OROncology Reports1021-335X1791-2431D.A. Spandidos10.3892/or.2020.7703or-44-04-1299ReviewMicroRNAs target the Wnt/β-catenin signaling pathway to regulate epithelial-mesenchymal transition in cancerLeiYuhe1*ChenLei1*ZhangGe2*ShanAiyun1YeChunfeng3LiangBin4SunJiayu1LiaoXin1ZhuChangfeng1ChenYueyue4WangJing4ZhangEnxin5DengLijuan4Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. ChinaDepartment of Big Data Research of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. ChinaDepartment of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. ChinaFormula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. ChinaDepartment of Oncology, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P.R. ChinaCorrespondence to: Professor Enxin Zhang, Department of Oncology, Shenzhen Hospital of Guangzhou University of Chinese Medicine, 6001 Beihuan Avenue, Shenzhen, Guangdong 518000, P.R. China, E-mail: ergep53@126.comDr Lijuan Deng, Formula Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, 605 Huangpu Avenue West, Guangzhou, Guangdong 510632, P.R. China, E-mail: ljdeng@jnu.edu.cn
Epithelial-mesenchymal transition (EMT), during which cancer cells lose the epithelial phenotype and gain the mesenchymal phenotype, has been verified to result in tumor migration and invasion. Numerous studies have shown that dysregulation of the Wnt/β-catenin signaling pathway gives rise to EMT, which is characterized by nuclear translocation of β-catenin and E-cadherin suppression. Wnt/β-catenin signaling was confirmed to be affected by microRNAs (miRNAs), several of which are down- or upregulated in metastatic cancer cells, indicating their complex roles in Wnt/β-catenin signaling. In this review, we demonstrated the targets of various miRNAs in altering Wnt/β-catenin signaling to promote or inhibit EMT, which may elucidate the underlying mechanism of EMT regulation by miRNAs and provide evidence for potential therapeutic targets in the treatment of invasive tumors.
Cancer metastasis has always been a challenge in the clinic, and is largely responsible for treatment failure and high mortality. It is known that invasive tumors undergo the EMT process where cells fail to maintain an epithelial phenotype and acquire a mesenchymal phenotype, thus transmitting from the primary tumor to other locations and forming secondary growths (1). To solve this problem, scientists have dedicated themselves to exploring the molecular mechanisms of this process. After four decades of work, various signaling pathways are known to participate in EMT including the transforming growth factor-β (TGF-β), Wnt/β-catenin, Hedgehog (Hh), Notch, fibroblast growth factor receptors (FGFRs), and nuclear factor kappa B (NF-κB) signaling pathways (2). Of these, the connections of cell adhesion, the Wnt/β-catenin pathway and EMT are more clearly studied.
The formation of adherens junctions needs cell-cell adhesion molecules, such as the cadherin superfamily, and nectins (3). Cadherins and nectins bind to their anchoring proteins, catenins and afadin, respectively, to form functional modules that affect the actin cytoskeleton (4). The nectin family, which is composed of four members, namely, nectin-1, −2, −3, and −4 (5), is involved in cell-cell adhesion in various cell types by forming a nectin-afadin complex (6,7). Previous findings have shown the significant role of the E-cadherin/β-catenin complex in maintaining stabilized cell-cell junctions (8). E-cadherin is regarded as the key component of the adherens junction complex (9), and invasive tumor is characterized by a marked decrease in E-cadherin expression (10). Several transcription factors such as Twist, Snail and zinc finger E-box-binding homeobox 1/2 (ZEB1/2) trigger EMT by directly binding to the E-box sequences of E-cadherin promoter, thus repressing its transcription (11). For example, Snail1 and Snail2 bind to CDH1 (gene of E-cadherin) promoter-based E-box DNA sequences and summon the polycomb repressive complex 2 (PRC2), resulting in CDH1 histone methylation and acetylation (12). Activation of these transcription factors is attributed to the translocation of β-catenin from the cytoplasm to the nucleus, which is considered to be the central event in EMT (13). β-catenin has demonstrated its crucial role in Wnt signal transduction (14). In the presence of Wnt signals, the phosphorylation of β-catenin by glycogen synthase kinase 3β (GSK3β) is inhibited, followed by β-catenin disassembly from the destruction complex and accumulation in the cytoplasm (15). Therefore, current research primarily focuses on the canonical Wnt signaling (β-catenin dependent) pathway in which the mechanisms are more clearly established.
