Wnt-regulating microRNAs role in gastric cancer malignancy

Journal Pre-proof Wnt-regulating microRNAs role in gastric cancer malignancy

Milad Ashrafizadeh, Hossein Rafiei, Reza Mohammadinejad, Tahereh Farkhondeh, Saeed Samarghandian PII:

S0024-3205(20)30295-2

DOI:

https://doi.org/10.1016/j.lfs.2020.117547

Reference:

LFS 117547

To appear in:

Life Sciences

Received date:

11 January 2020

Revised date:

6 March 2020

Accepted date:

11 March 2020

Please cite this article as: M. Ashrafizadeh, H. Rafiei, R. Mohammadinejad, et al., Wntregulating microRNAs role in gastric cancer malignancy, Life Sciences (2020), https://doi.org/10.1016/j.lfs.2020.117547

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© 2020 Published by Elsevier.

Journal Pre-proof Wnt-regulating microRNAs role in gastric cancer malignancy Milad Ashrafizadeh1, Hossein Rafiei2, Reza Mohammadinejad3, Tahereh Farkhondeh4, Saeed Samarghandian5* 1

Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz,

Iran 2

Department of Biology, Faculty of Sciences, Shiraz Branch, Islamic Azad University, Shiraz,

Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of

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Iran

Medical Sciences, Kerman, Iran

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Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran

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5

Correspondence: Saeed Samarghandian, Department of Basic Medical Sciences, Neyshabur

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University of Medical Sciences, Neyshabur, Iran, Email: [email protected]

Abstract

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Gastric cancer (GC) is responsible for high morbidity and mortality worldwide. This cancer

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claims fifth place among other cancers. There are a number of factors associated with GC development such as alcohol consumption and tobacco smoking. It seems that genetic factors play significant role in GC malignancy and progression. MicroRNAs (miRs) are short noncoding RNA molecules with negative impact on the expression of target genes. A variety of studies have elucidated the potential role of miRs in GC growth. Investigation of molecular pathways have revealed that miRs function as upstream modulators of Wnt signaling pathway. This signaling pathway involves in important biological processes such as cell proliferation and differentiation, and its dysregulation is associated with GC invasion. At the present review, we demonstrate that how miRs regulate Wnt signaling pathway in GC malignancy. Keywords: MicroRNAs, Gastric cancer, Cancer therapy, Wnt, Signaling pathway

Journal Pre-proof 1. Introduction Gastric cancer (GC) is one of the most malignant cancers with high morbidity and mortality. This cancer claims the fifth place among other cancers [1-4]. It seems that annually, more than 500,000 new cases are diagnosed with GC [5, 6]. Studies demonstrate that GC has high incidence rate in some areas such as Asia, Korea, Japan and China [7]. Based on the high prevalence of GC, it is considered as one of the most important health issues. A variety of factors contribute to the development of GC and Helicobacter pylori infection, alcohol consumption and tobacco smoking as well as inappropriate diet are among them [8, 9]. The World Health

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Organization (WHO) has divided GC into five categories such as papillary, tubular, mucinous,

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signet-ring cell and mixed carcinoma [10]. Surgery and chemotherapy are common strategies in GC therapy. However, the metastasis and recurrence challenge these methods [11]. Over the past

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decades, an improvement has been made in diagnostic tools that has enhanced our understanding of genetic factors involved in GC malignancy and progression.

