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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 1  |  Page : 17-27

An interplay between MicroRNA and SOX4 in the regulation of epithelial–mesenchymal transition and cancer progression

1 Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Anatomy, All Institute of Medical Sciences, New Delhi, India
3 Department of Biotechnology, I.P. College, Bulandshahr, Uttar Pradesh, India

Date of Submission15-Jan-2018
Date of Acceptance14-Feb-2018
Date of Web Publication26-Feb-2018

Correspondence Address:
Dr. Deepak Parashar
Department of Obstetrics and Gynecology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_4_18

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MicroRNAs (miRNAs) are abundant class of small, noncoding RNAs which are emerging as a potential therapeutic target for various cancers. Sex-determining region Y-related high-mobility group box 4 (SOX4) is an important member of SOX family and a crucial master regulator of epithelial–mesenchymal transition (EMT) that has been implicated in tumor growth and progression. In cancers of epithelial origin and in some others, growing evidence has revealed a close association between miRNAs and SOX4. Most miRNAs are reported to modulate SOX4 by directly binding to SOX4 3'-untranslated region, thereby regulating cancer cell proliferation, invasion, and EMT. In this review, we highlight the interaction of miRNAs with SOX4 in various cancers and discuss the possibility of combined miRNA-SOX4-based therapeutic approach that may serve as a targeted therapy for several cancers.

Keywords: Cancer, epithelial–mesenchymal transition, microRNA, SOX4

How to cite this article:
Geethadevi A, Sharma A, Sharma MK, Parashar D. An interplay between MicroRNA and SOX4 in the regulation of epithelial–mesenchymal transition and cancer progression. Cancer Transl Med 2018;4:17-27

How to cite this URL:
Geethadevi A, Sharma A, Sharma MK, Parashar D. An interplay between MicroRNA and SOX4 in the regulation of epithelial–mesenchymal transition and cancer progression. Cancer Transl Med [serial online] 2018 [cited 2018 Dec 14];4:17-27. Available from: http://www.cancertm.com/text.asp?2018/4/1/17/226171

  Introduction Top

Metastasis is the primary cause of mortality and morbidity in various types of cancers. It is a complex process, during which cancer cells disseminate from primary tumor through the circulation and establish their growth at distant organs. In comparison to benign tumors, metastatic tumors are difficult to remove by surgical resection and/or by irradiation, are resistant to treatment with chemotherapeutic drugs, and hence often have poor prognosis. Besides, chemotherapeutics are developed in such a way to target proliferation of cancer cells rather than dissemination. Hence, there is an utmost need to develop potential therapeutics, targeting or inhibiting the metastasis of cancer cells.

  Epithelial–Mesenchymal Transition: A Critical Player in Metastasis Top

Despite various advancements in therapeutics, recurrence due to metastasis remains a common issue for cancer patients. Cancer recurrence and metastasis are often associated with epithelial–mesenchymal transition (EMT). EMT is a significant regulatory process during normal embryogenesis as well as in cancer progression and metastasis,[1] wherein differentiated epithelial cells change to dedifferentiated and migratory mesenchymal state.[2],[3] EMT is often displayed by cancer stem cells (CSCs) which are self-renewing and heterogeneous population of cells that usually remain in resting phase, thus chemoresistant.[4],[5],[6],[7] Hence, there is an urgent need of prognosis detecting EMT – a characteristic of CSCs – and thereby regulating metastatic growth and mortality. EMT is characterized by several hallmark processes such as loss of cell–cell adhesion and downregulation of epithelial markers such as E-cadherin expression and components of tight junction[8] and increase in mesenchymal markers such as N-cadherin and vimentin expression. These events occur in conjunction with the upregulation of several transcription factors such as Snail, Twist, SOX, and ZEB by regulating epithelial and mesenchymal markers at transcriptional level. Snail1 induces EMT by inhibiting other epithelial markers that affect E-cadherin and bind to the E-cadherin promoter to inhibit its transcription. Twist induces EMT by repressing E-cadherin by inducing Snail1 or Snail2 followed by binding to its promoter. The ZEB family which includes ZEB1 and ZEB2 induces EMT by activating mesenchymal markers such as N-cadherin and vimentin and repressing epithelial markers E-cadherin, gap junctions by binding to E-box sequences in the E-cadherin promoter, and recruiting co-repressors such as SWI/SNF, NuRD, and CtBP. SOX transcription factors synergize with SNAIL1 or SNAIL2 in promoting EMT.[9] Furthermore, the key signaling pathway regulating EMT is the transforming growth factor-β (TGF-β) pathway. TGF-β is produced by immune and nonimmune cells and induces EMT in Smad dependent and independent pathway which eventually regulates Snail and Twist at transcriptional level. The oncogenic consequences of TGF-β during late tumorigenesis that eventually leads to EMT are mediated by PI3K/Akt axis. Other pathways that integrate with TGF-β to induce EMT are Wnt/-β-catenin, Notch pathway, and integrin-linked kinase (ILK) and integrin signaling pathway.[9]