MiRNAs are small noncoding molecules with 19–25 nucleotides, which regulate gene expression at the post-transcriptional level by inhibiting mRNA translation or facilitating mRNA degradation (16). Previous findings suggested that EMT is regulated by miRNAs through alteration of the Wnt/β-catenin pathway (17). However, the complex role of miRNA as an EMT inhibitor or promoter and its underlying mechanism need further clarification.
In this review, we focused on the interaction between miRNAs and the Wnt signaling pathway. Through literature retrieval, we summarized the distinct effects of miRNAs on Wnt signaling in the regulation of cancer metastasis, aiming to identify the mechanism of EMT regulation by miRNAs and potential therapeutic targets in invasive tumor treatment.
EMT and tumor metastasis
EMT comprises an essential biological process during which cells fail to maintain epithelial cell polarity and acquire the mesenchymal phenotype, thus increasing cell motility and invasion (18). EMT was reported to be involved in numerous biological activities such as embryogenesis (19), heart-valve (20) and neural crest formation (21). Scientists categorize EMT into three types including embryonic development and organ formation, wound healing and organ fibrosis, and cancer progression (22). The critical role of EMT in cancer has been extensively studied in recent years. It is generally accepted that EMT facilitates the invasion and metastasis of early stage tumors and contributes to cancer progression (23). The latest studies reveal that EMT-induced tumor progression is not only mediated by phenotypic change but also related to stemness (24), immune evasion (25), metabolic reprogramming (26), and therapeutic resistance (27) of cancer cells.
EMT is characterized by decreased expression of epithelial markers such as E-cadherin, γ-catenin and increased expression of mesenchymal markers such as N-cadherin, vimentin, Snail, Twist and ZEB (28). E-cadherin, a pivotal transmembrane adhesion protein in maintaining cell-cell junctions and polarity, was confirmed to stabilize cell junctions through forming the E-cadherin/β-catenin complex (8). The loss of E-cadherin, which contributes to the mesenchymal phenotype of cancer cells, is a basic event in tumor metastasis (10). As a result, the newly transformed mesenchymal cells detach from the primary tumor, invade into the circulation, and reform into epithelial cells through MET (29), thus leading to tumor formation at a distant secondary site (30).
EMT is regulated by various signaling pathways such as the TGF-β, Wnt/β-catenin, Hedgehog and Notch signaling pathway (18). These pathways trigger EMT by stimulating transcription factors including Snail, Twist, and ZEB1/2, which directly bind to the promoter-based E-box DNA sequences of E-cadherin and repress its transcription. In addition, Snail also facilitates the transcription of mesenchymal markers such as vimentin and N-cadherin (31). Among all the signaling pathways, the Wnt/β-catenin pathway shows its pivotal role in the regulation of EMT.
Wnt/β-catenin signaling pathway and EMT
Wnt (wingless and Int-1) signals are evolutionarily conserved consisting of secreted Wnt ligands, Frizzled (FZD) receptors and coreceptors, intracellular adaptors, and scaffolding proteins (32). The foremost roles of the Wnt signaling pathway in cell proliferation, differentiation, adhesion, invasion, migration, and stem cell self-renewal have been well established (17). Abnormal Wnt signaling is commonly correlated with multiple types of disease such as neural tube defects (33), rheumatoid arthritis (34), hepatic fibrosis (35), and cardiovascular disease (36). The Wnt signaling pathway is divided into two categories, a canonical pathway (β-catenin-dependent) and noncanonical pathway (β-catenin-independent), both of which are closely related to EMT (37). β-catenin is regarded as a key protein in Wnt signaling, since accumulation of β-catenin in the cytoplasm gives rise to its translocation and activation in the nucleus (15), further initiating the transcription of EMT-related genes (38).