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As short non-coding RNA molecules, microRNAs (miRs) have a length as low as 24 nucleotides

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that exert inhibitory effect on the expression of target genes [12-14]. MiRs affect the target genes at post-transcriptional level [15]. Accumulating data demonstrate that miRs play a significant role in various main biological processes including differentiation, apoptotic cell death,

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proliferation and metabolism [16]. In respect to the modulatory impact of miRs on expression, they have improved our comprehension towards regulation of protein expression [17-20]. The

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mRNA degradation, mRNA destabilization and translation inhibition are the strategies that miRs

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follow to negatively affect the expression of target genes [21]. It seems that miR dysregulation is associated with a number of pathological conditions, particularly cancer [22-26]. Hence, miR regulation is of importance in the field of cancer therapy. It has been reported that abnormal expression of miRs remarkably affects the viability, proliferation capability and metastasis of cancer cells [27-29]. Overall, miRs are divided into two characteristic categories in the field of cancer: A) oncogenic miRs that enhance the malignancy of tumor cells, and B) oncosuppressor miRs that are associated with cancer inhibition [30]. It is held that miRs are able to sensitize tumor cells to chemo- and radiotherapy showing the potential role of miRs in cancer therapy [3133].

2. Wnt signaling pathway

Journal Pre-proof Wnt signaling pathway includes 18 ligands and 10 receptors that have important rules in different processes including embryogenesis, homeostasis, cell growth, cell proliferation, cell migration and cell survival [2, 34-40]. Wnt1 gene is the first Wnt gene that was introduced in 1982 while working on Drosophila melanogaster [41]. Any impairment in Wnt signaling pathway is related to the generation of pathological conditions [42-44]. A number of studies have elucidated the role of aberrant Wnt signaling pathway in cancer progression and malignancy [45, 46]. So, targeting this molecular pathway is of importance in cancer therapy. Wnt signaling pathway is divided into two subsets including canonical or -catenin-dependent pathway, and

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non-canonical or -catenin-independent pathway [47]. In canonical pathway, a complex known

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as “destruction complex” contributes to the degradation of -catenin upon physiological condition. “Destruction complex” contains adenomatous polyposis coli (APC), Dishevelled

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(Dvl), casein kinase 1 (CK1) and Axin1/Axin2 that phosphorylate -catenin leading to its

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degradation by glycogen synthase kinase-3 (GSK-3) [48-50]. After the attachment of Wnt ligand to the membrane receptor, Frizzled (Fzd) and low-density lipoprotein receptor-associated

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protein 5/6 (LRP5/6) undergo induction to trigger Wnt signaling pathway. Then, a disruption occurs in the “destruction complex” by stimulation of Dvl and consequently, leads to the GSK-

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3 inactivation. Next, high amount of -catenin accumulates in the cytoplasm and then, translocates to the nucleus to induce the expression of target genes by interacting with lymphoid

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enhancer binding factors (LEF) and T-cell factors (TCF) [51, 52]. The non-canonical pathway is divided into two classes including Wnt/Ca2+ pathway, and planar cell polarity (PCP) pathway

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[53-55]. It seems that Wnt5a is the major ligand of non-canonical pathway. Wnt/Ca2+ pathway involves in migration, cell adhesion and cytoskeletal rearrangement. The Wnt/Ca2+ signaling pathway undergoes upregulation by calcium signaling stimulation through phospholipase C/protein kinase C (PKC)/Ca2+ and calmodulin-sensitive protein kinase II (CaMKII) resulting in induction of nuclear factor associated with T cells (NFAT) [56-58]. However, upon PCP signaling pathway, binding of Wnt ligand to Fzd receptor stimulates Dvl. Activated Dvl induces Rho/Rho-associated kinase and Rac/c-Jun N-terminal kinase (JNK) as well as actin polymerization. It appears that PCP pathway plays a remarkable role in cell polarization and motility [59-62]. It seems that Wnt signaling pathway dysregulation is one of the principal causes of cancer due to its critical role in important biological processes. The anti-tumor activity of some of the drugs is

Journal Pre-proof a consequence of their modulatory impacts on Wnt signaling pathway. Upregulation of Wnt signaling pathway improves the proliferation and malignancy of triple negative breast cancer (TNBC) cells. Oxymatrine remarkably inhibits the progression of TNBC cells by downregulation of Wnt signaling pathway [63]. The same story occurs in colorectal cancer. Guanylate-binding protein-1 (GBP-1) elevates the efficacy of chemotherapy by inhibition of Wnt signaling pathway [64]. Long non-coding RNAs (lncRNAs), miRs and signaling pathways such as Hedgehog function as upstream modulators of Wnt pathway to suppress the progression and invasion of cancer cells [65-68]. Receptor for activated C kinase 1 (RACK1) is suggested to be

