM1/GP73/ GOLPH2 protein, is located on chromosome 9q21.3. GOLM1 has

Table 2 The effect of miR-143 on signaling pathway and metastatic target genes in cancers. Target gene

Involved pathway

Cancer types

References

PAI-1 GOLM1 CD44 MMP-13 MMP-9 Limk1 MACC1 EGFR Limk1, fscn1 MYO6 TLR2, TLR4 QKI-5

Metastasis, invasion Metastasis, invasion Metastasis, invasion Metastasis, invasion Metastasis, invasion Metastasis, invasion Metastasis, invasion invasion, migration Invasion, mobility Cell proliferation, migration Invasion, metastasis Metastasis

Bladder cancer, osteosarcoma cancer Prostate cancer, lung cancer Lung cancer, oral squamous cell carcinoma Osteosarcoma, lung cancer, prostate cancer Osteosarcoma, pancreatic cancer Lung cancer Colorectal cancer Prostate cancer, Osteosarcoma, breast cancer Lung cancer, esophageal squamous cell carcinoma Gastric cancer, colorectal cancer Colorectal cancer, HCC ESCC

[104,105] [100,101] [114,115] [90,95,98,119] [87,120] [92,121] [114,122] [59,60,87] [92,123] [80,124] [66–68] [125]

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homology to type II Golgi transmembrane proteins. Many studies have disclosed that the Golgi complex plays a key role in protein modification and cell migration. It also functions as a platform for diverse signaling pathways comprising the MAPK, cyclin-dependent kinases (CDKs) and Rho family GTPases. Aberrant expression of GOLM1 has been shown to be associated with metastasis [99]. GOLM1 potentiated MMP-13 expression and both MMP-13 and GOLM1 were higher in human metastatic cancer compared with adjacent tissues. The cAMP responsive element binding protein (CREB) is the mechanical link between MMP-13 and GOLM1 and participates in proliferation and apoptosisas a nuclear transcription factor. It has been reported that overexpression of CREB via GOLM1 can lead to enhanced CREB transcription of MMP-13. Since MMP-13 augments GOLM1 expression in tumor cells, downregulation of both MMP-13 and GOLM1 by miR-143 can decrease the invasion and metastasis. Therefore, a better understanding of the interaction between GOLM1 and miR-143 can provide a new insight into prostate cancer (PCa) metastasis and oncogenesis and supports the development of more effective therapies [100–102]. PAI-1, also known as serpin E1, is a tissue inhibitor of MMPs and TIMP-1 which is associated with poor prognosis in cancer patients [103]. PAI-1 knockdown interferes with prostatic cancer cell invasion via decreased MMP-13 expression. Existence of seed matches to residues of miR-143 in MMP-13 coding region (between exon 7 and exon 8) can be an evidence of PAI-1 and MMP-13 being targeted by miR-143 in prostatic cancer cells. PAI-1 is encoded by the SERPINE1 gene in humans and is a pivotal inhibitor of the plasminogen activators. This protein is mainly involved in the suppression of urokinase plasminogen activator (uPA), wound healing, thrombosis, angiogenesis and degradation of ECM. The uPA, uPAR pathway is regulated via Lim domain kinase 1 (Limk1) and PAI-1 genes. Low PAI-1 levels were detected in osteosarcoma cases with higher expression of miR-143, suggesting that miR-143 may have negative correlation with PAI-1 expression. It has also shown that, the inhibition of PAI-1 expression results in decreased expression and secretion of MMP-13. These data showed that PAI1, an important metastatic target gene of miR-143, controls invasion and lung metastasis via improvement of MMP-13 expression in human osteosarcoma cancer cells, proposing that these molecules can be prospective therapeutic target genes for preventing lung metastasis in patients with osteosarcoma cancer [104]. Furthermore, elevated quantities of PAI-1 is an important predictive indicator in many types of cancer which is linked with poor prognosis [105] (Fig. 2). The uPAR is a receptor for uPA and a high level of Limk1 expression triggered uPA promoter activity. Interaction between uPAR, integrins and cofilin recruits signaling events that change cell adhesion and migration. Since, cofilin is an important actin-binding protein; it can regulate actin dynamics by F-actin depolymerization. Limk1 can disable it by phoshphorylating cofilin to bind a depolymerized actin. In addition to tumor progression and cytoskeleton reformation, it involves degradation of the extracellular matrix by the uPA [106]. Limk1 is highly conserved in cysteine-rich structures involving 2 zinc fingers that plays a key regulatory role in the actin cytoskeleton, invasion and cell motility and is believed to be a therapeutic target for metastatic cancers [92]. The level and activity of endogenous Limk1 are higher in invasive breast and prostate cancer cell lines than in less invasive cells. MiR-143 as an important tumor suppressor targets directly at Limk1 or upstream signaling pathway, such as ROCK, in NSCLC cells and many malignancies; this may lead to metastasis inhibition [24,92] (Fig. 2). The ROCK family is another member of Rho-associate protein kinase that is involved in cell adhesion and contraction of smooth muscle through Rho-Rock signaling pathway. Thus, phosphorylation and activation of cofilin by Lim-kinase occur as a result of Rho activation [107]. Smad/TGFb signaling pathway through PAI-1 and