  SOX4 As A Master Regulator of Epithelial–Mesenchymal Transition and its Role in Cancer Progression Top

Sex-determining region Y-related high-mobility group box 4 (SOX4) is one of the master transcription factors, which regulates EMT and contributes to cell survival and metastasis[10],[11] by TGF-β-induced upregulation of mesenchymal EMT markers such as vimentin and N-cadherin[12],[13],[14] and loss of epithelial markers such as E-cadherin [Figure 1] via transcription factor repressors – Snail, ZEB, and Twist,[15] or via an epigenetic regulator – polycomb-group protein enhancer of zeste homolog 2 (EZH2).[13],[16]
Figure 1: Interplay between SOX4 and microRNA in epithelial–mesenchymal transition in cancer. Red arrows: Overexpression of gene expression or protein expression. Green arrows: Downregulation of gene expression or protein activity

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SOX4 is a 47-kDa protein member of the Sex-determining region Y-related high-mobility group box (SOX) transcription factor family,[17] and the gene is located on chromosome 6p22.3 which encodes a protein of 474 amino acids with three distinct domains: an high-mobility group (HMG) box-DNA-binding region, a glycine-rich region which is a novel functional region for promoting apoptotic cell death, and a serine-rich region that acts as a transactivation domain [Table 1].[18],[19] SOX4 is a necessary transcription factor in many embryonic development processes such as the thymocyte differentiation, B-cell development,[20] T-cell development,[21] pancreatic cell differentiation,[22] osteoblast differentiation,[23] in the development of nervous system and embryonic cardiovascular system,[20],[24] and survival of multipotent neural cells and mesenchymal stem cells,[25] thereby functioning as a putative stem cell marker crucial for cell fate determination.[19] Many genes that are involved in embryogenesis have also been implicated in tumorigenesis. Among the 20 members of SOX family, SOX4 has been recognized as a “cancer signature gene”[26] based on its oncogenic role in multiple human cancers; majority having epithelial origin such as in breast cancer, ovarian cancer, lung cancer, hepatocellular carcinoma (HCC), and some others such as sarcomas [Figure 1].[27] In normal adults, expression of SOX4 is restricted to certain cell types, including hematopoietic stem cells, mammary stem cells, and hair follicle stem cells.[28],[29],[30] Of note, several lines of evidence suggest that SOX4 overexpression could promote tumor progression by inhibiting apoptosis, cell proliferation, and cell survival; expansion of CSCs; and initiation of EMT[19] through regulating transcription of genes involved in cancer signaling pathways such as Wnt/β-catenin pathway, Notch1 pathway, and p53 pathway[31],[32] [Figure 2] or by interaction with several microRNAs (miRNAs) components of miRNA processing machinery such as dicer, argonaute 1, and RNA helicase A.[26],[33] In contrast, SOX4 can also serve as a tumor suppressor which is evident from the fact that increased expression of SOX4 has been found to correlate with slower cancer progression, hence prolonged patient survival in bladder cancer, colon carcinoma, HCC, melanoma, and gallbladder cancer[19],[34],[35],[36] by inhibition of tumor initiation through DNA damage signaling or direct transcriptional regulation of dicer[37] and/or activation of apoptosis.[19] This differential expression of SOX4 in various tumor types may relate to either amplification of SOX4 chromosome loci such as in bladder and lung cancer[38],[39] or activity of signaling pathways such as TGF-β and Wnt, hormone regulation such as in breast cancer,[40] and posttranscriptional modifications or may occur through miRNA-mediated regulation of SOX4 mRNA stability and protein translation.[19]
Figure 2: SOX4/microRNA interaction in cancer. Red arrows: Overexpression of gene expression or protein expression. Green arrows: Downregulation of gene expression or protein activity. Red arrows: Inhibition of gene expression or protein activity