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influential in treatment of GC. Stimulation of RACK1 is associated with reduced malignancy of

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GC cells by Wnt inhibition [69]. Besides, family with sequence similarity 83, member D (FAM83D) promotes the growth of GC cells and is related to the poor prognosis of patients with

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GC due to enhancing the expression of Wnt//-catenin signaling pathway [70]. These studies highlight that Wnt pathway dysregulation occurs in cancer and this aberration is also of

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importance in GC therapy.

3. Interaction between microRNAs and Wnt pathway in cancer cells

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There are a number of phases involved in miR biogenesis [71-73]. This biogenesis is started in nucleus by transcription of miR via RNA polymerase II leading to the formation of primary-miR

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(pri-miR) .[74] Then, double stranded RNA-binding protein DiGeorge syndrome critical region 8 (DGCR8) and RNase III endonuclease Drosha involve in synthesis of a shorter miR from pri-

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miR known as precursor-miR (pre-miR) [75]. Exportin 5 (Exp5) contributes to the translocation of pre-miR from nucleus to cytoplasm [76]. Noteworthy, a mature miR with the length as low as 19-24 nucleotides is produced through the action of Dicer enzyme [77]. To be functionalized, mature miR is embedded into RNA-induced silencing complex [78] including Argonaute 2 (Ago2) protein, transactivating response RNA-binding protein (TRBP), protein kinase Ractivating protein (PACT) and Dicer [79]. Several studies have investigated the interaction between miRs and Wnt/-catenin signaling pathway in cancer cells. It appears that miRs affect Wnt pathway in following steps: A) affecting the translocation of -catenin from cytoplasm to nucleus [80]; B) down-regulation/upregulation of target genes of Wnt pathway [81], C) regulation of upstream modulators [40, 82, 83], and D) influencing the expression of -catenin and Wnt [84-86].

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4. Wnt-regulating microRNAs 4.1 MiR-503 MiR-503 is considered as an oncosuppressor miR that reduces the progression of tumor cells. It seems that miR-503 down-regulation is associated with enhanced malignancy of non-small celllung cancer (NSCLC) cells [87]. Besides, miR-503 diminishes the viability of osteosarcoma cells via targeting L1CAM [88]. The same story occurs in hepatocellular carcinoma and miR-503 is able to modulate cancer invasion [89]. Accumulating data demonstrates that miR-503 can be

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beneficial in treatment of GC [90, 91]. Investigation of molecular signaling pathways shows that

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miR-503 is able to significantly inhibit the viability and malignancy of GC cells by Wnt down-

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regulation through enhancing GSK-3 and phosphorylated (p)--catenin [92].

4.2 MiR-675

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Paired-like homeodomain transcription factor 1 (PITX1) is considered as a tumor suppression

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transcription factor and its minimal expression is related to the poor prognosis of patients with cancer [93-95]. MiR-675 is responsible for high viability and proliferation of GC cells. It is

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suggested that miR-675 reduces the expression of PTX1. The down-regulated PTX1 is associated with stimulation of Wnt/-catenin signaling pathway leading to the induction of

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epithelial-to-mesenchymal transition (EMT) and subsequently, an increase in invasion and migration. It was found that the expression of cyclin D1 and c-Myc undergo upreglation under

4.3 MiR-204

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Wnt pathway activation [96].