CD44 genes is another way for controlling metastasis. Since there is a Smad3/Smad4 binding site, named CAGA boxes, in the promoter region of PAI-1 gene, PAI-1 is potently stimulated in TGFb signaling pathway (Fig. 2) [108]. Thus, it may be effective to target PAI-1 or genes involved in smad signaling pathway that regulates the PAI-1 expression via miR-143. Malignant carcinomas have elevated levels of CD44 expression, compared with normal tissues [109–111]. CD44 as a cell-surface glycoprotein is involved in many cellular processes including regulation of cell division, migration, survival, and cell-cell interactions. Since CD44 is the hyaluronic acid (HA) receptor, it plays a role in actin cytoskeleton movement and metastasis. Cells with high levels of CD44 expression show stronger HA binding and enhanced migration capability [112]. Recently, some studies have designated that interaction of certain extracellular matrix constituents (e.g. HA) with cells activates the cytoplasmic domain of several CD44 isoforms to bind to unique molecules in downstream oncogenic signaling pathways [112,113]. In addition, there is an important relationship between CD44-associated MMPs and production of active form of TGF-b. However, there is no evidence of a direct interaction between CD44 and TGF receptors during breast cancer development. TGF-type I receptor (RI) is closely related with CD44 in metastatic breast cancer cells. In addition, both HA and TGF-b have been shown to trigger CD44 phosphorylation in vivo. In summary, CD44v3 closely reacts with TGF-RI. The CD44v3-associated TGF-RIkinase can be activated by HA and TGFRI and lead to phosphorylation of smad proteins and breast cancer metastasis (Fig. 2). Thus, miR-143 can prevent the invasion and metastasis of NSCLC and breast cancer by targeting CD44v3 gene (Fig. 2). MiR-143 can also inhibit the migration and invasion in human osteosarcoma, bladder carcinoma and prostate cancer [114,115]. Fibronectin type III domain containing 3B gene (FNDC3B) is another gene that promotes metastasis through Smad/TGFb signaling pathway. FNDC3B as a member of fibronectin family is another target of miR-143. FNDC3B promotes metastasis through TGFb-mediated pathway. It was shown that overexpression of this gene induces the smad/TGFb signaling pathway. Hence, the miR143 upregulation can reduce metastasis by suppressing FNDC3B and TGFb pathway [116,117]. Some of the previous researches indicated a relationship between the miR-143 and clinicopathological features of some cancers such as PCa. These findings revealed that miR-143 downregulation is associated with bone metastasis and poor prognosis in PCa patients [118]. PAI-1: plasminogen activator inhibitor-1. Limk-1: Lim domain kinase-1. 6. Apoptotic target genes of miR-143 in cancer Apoptosis is a programmed cell suicide which is responsible for controlled cell proliferation and establishment of homeostasis in adults by eliminating the unwanted cells. Apoptosis is characterized by a variety of morphologic changes in the cytoplasm and nucleus such as chromatin condensation, pyknosis (reduction of cell volume and nuclear fragmentation) and biochemical changes including DNA and protein breakdown and caspase activation [126–128]. MiRNAs have recently been shown to regulate essential cellular processes such as apoptosis which are changed in some tumors. During intrinsic apoptosis, the process that leads to downstream caspase activation is sometimes suppressed by antiapoptotic proteins such as BCL2 family members. Since miR-143 downregulates anti-apoptotic Bcl-2, it can be considered in the treatment of the malignant cells which are resistant to apoptosis [17,18] (Table 3). Caspase 3 has been recognized to be involved in the development of cell death [129]. MiR-143-dependent apoptosis in osteosarcoma cells ishighly correlated with the activation of caspase 3 and caspase 9. The activity of caspase 3 is strongly related