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Table 1: Different domains of sex determining region Y-box 4 with their functions and interaction partners

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  Micro-RNAs Directly Target SOX4 to Regulate Cancer Progression Top

miRNAs are small (18–25 nucleotides in length) class of endogenous noncoding RNAs that regulate gene expression by binding to 3'-untranslated region (3'-UTR) of their target messenger RNAs (mRNAs), thereby either degrading or suppressing their translation.[41] miRNAs are critical regulators of cell proliferation, differentiation, metabolism, and apoptosis in normal cells.[42] Deregulation of miRNAs such as downregulation or aberrant amplification/deletion of miRNA mapped to genomic loci has been implicated in tumorigenesis, making them either tumor suppressors or oncogenes, respectively.[43],[44] Most miRNAs have been observed to be downregulated in many human cancers.[45] Recent studies have demonstrated that miRNAs can modulate SOX4; moreover, SOX4 also regulates the expression of several miRNAs. Most of the miRNAs are reported to be downregulated in many cancers that causes an upregulation of SOX4. In this review, we provide a comprehensive overview of interactions between miRNAs and SOX4 and their roles in various cancers while focusing on how we can utilize this knowledge in developing novel cancer therapies. Functions of these miRNAs in cancer progression and metastasis are discussed below.


miR-338-3p is located on chromosome 17q25.3 on 7th intron of apoptosis-associated tyrosine kinase gene. Recent studies have identified that miR-338-3p is downregulated in gastric cancers,[46] ovarian cancer,[47] breast cancer,[48] colorectal cancers (CRCs),[49] highly metastatic non-small cell lung carcinoma (NSCLC) cells, and metastatic tissue specimens.[50] Recently, Sun et al.[51] reported that downregulated miR-338-3p enhanced proliferation and suppressed apoptosis in NSCLC by targeting RAB14. Overexpression experiments caused suppression of cancer cell migration, invasion, and EMT through directly targeting SOX4 on 3'-UTR and decreasing its mRNA and protein expression both in vitro and in vivo.[50] Of note, upregulation of miR-338-3p also reported to inhibit cell proliferation, migration, and invasion of renal cell carcinoma (RCC)[52] and breast cancer[48] and caused downregulation of SOX4, thereby modulating SOX4 mRNA and protein levels. The authors suggest that miR-338-3p and SOX4 expression are inversely correlated in NSCLC, RCC, and breast cancer. Furthermore, Li et al.[53] found that histone 3 (H3) lys27 (H3K27me3) methylation but not DNA methylation unlike in gastric cancer is activated in the promoter region of miR-338-3p, which is responsible for downregulation of miR-338-3p, suggesting an epigenetic regulatory mechanism of this miRNA in cancer progression.[50]