Plant-derived chemicals are potential candidates in treatment of cancers [97-99]. It has been demonstrated that naturally occurring compounds are able to target various signaling pathways in cancer therapy [100-102]. Sinomenine (SIN) is a plant-derived chemical alkaloid with the capability of suppressing the proliferation and metastasis of cancers [103-108]. SIN is capable of reducing the migration and malignancy of GC cells by inhibition of Wnt signaling pathway through down-regulation of Wnt3a and -catenin. It seems that these anti-tumor effects of SIN are mediated through miR-204 upregulation [109].

Journal Pre-proof 4.4 MiR-17HG MiR-17HG is a pri-miR located in the 800-base-pair region of human chromose 13 that involves in production of six main miRs including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1 [110]. A number of studies have revealed that miR-17HG contributes to the metastasis of cancer cells and its members undergo upregulation in various cancers such as colorectal cancer and pancreatic cancer [78, 111, 112]. On the other hand, IRF-1 plays a significant role in some biological processes such as proliferation and differentiation [113, 114]. IRF-1 dysregulation occurs in GC and leukemia [115]. IRF-1 binds to the transcriptional site at the

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miR-17HG promoter to down-regulate miR-18a and miR-19a resulting in inhibition of Wnt

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signaling pathway and GC malignancy [116].

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4.5 MiR-876-5p

MiR-876-5p is a potential oncosuppressor miR that involves in sensitizing tumor cells to

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chemotherapy, inhibition of EMT and suppressing the proliferation of cancer cells [117-122].

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Investigation of molecular signaling pathways in GC has shown that miR-876-5p is able to bind to the 3/ untranslated region (3/ UTR) of Wnt5a resulting in an increase in apoptotic cell death

4.6 MiR-188-5p

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and a decrease in cell viability and progression [123].

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Another important oncosuppressor factor is miR-188-5p that has demonstrated great potential in

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inhibition of NSCLC, glioma and so on [124-127]. In contrast, it seems that miR-188-5p is associated with poor prognosis of patients with GC. MiR-188-5p phosphorylates GSK-3 at serin9 (Ser9) leading to the invasion and metastasis of GC both in vitro and in vivo [128].

4.7 MiR-15a-3p Zinc proteins play a remarkable role in cell growth, cell proliferation, cell differentiation and synthesis of genetic material [129, 130]. Zinc influx (SLC39/ZIP) and zinc efflux (SLC30/ZnT) are two important zinc proteins in mammals [131]. SLC39A7 is a member of zinc proteins [132]. Accumulating data demonstrates that SLC39A7 mediates the resistance of tumor cells to chemotherapy and is associated with proliferation and malignancy of cancer cells. MiR-15a-3p exerts inhibitory impact on the metastasis and invasion of GC cells by suppressing the nuclear

Journal Pre-proof translocation of -catenin. SLC39A7 undergoes inhibition under Wnt down-regulation leading to the good prognosis of patients with GC [133].

4.8 MiR-216a-3p BRD4 is a bromodomain and extra-terminal domain (BET) that has emerged as a therapeutic target in cancer therapy [134]. It seems that BRD4 overexpression is related to the EMT induction and tumor malignancy [135]. In GC, BRD4 seems to be involvement in GC progression by inhibition of Wnt3a. It has been reported that this inhibitory impact on the Wnt3a

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is mediated through miR-216a-3p upregulation [136].

4.9 MiR-23b-3p and miR-130a-5p

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Cannabinoid receptor 1 (CB1R) is a G-protein-coupled receptor and undergoes upregulation under the stimulation by endogenous ligands, anandmide and 2-arachidonoglycerol. It has been

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demonstrated that a plant-derived compound known as Cannabis sativa induces CB1R through

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its ligand delta-9-tetrahydrocannabinol [137, 138]. It seems that the abnormal expression of CB1R occurs in a number of tumors [139]. In GC cells, the expressions of oncosuppressor miRs,

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miR-23b-3p and miR-130a-5p significantly reduce resulting in upregulation of CB1R. The activated CB1R enhances the proliferation and malignancy of GC cells by stimulation of Wnt

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signaling pathway via upregulation of -catenin, c-Myc and cyclin D1 [140].