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Fig. 2. Roles of miR-143 in metastatic pathways. a: Blocking EGFR by miR-143 inhibits the expression of MMP9 and metastasis. b: CD44 is the hyaluronic acid (HA) receptor; it plays a role in actin cytoskeleton movement and metastasis. Cells with high levels of CD44 expression show stronger HA binding and enhanced migration capability. CD44 promotes colocalization of ankyrinand CD44 in cholesterol-containing lipid rafts by directly binding to Ankyrin transmembrane cytoskeletal protein, and this colocalization acts as a key mechanism in regulating HA-mediated cytoskeleton function and tumor cell-specific behaviors (e.g., cell growth, cell survival and migration). MiR-143 inhibits metastasis by targeting CD44. c and d: TGFb can induce the binding of a Smad3/Smad4 nuclear complex to CAGA sequences in promoter regions of PAI-1. Thus, PAI-1 activating by this pathway or other mechanisms has led to invasion and metastasis. MiR-143 inhibits invasion and metastasis by directly targeting PAI-1 or suppressing of TGFb/smad signaling.

Table 3 The effect of miR-143 onsignaling pathway and apoptotic target genes in cancers. Target gene

Involved pathway

Cancer types

References

Bcl2 PARP, Bax, Bak, Bad, Caspase3 BAG3 PKCe p53 Cox-2

apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis

Lung cancer, cervical cancer, osteosarcoma osteosarcoma glioblastoma NSCLC Cervical cancer, colorectal cancer Gastric cancer

[18,132] [129] [136] [78] [15,17] [88]

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Fig. 3. Schematic drawing of miR-143 in apoptosis regulation. a: HIF-1a overexpression leads to decreased apoptosis and increased cell growth and angiogenesis through miR-143 downregulation. b: Suppressing IGFBP3 by MiR-143 can promote PI3K/Akt signaling and inhibit apoptosis. c: HIF-1a overexpression results in downregulation of miR-143 and subsequently reduces apoptosis. d and e: Following the increased expression of HIF-1a, angiogenesis increases and the expression of anti-angiogenic proteins decreases.

to its upstream signals, containing Bcl-2, Poly ADP ribose polymerase (PARP), Bak, Bax, and Bad (Fig. 3). Overexpression of cleaved PARP, Bad, Bax and Bak has been observed in cells treated with miR-143 mimics. The Bcl-2 family proteins exhibit genetic variations in many malignancies, assisting to avoid apoptosis by promoting anti-apoptotic and removing pro-apoptotic genes such as Bax, Noxa and Puma [130]. Additionally, similar to B-cell lymphoma-extra large (Bcl-xl), Bcl-2-associated death promoter (Bad), are crucial members of the Bcl-2 family, participating in anti-apoptotic signaling [131]. Thus, miR-143 reduces survival by triggering caspase3 activation, and hence Bcl-2 plays a critical role [129]. Targeting miR-143 expression is the anti-apoptotic function proposed for Bcl-2. Thus, inhibition of Bcl-2 by miR-143 was recognized to be a novel therapeutic approach in the treatment of cancer [132]. MiR-143 was shown to prompt apoptosis in osteosarcoma cells by caspase3-mediated Bcl-2 inhibition. In addition, the overexpressed Bcl-2, in turn, induces cell cycle arrest in S phase, whereas it interferes with the cell cycle arrest in G0/G1 phase [132,133]. MiRNAs also play important roles in the regulation of apoptosis by p53. P53 gene is located on chromosome 17 (17p13.1). Activation of p53 can occur in response to hypoxia, DNA damage and stress conditions for different groups of genes which may prompt DNA repair, senescence, apoptosis and cell cycle arrest. MiRNAs regulate apoptosis through interaction with p53 and its transcriptional

network. This happens by controlling the upstream regulation of p53 [15,134]. BAG family molecular chaperone regulator (BAG3) belongs to the co-chaperone family which involves the BAG (Bcl-2-Associated Athanogene) domain. This protein has been shown to contribute in the regulation of intrinsic apoptotic pathway [135]. BAG3 is biochemically and functionally related to Bcl-2, heat shock proteins (Hsps) and receptors of steroid hormones which are involved in the modulation of apoptosis. Thus, restoration of miR-143 expression can result in decreased BAG3 expression in human glioblastoma stem cells [136]. Another target of miR-143 is PKCe, an anti-apoptotic and pro-proliferative enzyme that can improve the Bcl-2 phosphorylation and assist the cells to evade apoptosis. Moreover, PKCe can activate PKB/AKT signaling to increase survival. As a result, restoration of miR-143 expression to normal levels can be an expected therapeutic method for cancers with high PKCe expression [78]. ARNT: aryl hydrocarbon receptor nucleartranslocator, also known as HIF-1b. 7. Conclusions and future prospective Based on the information provided about genes targeted by miR-143 in different cancers, it can be deduced that there is a correlation between these targets and downstream signaling events. To such an extent that dysregulation of miR-143 due to mutations, epigenetic modifications and interaction with

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