When the Wnt signal is absent, β-catenin forms a destruction complex with Axin, adenomatous polyposis coli (APC), casein kinase I α (CKIα) and GSK3β (39). In this stage, β-catenin is phosphorylated by GSK3β and CKIα, forming β-catenin degradation by ubiquitination (40). In addition, Wnt signaling inhibitory factors such as Dickkopf (DKK) family, secreted frizzled-related protein (SFRP) family and Wnt inhibitory factor 1 (WIF1) contribute to the inactive status of β-catenin (41). Dkk, a small family of secreted glycoproteins, is comprised of four members, Dkk1-4. Dkk1 and Dkk2 bring about Wnt signal inhibition by binding to low-density lipoprotein receptor-related protein (LRP) 5/6 with high affinity (42). However, Dkk2 plays a dual role as an inhibitor or activator of the Wnt signaling pathway, depending on the cellular context (43,44). Dkk3 was reported to be different from other members of the DKK family as it does not bind LRP6 and does not affect Wnt signaling (45). In addition, there are some studies demonstrating the inhibitory effects of Xenopus Cerberus and Wise proteins on Wnt (46). Xenopus Cerberus binds to Wnt proteins via independent sites to inhibit the Wnt signaling pathway (47), whereas Wise may inhibit or activate Wnt signaling in a context-dependent manner (48). In addition to Wnt signaling inhibitory factors, E-cadherin also suppresses β-catenin by forming the E-cadherin/β-catenin complex to prevent nuclear translocation of β-catenin (49). When receptors receive Wnt ligands such as Wnt1 and Wnt3 binding to the FZD and LRP 5/6, LRP 5/6 and FZD form a complex to affect the stabilization of β-catenin and prevent its degradation, resulting in β-catenin accumulation in cytoplasm (50). As a consequence, β-catenin translocates to the nucleus and forms a complex with the T-cell factor/lymphoid enhancer factor (TCF/LEF), which promotes transcription of Wnt target genes including Twist, Snail and other oncogenes such as Cyclin D1, matrix metalloproteniase-7 (MMP-7) and cellular myelocytomatosis oncogene (c-Myc) (51), thus facilitating EMT (52).
miRNAs target the Wnt/β-catenin signaling pathway to regulate EMT
MicroRNAs are small noncoding molecules with 19–25 nucleotides that play fundamental roles in almost every cellular process such as cell differentiation and homeostasis (53) by regulating gene expression at the post-transcriptional level (54). MiRNA genes are transcribed into primary miRNA (pri-miRNA) by RNA polymerase II (55). Exportin 5 recognizes the 2-nucleotide overhang of the pre-miRNA and transports it to the cytoplasm, then pre-miRNA undergoes multistep biogenesis to become mature miRNAs (56). MiRNAs bind to the 3′-untranslated region (UTR) of target mRNAs to suppress their translation or accelerate degradation. It is reported that approximately 10–40% of mRNAs are regulated by miRNAs in humans (57) and dysregulation of miRNA may result in tumor metastasis (58). Research has increasingly focused on the interaction between miRNA and EMT as miRNAs affect multiple EMT-related signaling pathways such as Wnt/β-catenin, North, TGF-β pathway and their target genes (59). The role of miRNA as a tumor suppressor or oncogene during EMT has attracted much attention. Elucidating miRNA functions in the regulation of EMT may contribute to the finding of potential therapeutic targets.
MiRNA as an inhibitor of EMT
A large number of miRNAs were found to be downregulated in a wide spectrum of cancers (60,61), indicating their inhibitory effect on tumorigenesis and development. Furthermore, clinicopathological analysis also revealed that tumor migration and invasion was negatively correlated with a number of miRNAs (62). Numerous studies reported that miRNAs may function as EMT inhibitors by targeting the Wnt signaling pathway or its downstream transcription factors (Table I, Fig. 1); thus, overexpression of these miRNAs may be a therapeutic method to reverse EMT.