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4.10 MiR-29c-3p

KIAA1199 responsible for nonsyndromic hair loss is related to the proliferation and viability of cancer cells, and poor prognosis of patients with GC through EMT induction [141-146]. This stimulatory effect has been shown on the malignancy of GC cells [147]. Activation of KIAA1199 occurs in GC cells leading to the high progression, lymph node metastasis and inhibition of apoptosis in GC cells. Investigation of molecular signaling pathways exhibits that KIAA1199 enhances the malignancy of GC cells by upregulation of Wnt/-catenin signaling pathway through EGFR. It seems that activation of KIAA1199 occurs by down-regulation of miR-29c-3p [148].

4.11 MiR-141-3p

Journal Pre-proof Signal transducer and activator of transcription 4 (STAT4) is suggested to be involvement in invasion and metastasis of cancer cells [89]. A same story occurs in GC. It appears that STAT4 undergoes upregulation in GC leading to the induction of Wnt/-catenin signaling pathway via on of oncosuppressor miR to reduce the malignancy of GC cells and induce apoptotic cell death by STAT4 inhibition [149].

4.12 MiR-125b Although miRs function as upstream modulators of Wnt signaling pathway in tumor cells, it has

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been reported there are epigenetic factors regulating the function of miRs. KDM4 is a subfamily

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of dimethylases and accounts for controlling cell growth [150]. Accumulating data demonstrates that KDM4 upregulation considerably promotes the viability and proliferation of tumor cells

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through genomic instability [151]. More importantly, KDM4B increases the expression of miR125b. The induced miR-125b activates Wnt signaling pathway by upregulation of -catenin

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nuclear translocation [152].

4.13 MiR-375-3p

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As a oncosuppressor miR, the down-regulation of miR-375-3p occurs during cancer to ensure the progression of tumor cells [153, 154]. Noteworthy, YWHAZ seems to be a potential prognostic marker of various cancers and has a negative relationship with miR-375-3p [155-158]. YWHAZ

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stimulates Wnt signaling pathway by nuclear translocation of -catenin. MiR-375-3p induces

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apoptotic cell death in GC cells by inhibition of YWHAZ/Wnt axis [159].

4.14 MiR-142-5p

MiR-142 contains two major subsets including miR-142-3p as guide strand and miR-142-5p as passenger strand [160]. It seems that miR-142-5p suppresses apoptosis in cancer cells [161]. Besides, miR-142-5p has shown to enhance the proliferation of tumor cells via inhibition of TGF- signaling pathway [162]. These studies highlight the function of miR-142-5p as an oncogenesis miR. However, the strategy of miR-142-5p is a little different in GC, so that inhibition of miR-142-5p expression is associated with high proliferation capability of cancer cells. The inhibitory impact of this miR on GC cells is a result of Wnt pathway inhibition

Journal Pre-proof through CYR61. It seems that CYR61 enhances the nuclear translocation of -catenin and miR142-5p reduces the expression of CYR61 and subsequently, Wnt pathway [92].

4.15 MiR-106a-3p LncRNAs are RNA polymerase II transcripts with the size of 200 nucleotides [163]. During the past decades, much attention has been directed towards lncRNAs due to their critical roles in important biological processes. Aberration expression of lncRNAs is associated with development of pathological conditions, particularly cancer [164, 165]. LINCO1133 negatively

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affects the proliferation of GC cells. It has been demonstrated that LINCO1133 down-regulates

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the expression of miR-106a-3p resulting in inhibition of EMT and stimulation of apoptosis. It is suggested that by miR-106a-3p inhibition, LINCO1133 exerts inhibitory effect on the nuclear

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translocation of -catenin leading to the inactivation of Wnt/-catenin signaling pathway and

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reduced malignancy of cancer cells [166].