miR-25 is located on chromosome 7 (7q22.1) in the 13th intron of the MCM7 gene[54] and is a member of the miR-106b-25 cluster (consisting of miR-106b, miR-25, miR-93, miR-363-3p, and miR-367).[55] miR-25 functions as an oncogene in NSCLC,[56] breast cancer,[57] ovarian cancer,[58] cervical cancer,[59] and gastric cancer,[60] whereas it acts as a tumor suppressor in colon cancer[61] and glioblastoma multiforme.[62] Recent studies by Chen et al.[63] revealed that miR-25 acts as tumor suppressor which is evident from the fact that miR-25 is downregulated in osteosarcoma and is associated with advanced tumor–node–metastasis stage and lymph node metastasis. However, introduction of miR-25 by overexpression experiments showed suppression in cell proliferation, migration, and invasion of osteosarcoma cells in vitro and in vivo. This study also showed a direct association of miR-25 with SOX4 using bioinformatics analysis and luciferase reporter assay. Furthermore, this tumor suppression effects of miR-25 is partially reversed by SOX4 following interaction, thus suggesting an inverse correlation of miR-25 with SOX4 expression in osteosarcoma tissues.[63]


miR-138 is known to be frequently downregulated in CRC, esophageal cancer, bladder cancer, and NSCLC through PD-L1 downregulation, repression of EZH2 or targeting YAP1.[64],[65],[66] Recent studies showed that downregulated miR-138 is associated with increased expression of SOX4 and upregulation of miR-138 inhibited proliferation, invasion, metastasis, and EMT of NSCLC cells[66] and highly invasive ovarian cancer cells both in vitro and in vivo.[67] In addition, authors used bioinformatic analyses such as Target Scan and luciferase reporter assay to predict that SOX4 is a direct potential target of miR-138, which binds to 3'-UTR of SOX4 mRNA. Hence, based on this study, miR-138 negatively regulates SOX4. Furthermore, earlier studies reveal that SOX4 can suppress the effects of p53[32] as p53 being a downstream target of SOX4.[18] Li et al.[66] also demonstrated that in NSCLC cells, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Hence, introduction of miR-138 inhibited growth, invasion, and EMT of NSCLC cells through SOX4/p53 feedback loop. Similar results were shown by other studies in ovarian cancer providing substantial evidence of miR-138 to be used for suppression of NSCLC as well as ovarian cancer by targeting SOX4 via p53 [Figure 2].[66],[67]


Reports have identified miR-129-5p deregulation in some cancers such as esophageal cancers and chondrosarcoma,[68] which resulted in upregulation of SOX4. A recent study by Zhang et al.[68] demonstrated that overexpressed miR-129-5p caused suppression of cell proliferation, migration, and promoted apoptosis both in vitro and in vivo xenograft models by targeting SOX4 and causing its downregulation. Aberrant Wnt/β-catenin signaling has been observed in many cancers including chorndrosarcoma[69] and is associated with SOX4 in melanoma cells.[70] Moreover, miR-129-5p also inhibited over-activation of Wnt signaling components such as β-catenin, cyclin D1, and c-Myc by targeting SOX4 bringing about regulation of proliferation and migration in chondrosarcoma cells.[68]


miR-129-2 is located on chromosome 11 at locus 11p11.2.[71] miR-129-2 is often reported to be downregulated in bladder cancers, CRC,[72] β-catenin/TCF-mediated hepatocarcinoma,[73] gastric cancer,[74] endometrial cancer,[75] and esophageal cancer cells and adjacent nontumor tissues from patients who underwent primary surgical resection for esophageal cancer[8] and correlates with advanced TNM stage in esophageal cancers. This is further associated with increased expression of SOX4 and SOX4-mediated epigenetic silencing of miR-129-2. SOX4 is found to be inversely correlated with epigenetic repression of miR-129-2; however, restoration of miR-129-2 brought a downregulation of its direct target-SOX4 expression along with a reduction in migration, proliferation, and cell arrest of the cancer cells.[74],[75],[76]