The EMT-induction transcription factors, most of which are downstream of the Wnt signaling pathway, have been studied extensively, including E-cadherin suppressors such as ZEB, Twist and Snail, which are considered to be regulated by miRNAs in various types of cancer (10).
The miR-200 family, comprising of 5 miRNA sequences (miR-200a, miR-200b, miR-200c, miR-141 and miR-429), is believed to play a significant role in EMT (63). The EMT initiated in several types of cancer has been shown to be correlated with the underexpression of the miR-200 family such as bladder cancer (64), breast cancer (65), melanoma (66), ovarian cancer (67), gastric cancer (68), and prostate cancer (69). Gregory et al found the levels of the miR-200 family were significantly reduced following TGF-β-mediated EMT in invasive breast cancer since the low level of miR-200 leads to the absence of E-cadherin, indicating miR-200 as a negative regulator of EMT (70). A mechanism study demonstrated that miR-200 inhibits Wnt signaling by targeting transcription factors ZEB1/2 and binding to β-catenin mRNA to suppress its translation (71). The ZEB family, containing two members ZEB1 and ZEB2, binds to the promoter-based E-box DNA sequences of E-cadherin thus repressing its transcription and facilitating the activation of mesenchymal genes (72). The inhibitory effects of miR-200 on β-catenin and ZEB1/2 were further confirmed in gastric adenocarcinoma (73,74), colonic adenocarcinoma (75), and hepatocellular carcinoma (HCC) (76). Overexpression of miR-200 results in E-cadherin upregulation by targeting ZEB1 and ZEB2, thereby inhibiting EMT and restoring the epithelial phenotype of cancer cells (77). However, components of Wnt signaling can inversely affect the miR-200 family. Tian et al reported that a downstream target of Wnt signaling, Achaete scute-like 2 (Ascl2) negatively regulates miR-200 family expression, thus inhibition of Ascl2 obviously restores miR-200 expression and suppresses EMT, making Ascl2 a promising target to reverse EMT (75). In addition to EMT inhibition, restoring the level of miR-200 can also induce cancer cell apoptosis and increase the sensitivity of cancer cells to chemotherapeutic drugs. For instance, niclosamide potentially induces the apoptosis of colon cancer cells by upregulating the miR-200 family members (78). Another study demonstrated that the overexpression of miR-200b could inhibit cell proliferation and enhance apoptosis and then reverse docetaxel chemoresistance of lung adenocarcinoma (LAD) cells by directly targeting E2F transcription factor 3 (E2F3), which were also verified in tissues of LAD patients (79).
In addition to the miR-200 family, miR-33b binds to 3′-UTR of ZEB1 and inhibits ZEB1 expression in lung adenocarcinoma cells, thus blocking Wnt/β-catenin signaling and suppressing tumor growth and EMT in vitro and in vivo (80). Research by Zhang et al identified miR-498 which was downregulated in liver cancer, and suppressed the growth and metastasis of liver cancer cells partly by directly targeting ZEB2, making miR-498 a potential biomarker for diagnosis and a promising therapeutic target for liver cancer treatment (81). Snail and Twist are also targeted by miRNAs in the regulation of EMT. Yue et al demonstrated that miR-519d directly binds to 3′-UTR of Twist1 to facilitate its degradation in gastric cancer cells, suggesting miR-519d as a potential therapeutic target for gastric cancer treatment (82). Jin et al reported that miR-122 inhibits EMT in HCC by targeting Snail1 and Snail2 to suppress the Wnt/β-catenin signaling pathway (83).