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4.16 MiR-361-5p

Studies show that EMT plays a significant role in tumorigenesis by transformation of epithelial

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phenotype into mesenchymal one [167-169]. A number of molecular alterations occur during EMT induction. The expression of epithelial markers such as E-cadherin undergo down-

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regulation, while mesenchymal markers show high expression [170, 171]. Inhibition of EMT is a great strategy in cancer therapy. MiR-361-5p significantly diminishes the EMT by enhancing E-

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cadherin levels while reducing N-cadherin. It appears that miR-361-5p inhibits EMT by decreasing the expression of TCF4, cyclin D1 and c-Myc as targets of Wnt signaling pathway [172].

5. Wnt and miRs interactions It seems that miRs have a great potential in regulation of Wnt signaling pathway. This regulation occurs in several stages as following: A) affecting GSK-3; B) upregulation/down-regulation of -catenin nuclear translocation; C) influencing the expression of -catenin and target genes such as cyclin D1 and c-Myc; D) affecting Wnt ligands such as Wnt1, Wnt3a and Wnt5a; and E) regulation of upstream modulators of Wnt signaling pathway such as Smad4, NKD1, TRIM24 and TRIMP29 (Figure 1).

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6. Conclusion and remarks Accumulating data demonstrates that Wnt signaling aberration is associated with a number of pathological conditions, particularly cancer. Much attempt has been made in regulation of this important signaling pathway. In respect to the potential role of miRs in various important biological processes such as cell proliferation, cell growth and cell differentiation as well as apoptotic cell death, we concluded that Wnt signaling pathway may be a target of miRs. It was found that miRs based on their roles as being oncosuppressor or oncogenesis dually affect Wnt

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signaling pathway to ensure the proliferation and malignancy of GC cells, while oncosuppressor

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miRs negatively affect Wnt signaling pathway to suppress GC invasion. However, more studies are needed to identify other miRs with their modulatory impact on Wnt signaling pathway.

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Competing interests: The authors declare no conflict of interest. Funding: Not applicable

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Ethical approval and consent to participate: Not applicable

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Availability of supporting data: Not applicable

Authors' contributions: Study conception and design: S. S. and M.A. Acquisition of data: T.F., H.R. and R. M. Drafting of the manuscript: M. A., H.R. and R.M. Critical revision: S. S.

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Abbreviations:

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Acknowledgements: Not applicable

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GC, gastric cancer; WHO, World Health Organization; miR, microRNA; APC, adenomatous polyposiscoli; Dvl, dishevelled; CK1, casein kinase 1; GSK-3, glycogen synthase kinase-3; Fzd, Frizzled; LRP5/6, low-density lipoprotein receptor-associated protein 5/6; LEF, lymphoid enhancer binding factors; TCF, T-cell factors; PCP, planar cell polarity; PKC, protein kinase C; CaMKII, calmodulin-sensitive protein kinase II; NFAT, nuclear factor associated with T cells; JNK, c-Jun N-terminal kinase; TNBC, triple negative breast cancer; GBP-1, guanylate-binding protein-1; lncRNAs, long non-coding RNAs; RACK1, receptor for activated C kinase 1; FAM83D, family with sequence similarity 83, member D; pri-miR, primary-miR; DGCR8, DiGeorge syndrome critical region 8; pre-miR, precursor-miR; Exp5, Exportin 5; Ago2, Argonaute 2; TRBP, transactivating response RNA-binding protein; PACT, protein kinase Ractivating protein; NSCLC, non-small cell lung cancer; PITX1, paired-like homeodomain

Journal Pre-proof transcription factor 1; EMT, epithelial-to-mesenchymal transition; SIN, sinomenine; 3/ UTR, 3/ untranslated region; Ser9, Serin9; CB1R, cannabinoid receptor 1; STAT4, signal transducer and activator of transcription 4.

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Zhang, X., et al., SMG‐1 inhibition by miR‐192/‐215 causes epithelial‐mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling. Cancer medicine, 2018. 7(1): p. 146-156.

181.