miR-449a is a member of miR-34/miR-449 family consisting of miR-34a, miR-34b, miR-34c, miR-449a, miR-449b, and miR-449c.[77] Notably, one of its family members miR-34a is the first currently tested miRNA in a clinical trial for patients with primary liver cancer. miR-449 is known as a tumor suppressor in prostate cancer,[78] gastric cancer, bladder cancer,[79] lung cancer,[80] and HCC.[77] Sandbothe et al.[77] in their recent study demonstrated an epigenetic regulation of miR-449a induced by TSA-mediated histone deacetylase (HDAC) inhibition in HCC and normal liver cell lines, suggesting a regulation by histone acetylation. Using target gene prediction databases, the authors identified putative targets for miR-449 family members and SOX4 to be among one of the targets, which is overexpressed in HCC tissues and has poor prognosis. Moreover, the authors have also shown that overexpression of miR-449 family members was inhibited by TGF-β-mediated SOX4 overexpression which further inhibits cell migration.[77]


miR-381 is reported to be a tumor suppressor which is downregulated in breast cancer,[81] chondrosarcoma,[82] osteosarcoma,[83] and ovarian cancer[84] through targeting Cx43, VEGF-C, LRRC4, and YY1. In a recent novel study, Zhang et al.[85] identified miR-381 to be downregulated in gastric cancer. However, overexpression of miR-381 inhibited migration and invasion and EMT in gastric cancer cells through direct targeting and downregulating SOX4. Mechanistic studies by Zhang et al.[85] revealed that a long noncoding RNA taurine 1 (TUG1) negatively regulates miR-381 expression in gastric carcinoma [Figure 2].


Earlier, miR-204 is known to suppress tumor initiation in esophageal cancer, lung cancer, and gastric cancer.[86],[87],[88] Few known targets of miR-204 are USP47, SOX4, RAB22A, SIRT1, and Snai1.[86],[89],[90] In a very recent study, Yuan et al.[91] reported that miR-204 suppressed gastric cancer cell proliferation and metastasis and negatively correlate with its target SOX4.[92] Further, a comprehensive analysis with clinicopathological parameters of gastric cancer patients revealed that miR-204 and SOX4 are associated with lymph node metastasis and tumor Stages I–IV.[91] Another study by Yin et al.[93] identified downregulation of miR-204 in T-cell acute lymphoblastic leukemia and overexpression by mimics inhibited the cell proliferation, migration, and invasion ability and SOX4 expression, thereby negatively modulating SOX4 expression by binding to its 3'-UTR.


A recent study identified that frequent downregulation of miR-320 occurs in primary colon cell carcinoma (CRC) tissues and cell lines. Lentiviral-mediated overexpression of miR-320 is reported to inhibit HCT116 CRC growth and migration in vitro and inhibit tumor formation in SCID mice. Furthermore, there exists an inverse correlation between the expression of miR-320 and its targets such as SOX4, FOXM1, and FOXQ1.[94]


Like other miRNAs discussed here, miR-363-3p and miR-140 are tumor suppressors which are downregulated in CRC tissue specimens with lymph node metastasis and gastric cancer tissues and cell lines, thus promoting cell migration and invasion and EMT induction both in vitro and in vivo via its direct target SOX4.[95] Hu et al.[95] further demonstrated that exogenous miR-363-3p reversed the EMT and phenotypic metastasis in CRC cells. Zhou et al.[95] revealed that miR-140 overexpression in HGC-27 cells inhibited SOX4 expression, resulting in decreased cell viability, colony formation, and resulted in G0/G1 cell arrest.


A recent study by Zhang et al.[96] has shown that miR-187 is downregulated in CRC cell lines and tissues and SOX4 is upregulated which is correlated with poor disease prognosis. On the contrary, exogenous miR-187 can inactivate TGF-β-mediated Smad pathway, thus preventing EMT and suppressing cell proliferation and migration in vitro, and inhibit CRC growth and progression in vivo. Furthermore, authors also found SOX4-upstream effector of Smad as a direct target of that miR-187.