The translocation of β-catenin in the nucleus is followed by the activation of TCF/LEF-Legless-Pygo DNA binding proteins, which triggers transcription of many oncogenes such as extracellular matrix receptor III (CD44), c-Myc, MMP-7, and cyclin D1 (52). LEF1, a pivotal transcription factor in the Wnt signaling pathway, was reported to be a target of miR-708 and miR-34a by directly binding to 3′-UTR of LEF1, suggesting miR-708 and miR-34a as EMT inhibitors in melanoma and prostate cancer, respectively (84,85). Pygopus2 (Pygo2) is regarded as a tumor promoter in various types of cancer due to its combination with free β-catenin to cause abnormal activation of downstream oncogenes (86). A study demonstrated that miR-516a-3p inhibits breast cancer cell growth, metastasis and EMT by binding to 3′-UTR of Pygo2 mRNA, resulting in blockage of the Pygo2/Wnt pathway (87). In addition, transcription factor 4 (TCF4) has been found to promote the occurrence and development of several cancers by recognizing β-catenin to initiate the transcription of Wnt target genes (38). MiR-495 was reported to bind to the 3′-UTR of TCF4, thereby suppressing the migration, invasion, and proliferation of non-small-cell lung cancer (NSCLC) by inactivating the Wnt/β-catenin pathway (88).
Some other transcription factors were also reported to be affected by miRNA in the regulation of Wnt/β-catenin signaling. Melanogenesis-associated transcription factor (MITF), as one of the representative target genes of β-catenin, plays a carcinogenic role in gastric cancer. A study reported that miR-876-5p was able to bind to 3′-UTR of MITF and downregulate its expression, thus suppressing viability and migration of gastric cancer cells, and inducing cell apoptosis (89). Octamer-binding protein 4 (Oct4), an octamer motif-binding transcription factor, has been confirmed to exhibit an oncogenic effect in several types of cancer (90,91). A study by Ling et al demonstrated that miR-145 suppresses EMT in lung cancer cells by targeting Oct4 to inactivate the Wnt/β-catenin signaling pathway (92).
Targeting key proteins of the Wnt/β-catenin signaling pathway
Accumulation of β-catenin in cytoplasm is the central event in Wnt signaling activation; thus, miRNAs targeting β-catenin may act as EMT inhibitors. In addition to the miR-200 family mentioned above, miR-34b/c suppress β-catenin mRNA expression by targeting the 3′-UTR of β-catenin in prostate cancer (93). MiR-3619-5p directly binds to 3′-UTR of β-catenin and causes its downregulation in bladder carcinoma (94). Similarly, miR-33a targets the 3′-UTR of β-catenin to block EMT in human pancreatic cancer cells (95).
It is generally recognized that Wnt ligands are regulated by various miRNAs. For example, Wnt1 is a direct target gene of miR-122 in HCC HepG2 and Huh7 cell lines, thus downregulation of miR-122 facilitates EMT in HCC cells by activating Wnt signaling (96). Another study confirmed that Wnt1 is a target gene of miR-148a in HCC cells, suggesting miR-148a acts as an HCC metastasis suppressor by blocking the Wnt signaling pathway (97). In addition, Peng et al reported that miR-148a suppresses EMT and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt signaling pathway, making miR-148a a novel therapeutic target for pancreatic cancer treatment (98). Wnt5A was found to be targeted by miR-876-5p, which suppresses the viability and migration of gastric cancer cells and induces cell apoptosis (89). Moreover, Wnt7a, which activates Wnt signaling to promote EMT of bladder cancer, can be inhibited by miR-370-3p (99).
Wnt ligands transduce signals by binding to several receptors such as FZD and LRP5/6, this process was described to be regulated by miRNAs. When Wnt ligands bind to receptors, FZD and LRP5/6 form a complex on the surface of the cell membrane. Then, Dsh protein is recruited and constitutes a complex with Axin, which binds GSK3β and CKIα to release β-catenin, thus forming β-catenin accumulation in the cytoplasm (50). MiR-3127-5p was reported to block Wnt/β-catenin signaling by directly targeting FZD4 in NSCLC (100). Moreover, miR-504 negatively regulates the Wnt/β-catenin pathway by directly targeting FZD7, thus suppressing the mesenchymal phenotype of glioblastoma (101).