Huang, T., et al., SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis. Oncogene, 2018. 37(9): p. 1159.

182.

Zhang, L., et al., SLC34A2 regulates miR‐25‐Gsk3β signaling pathway to affect tumor progression in gastric cancer stem cell‐like cells. Molecular carcinogenesis, 2018. 57(3): p. 440-450.

183.

Cheng, C., et al., Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/β-catenin signaling pathways by up-

of

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184.

-p

Twist1 and inhibits Wnt/β-catenin signaling pathway. American journal of translational research, 2017. 9(8): p. 3654.

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re

185.

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186.

Journal of Experimental & Clinical Cancer Research, 2017. 36(1): p. 17. Fan, D., et al., Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and

na

187.

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Table 1: Wnt-regulating miRs in gastric cancer malignancy. MiR

Cell line

Effect

on Interaction

Major outcomes

Refs

Journal Pre-proof Wnt pathway

MiR876-5p

MiR-188-5p

Inhibition

Induction

Inhibition

Jo

MiR-195-5p

GC cells

MiR-216a3p

Gastric cancer cell lines Inhibition AGS, BGC-823, MKN-45, MGC-803, SCG-7901 GC cell lines, BGC823, Inhibition MGC803, SGC7901, AGS and N87

MiR-142-5p

MiR-106a3p

of

ro

Induction

ur

MiR-15a-3p

Human GC cell lines (MKN45, AGS and SGC7901) Human GC cell lines (MGC803, MKN-45, MKN-28) Human GC cell lines (MKN74, AGS, KATOIII, NUGC3, MGC803, MKN45, and HGC27) Tumor xenografts Human PCa cell lines, including PC3, DU145, LNCaP, and 22Rv1

-p

MiR-17HG

Inhibition

Human GC cell lines Induction (SUN-216, BGC-823, AGS, BGC-803, NUGC4,

DownSuppressing the migration and regulation of invasion of cancer cells Wnt3a and catenin Expression of Enhancing the malignancy of Wnt cancer cells by stimulation of Wnt signaling pathway DownInhibition of EMT and regulation of reducing the proliferation and Wnt5a migration of cancer cells Enhancing the Enhancing the migration and level of p-GSK- invasion of cancer cells 3

re

MiR-204

Enhancing the Promoting the progression and [173] nuclear induction of EMT translocation of -catenin

lP

MiR-675

Human GC cell lines Inhibition MKN-45, BGC-823, SGC7901, MKN-28, and AGS Xenograft tumor model Human gastric normal Induction epithelial mucosa cell line GES-1 and GC cell lines (MGC-803, SGC-7901 and AGS) GC cells of AGS, MKN28, Inhibition MKN45 and SGC‐7901

na

MiR-503

between miR and Wnt pathway Elevating GSK- Suppressing the proliferation [152] 3 and p-- and invasion of cancer cells catenin

Downregulation nuclear catenin translocation Inhibition of catenin expression Inhibition Wnt3a

[174]

[175]

[123]

[176]

Inhibition of Wnt pathway [133] of results in down-regulation of - SLC39A7 and subsequently, decreased migration and viability of cancer cells - Induction of apoptotic cell [177] death of Reducing the progression and [136] malignancy of cancer cells

Downregulation of nuclear catenin translocation Enhancing the nuclear translocation of