Several studies revealed miR-191 to be an estrogen and hypoxia responsive miRNA that promotes estrogen receptor-positive breast cancer cell proliferation and migration. Apart from its role in breast cancer, miR-191-5p has been identified in other cancers such as lung cancer, colon cancer, and gastric cancer as an oncogenic miRNA.[97] A recent study by Sharma et al.[97] demonstrated that p53 downregulates miR-191-5p in breast cancer, whereas SOX4 – a direct target of miR-191 – increases p53 protein levels. In fact, overexpression of miR-191 caused a downregulation of SOX4 and p53 levels.

  Microrna-212 And Microrna-132 Top

miR-212 and miR-132 are located in chromosome 17 and is derived from the miR-212/132 cluster.[98] Earlier studies reported that miR-212 and miR-132 are tumor suppressor and are downregulated in ovarian cancer by targeting E2F5 and HBEGF[99] and NSCLC by targeting SOX4.[100] SOX4 is a downstream effector of miR-212 and miR-132 modulating EMT of ovarian cancer cells. A recent study by Lin et al.[101] identified that SOX4/EZH2 complex can silence miR-212/132 expression by binding to its promoter region and promoting H3K27me3, whereas miR-212 and miR-132 can directly bind to the 3′UTR of SOX4, suppress its expression, and thus form a miR-132/212-SOX4/EZH2-H3K27me3 feedback loop in ovarian cancer cells. EZH2 is a subunit of the polycomb repressor complex 2 that promotes DNA methylation.[102] In addition, EZH2 can catalyze H3 (H3K27me3) trimethylation, an epigenetic modification that silences gene transcription.[103] Therefore, the downregulation of miR-212 and miR-132 in ovarian cancer cells is due to epigenetic upregulation of EZH2 and SOX4. The authors further showed an interaction between EZH2, SOX4, and HDAC3 that form a co-repressor complex to silence miR-212 and miR-132 expression in ovarian cancer cells.[101] Exogenous introduction of miR-132 significantly inhibits proliferation and EMT and induces cell cycle arrest and apoptosis in ovarian cells and osteosarcoma cells [Figure 1] and [Figure 2].[104]

  Microrna-211 Top

miR-211 plays a dual role as a tumor suppressor in epithelial ovarian cancer, HCC, and breast cancer[105],[106],[107] as well as an oncogene in colon cancer, oral carcinoma, head and neck squamous cell carcinoma, often associated with poor prognosis of patients.[108] In one of the studies in gastric cancer, Wang et al.[109] demonstrated that miR-211 is downregulated and its overexpression inhibited gastric cancer cell proliferation and invasion in vitro by targeting and downregulating SOX4. This highlights the role of miR-211 as a tumor suppressor by interacting with SOX4.


miR-30a plays an important role in development of endometrial carcinoma,[110] HCC,[111] and chronic myelogenous leukemia.[112] One of the recent studies has shown that miR-30a is downregulated in chondrosarcoma patients[113] and is negatively correlated with SOX4 expression. miR-30a directly targets SOX4 and its overexpression downregulates SOX4 expression, thereby suppressing proliferation, migratory, and invasive capacity of SW1353 chondrosarcoma cells in vitro[113] and TGF-β-mediated EMT in prostate cancer cells.[114]


miR-133a is a muscle-specific miRNA where the gene is located on chromosome 18 and chromosome 20 as two copies.[115] Several studies have shown that low levels of this miRNA are expressed in several cancers including ovarian cancer,[116] CRC,[117] lung cancer,[118] breast cancer,[119] prostate cancer,[120] and esophageal cancer.[121] Li et al.[122] have demonstrated that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC) cell lines and clinical ESCC tissue samples and is inversely correlated with tumor progression in ESCCs, suggesting that miR-133a may function as a novel tumor suppressor. Furthermore, SOX4 is reported to be a direct target of miR-133a with the 3'-UTR, thereby regulating EMT markers as well. Notably, there is a reciprocal effect of miR-133a over tumor progression upon targeting SOX4, similar to other miRNAs discussed above. For instance, following overexpression of miR-133a, SOX4 is decreased thereby decreasing migration and invasion and EMT in ESCC which clearly suggests that miR-133a could act as a potential tumor suppressor in ESCC through targeting SOX4 and the EMT process.[122]