The phosphorylation of β-catenin by GSK3 is necessary for β-catenin degradation when the Wnt signal is absent. Researchers found that proto-oncogene frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) belongs to the GSK3-binding protein family, which inhibits GSK3-mediated phosphorylation of β-catenin and positively regulates the Wnt signaling pathway (102). MiR-490-3p is identified to directly target FRAT1, suggesting its tumor suppressive effects (103). SLC39A7 (ZIP7), a zinc transporter essential for the activation of tyrosine kinase, is considered to be a potential target of Wnt/β-catenin. A study by Cui et al suggested that miR-15a-3p suppresses prostate cancer by targeting SLC39A7 to inhibit the Wnt/β-catenin signaling pathway (104). In addition, Nimmanon et al reported that activation of SLC39A7 drives the PI3K/Akt pathway (105). Thus, targeting SLC39A7 by miR-15a-3p to suppress cancer cell progression may also result from inhibition of the PI3K/Akt pathway.
Targeting other signaling pathways
MiRNAs may regulate Wnt signal transduction by crosstalk with other signaling pathways (106). Signal transducer and activator of transcription 3 (STAT3) has been confirmed to be associated with EMT via regulation of β-catenin (107). Guo et al reported that miR-125b-5p targeting STAT3 results in β-catenin phosphorylation and degradation in HCC cells, indicating the inhibitory effect of miR-125b-5p on β-catenin-mediated EMT (62). Cyclin-dependent kinase 2 (CDK2), a member of the Ser/Thr protein kinase family, plays a crucial role in cancer proliferation and metastasis (108). Zhang et al found miR-3619-5p directly targets CDK2 and β-catenin to suppress bladder carcinoma progression, while further studies revealed that miR-3619-5p inhibits Wnt signaling partly through the induction of p21 following CDK2 and β-catenin inhibition (94). Cullin 4B (CUL4B), a scaffold protein assembling the cullin-RING-based E3 ubiquitin-protein ligase complexes, plays a critical role in proteolysis and tumorigenesis (109). Zhang et al reported that CUL4B is a direct target of miR-300 in pancreatic cancer cells, and downregulation of CUL4B by miR-300 results in inhibition of the Wnt signaling pathway and EMT (110). Similarly, Cullin 4A (CUL4A), also known as a core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes, is negatively regulated by miR-377, indicating the inhibitory effect of miR-377 on the Wnt signaling pathway (111). A member of the receptor tyrosine kinases (RTKs) family, EPH receptor A2 (EphA2) is highly expressed in solid tumors, suggesting its important role in tumor initiation, progression, and invasion (112). MiR-302b and miR-338 serve as EphA2 inhibitors to suppress gastric cancer tumorigenesis and metastasis by inactivating the Wnt/β-catenin pathway (113,114). LIM Homeobox 2 (LHX2), a member of the LIM homeobox family, is involved in elevated β-catenin level and cell proliferation in pancreatic ductal adenocarcinoma (115). Liang et al revealed that miR-506 targets LHX2 to repress EMT and lymph node metastasis in nasopharyngeal carcinoma. They also found decreased TCF4 following LHX2 inhibition is responsible for Wnt/β-catenin signaling inactivation (116). Moreover, protein regulator of cytokinesis 1 (PRC1) was reported to mediate early HCC formation, transfer, stemness and development through Wnt/β-catenin signaling (117) and miR-194 could target PRC1 to suppress EMT in HCC cells by inactivating the Wnt/β-catenin signaling pathway (118). Additionally, Chen et al found that YWHAZ (14-3-3ζ) regulates the EMT process by interaction with β-catenin in NSCLC (119). On this basis, Guo et al demonstrated miR-375-3p targets YWHAZ to inhibit migration, invasion, and the EMT processes of gastric cancer cells by blocking the Wnt/β-catenin signaling pathway (120).