Induction of apoptotic cell [92] death and reducing the migration capability

Elevating EMT and inhibition [166] of apoptosis

Journal Pre-proof

MiR-630

Human gastric cancer cell Induction lines SGC-7901, BGC-823, MGC803

MiR-214

GC tissues

MiR-302b

Human gastric Inhibition adenocarcinoma cell line SGC-7901

lP

cell

lines Induction

Inhibition

Jo

ur

MiR-340 GC cell lines and miR124

-p

Inhibition

na

MiR-192 Human GC and miR- BGC‐823 215

MiR-25

Animal models patients with GC

and Induction

MiR-324-3p

GC cells and tissues

Induction

MiR-34a

GC cell lines

Inhibition

Inactivation of Wnt signaling [172] pathway suppresses EMT mechanism

Inhibition of growth, invasion [26] and migration of cancer cells

Suppressing the EMT and [178] stimulation of apoptosis

of

Human gastric carcinoma Inhibition cell line NCI-N87

ro

MiR-3200

Reducing the expression of targets genes such as cyclin D1 and c-Myc Downregulation of catenin, Wnt3a and Wnt5a Upregulation of -catenin, Wnt3a and Wnt5a Downregulation of GSK-3 Decreasing the expression of catenin

re

MiR-361-5p

-catenin

MKN74, MKN45, SGC7901, and HGC-27) GC cell lines (SGC-7901, Inhibition MGC-803, MKN-28, TMK-1)

Enhancing the expression of target genes such as cyclin D1 Downregulation of nuclear catenin translocation Downregulation of GSK-3

Smad4/Wnt signaling pathway stimulation Downregulation of catenin and Wnt1

Promoting the proliferation of [178] cancer cells and inhibition of apoptosis Prevention of EMT [179] mechanism and subsequently, inhibition of invasion and metastasis Induction of EMT and [180] promoting the viability of cancer cells

Down-regulation of signaling pathway suppressing SRGAP1

Wnt [181] by

SLC34A2 enhances the [182] malignancy of GC cells by down-regulation of miR-25 leading to the activation of Wnt signaling pathway Stimulation of an increase in [163] cell growth and migration, and a decrease in apoptosis HOTAIR induces [183] chemotherapy resistance in GC cancer cells by inhibition of miR-34a and subsequently, stimulation of Wnt signaling

Journal Pre-proof

Human GC cell lines Inhibition (SGC-7901, BGC-823, SGC-7901 and HGC-27) GC cell lines AGS, HGC- Inhibition 27, KATO III, HGC-27, 108 and NCI-N87 GC tissues GC tissues and cells Induction

MiR-149-3p

Transgenic mice

MiR-544a

GC cell line, MKN1

MiR-185

GC-derived MGC803

MiR-200b and miR-22

MGC-803 cells

Inhibition

of

MiR-501-5p

GC tissues Inhibition Human gastric cancer cell lines (AGS, BGC823, MGC803, HGC-27and SGC7901) GC cells and tissues Induction

na ur

line Inhibition

Jo

cell

Induction

Inhibition

Suppressing the proliferation [185] and invasion of cancer cells through FBN1/Wnt axis

MiR-532 exerts inhibitory [168] effect on the NKD1 to induce Wnt signaling pathway resulting in increased cancer progression DownInhibition of Wnt signaling [186] via TRIM24 regulation of - pathway catenin, cyclin inhibition leading to the decreased cancer malignancy D1 and c-Myc

lP

MiR-511

Downregulation GSK-3 Downregulation Wnt1

Promoting the malignancy of [187] of cancer cells through Wnt induction Attenuation of inflammatory [188] of microenvironment and induction of apoptosis by inhibition of Wnt signaling pathway Upregulation of Induction of EMT [189] nuclear catenin translocation DownMiR-185 inhibits TRIMP29 to [190] Wnt pathway regulation of - suppress resulting in decreased catenin, cyclin malignancy of cancer cells D1 and c-Myc DownStimulation of apoptosis and [191] regulation of inhibition of proliferation Wnt1

Figure 1. Regulation of Wnt signaling pathway by miRs in GC cells. MiR, microRNA; APC, adenomatous polyposiscoli; Dvl, Dishevelled; CK1, casein kinase 1; GSK-3, glycogen synthase kinase -3.

Graphical abstract

[184]

ro

MiR-532

Downregulation of catenin and Wnt1 Upregulation of nuclear catenin translocation

-p

MiR-133b

re

MiR-519d

pathway Upregulation of Inhibition of EMT mechanism p-GSK-3

Figure 1