  Concluding Remarks and Future Directions Top

Challenges faced in curbing metastasis and developing prognostic tools are mainly due to the clinical and molecular heterogeneity of tumor cells exhibiting EMT. Not all cells undergo EMT simultaneously and the cells which have undergone EMT not usually metastasize simultaneously. In fact, extracellular and intracellular cues, environmental changes, and epigenetic factors affect the EMT and metastatic process. Drug resistance is another serious issue that accompanies EMT and metastasis. For instance, in breast and pancreatic cancer, higher resistance to drugs such as oxaliplatin and paclitaxel[4],[123] is reported to be seen in cells expressing EMT markers. Therefore, a more robust prognostication is required to overcome this challenge. In recent years, miRNA-based therapy is emerging rapidly. For instance, high level of Ki-67 is used as a prognostic marker; however, miR-21 has gained popularity and can be used as a prognostic marker due to the fact that a similar high level of this miRNA can be seen in liver cancer; therefore, in place of Ki-67, miR-21 can be used as a cancer biomarker and marker for metastasis.[124] Recent studies reveal that exosomes released from the tumor milieu may mediate cell-to-cell communication that can be exploited to inhibit tumor growth by delivering antitumor therapeutics such as miRNAs packed in nanoliposomes or exosomes. Therefore, miRNA packed in exosomes can be promising therapeutic approach.[125]

In this review, we have discussed the role of various tumor suppressor miRNAs in regulating a significant transcription factor, SOX4, also known as a master regulator of EMT in different cancers. We also highlighted the importance of their interplay in regulating cancer cell proliferation, migration, and EMT. These miRNAs regulate SOX4 directly via components of multiple signaling pathways such as Hedgehog pathway, Notch pathway, TGF-β pathway, and Wnt/β-catenin pathway [Table 2]. SOX4 is often reported to be overexpressed in many aggressive cancers. Many recent studies have reported that miRNAs which are particularly tumor suppressors modulate the function of SOX4 by binding to 3'-UTRs and initiate their degradation at translational level, thus downregulating its expression as well as tumor growth and proliferation both in vitro as well as in vivo. In fact, there exists an inverse correlation between various miRNAs and SOX4 in most of the cancers. For instance, miRNAs that are downregulated in various aggressive cancers predominantly of epithelial origin and some of nonepithelial ones correlated with an upregulation of SOX4 expression levels, thereby adding to the aggressiveness of the cancer phenotype. Some studies reported that epigenetic repression of miRNAs can lead to overexpression of SOX4[74],[75] and exogenous expression of these miRNAs can downregulate SOX4 expression and potentially inhibit metastasis in vitro and in vivo by inhibiting cancer cell proliferation, migration, and invasion and induce apoptosis.[95],[96] Notably, this suggests that miRNA–SOX4 overexpression and downregulation switch may serve as a prognostic marker for cancer patients. It is fundamental to delineate the interplay between miRNAs and SOX4 to understand the mechanisms involved in EMT. This can further our understanding of cancer progression and metastasis. Further research is required to understand the molecular mechanism and the epigenetic mechanism involved in the interaction of various miRNAs with SOX4 to develop novel anticancer therapeutic approaches that involve modulation of miRNA–SOX4 interaction by epigenetic drugs. In summary, miRNA–SOX4 interplay highlighted here provides critical insights into the regulatory networks by which miRNA regulates the transcription factor – SOX4 and how their interaction can modulate critical cell-fate and metastatic event called EMT. Remarkably, in the future, upregulation/restoration of tumor suppressor miRNAs along with downregulation of SOX4 with an epigenetic approach or signaling pathway-targeted approach could possibly evolve as a promising option to improve patient survival and decrease mortality.[126]
Table 2. MicroRNAs that directly regulate sex determining region Y-box 4 in various cancers and functions they perform upon interaction with sex determining region Y-box 4

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