Although miRNAs may regulate Wnt signaling by affecting other signaling pathways, the underlying mechanism on how they interact has not been clearly defined. For example, miR-22 targeting formin-like 2 (FMNL2) (121), miR-136 targeting premelanosome protein (PMEL) (122), miR-29c targeting protein tyrosine phosphatase 4A2 (PTP4A2) and G protein subunit alpha 13 (GNA13) (123), and miR-378 targeting SDAD1 (60) all participate in Wnt/β-catenin signaling inhibition; however, the relationship between these targets and Wnt signaling needs further exploration. Therefore, the study of miRNAs targeting Wnt/β-catenin signaling, not only reveals the complex process of EMT, but also gives us better understanding of the crosstalk between Wnt signaling and other signaling pathways. For instance, Zhang et al found that miR-770 functions as a tumor suppressor by directly targeting the Jumonji domain containing 6 (JMJD6) 3′-UTR and inhibiting the Wnt/β-catenin pathway in NSCLC, suggesting Wnt/β-catenin as the downstream signal of JMJD6 in NSCLC cells (124).
miRNA as promoter of EMT
MiRNAs upregulated in various types of cancer display their carcinogenic role in tumor progression, migration, and invasion (125,126). There is a smaller quantity of miRNAs as EMT promoters compared with EMT inhibitors by targeting the Wnt signaling pathway (Table II, Fig. 1), but exploration of these miRNAs as potential therapeutic targets is also meaningful in combating EMT (127).
E-cadherin is an important intercellular adhesion molecule in maintaining cell-cell junctions and polarity. It is known that suppression of E-cadherin may result in cell detachment, invasion, and metastasis (128). Therefore, miRNAs which target E-cadherin are involved in EMT initiation. According to research, miR-9 (129), miR-23a (130), miR-544a (125) and miR-199a-5p (131) suppress E-cadherin to trigger EMT in particular cancer types, indicating these miRNAs are potential targets in cancer therapy.
Axin, APC, and GSK3β are β-catenin suppressors that act by forming a destructive complex to anchor β-catenin thus making it degrade. Therefore, miRNAs which target Axin, APC, and GSK3β activate Wnt signaling to trigger EMT by stabilization of β-catenin in the nucleus (132). A study by Mao et al demonstrated that miR-135a activates the Wnt/β-catenin signaling pathway by directly targeting GSK3β to accelerate the EMT, invasion, and migration of bladder cancer cells (133). In addition, miR-1246 facilitates the Wnt/β-catenin pathway through targeting GSK3β, which partly contributes to lung cancer metastasis (134). However, there is another study demonstrating different effects and mechanisms of miRNA on GSK3β. GSK3β modulates the NF-κB signaling pathway as it facilitates NF-κB function through post-transcriptional regulation of the NF-κB complex (135). Liu et al found that GSK3β is a direct target of miR-377-3p and is upregulated by miR-377-3p. Consequently, miR-377-3p promotes cell proliferation and EMT by upregulating GSK-3β expression and activating the NF-κB pathway in human colorectal cancer (136). In addition, miR-197 was reported to directly target Axin2 in HCC, leading to activation of Wnt/β-catenin signaling and EMT (126). Similarly, miR-544a plays an oncogenic role by directly targeting Axin2 to trigger EMT of gastric cancer (125). Moreover, APC was identified as the direct and functional target of miR-27 (132) and miR-125b (137) in gastric cancer and breast cancer, respectively, making miR-27 and miR-125b promising therapeutic targets for invasive cancer treatment.
The Wnt/β-catenin signaling pathway could be negatively regulated by antagonist molecules, therefore miRNAs targeting antagonists of the Wnt signaling have been regarded as EMT drivers. The DKK gene family, composed of DKK1-4 (138), was found to inhibit tumor invasion and migration by negative regulation of β-catenin (139). Some studies focused on the DKK family and found that miR-95-3p targeting DKK3 in prostatic cancer (140), miR-197 targeting DKK2 in HCC (126), and miR-373-3p targeting DKK1 in tongue squamous cell carcinoma (141) are responsible for the activation of Wnt/β-catenin signaling and EMT. Secreted frizzled-related protein 1 (SFRP1) acts as an antagonist of Wnt signaling by binding to Wnt proteins through its CRD domain against the transmembrane frizzled receptor (142). MiR-27a-3p was confirmed to promote EMT in oral squamous carcinoma stem cells by targeting SFRP1 (143). Zinc and ring finger 3 (ZNRF3) belongs to the E3 ubiquitin ligase family, which negatively regulates Wnt/β-catenin signaling by promoting the turnover of FZD and LRP6 (144). Qiao et al found that miR-106b-3p promotes cell proliferation and invasion by directly targeting ZNRF3, thus triggering EMT of esophageal squamous cell carcinoma (ESCC) (145). In addition, miR-146b-5p induces EMT in thyroid cancer by silencing of ZNRF3 (146). KLF4 (Kruppel-like factor 4), highly expressed in the adult intestine, is another negative regulator of Wnt signaling by interacting with β-catenin (147). Chen et al showed that miR-92a acts as an oncogene by directly targeting KLF4, thus affecting Wnt/β-catenin pathway and participating in colorectal cancer progression (148). A study by Parenti et al also demonstrated that Mesalazine treatment suppresses the expression of miR-130a and miR-135b, which target KLF4 mRNA, to mediate β-catenin inhibition in colon cancer (149). Furthermore, it was identified that miR-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis by targeting multiple negative regulators of Wnt including WIF1, PTEN, and Wnt5A (15). Similarly, downregulation of PTEN and Wnt5A by miR-26b also results in colorectal cancer metastasis (150). However, the effect of the miR-29 family on WIF1 in NSCLC is completely opposite, as miR-29 positively regulates WIF1 expression by inhibiting the methylation of its promoter, thus inhibiting the Wnt signaling pathway (151).
Use of miRNAs to regulate EMT
Since miRNAs play important roles in the regulation of EMT by activating or inhibiting the Wnt signaling pathway, miRNA-based therapies including those inhibiting miRNA function or restoring miRNA expression have been suggested as efficient strategies in cancer treatment (152) (Fig. 2). Delivering miRNA mimics contributes to the restoration of tumor-suppressive miRNA, while miRNA sponges, anti-miRNA oligonucleotides, small molecule inhibitors are useful approaches to block tumor promotive miRNA (153).
The first miRNA-based therapy for cancer is MRX34, which was designed to deliver miR-34 mimic to cancer cells. MiR-34, which exerts a suppressive effect on Wnt signaling and tumor metastasis, is downregulated in various types of cancer including colon cancer, liver cancer, NSCLC, and cervical cancer (154). Several preclinical studies demonstrated that delivery of miR-34 mimic has promising effects against liver cancer (155), lung cancer (156), and prostate cancer (157). MRX34 encapsulated in lipid is under clinical testing (NCT01829971) in several solid and haematological malignancies (158). In addition, miravirsen, a locked nucleic acid (LNA)-based antisense oligonucleotide targeting miR-122, reached phase II trials for treating hepatitis (127). Recently, LNA-modified miR-92a inhibitor MRG-110 and miR-29 mimic MRG-201 are under phase I clinical trials by miRagen Therapeutics, Inc. (159). RGLS5579, which targets miR-10b, demonstrated statistically significant improvements in survival in an orthotopic glioblastoma multiforme animal model, and the addition of a single dose of RGLS5579 combined with temozolomide led to a >2-fold improvement in survival compared to TMZ alone (https://www.sec.gov/Archives/edgar/data/1505512/000162828020003483/rgls20191231-10k.htm). Moreover, replenishing tumor-suppressive miRNAs such as miR-200, miR-26a, miR-506, miR-520, miR-15/16 and inhibiting tumor-stimulating miRNAs such as miR-10b, miR-221, miR-155, miR-630 have also been included in preclinical studies (160).
Efforts have been made to explore small molecular compounds targeting EMT-related miRNAs. A natural compound isolated from Tripterygium wifordii Hook F, namely, Triptolide (TPL), was reported to exert anti-colorectal cancer properties by downregulating miR-191, thus blocking NF-κB and Wnt/β-catenin signaling activation (161). Toosendanin (TSN), a triterpenoid extracted from the bark or fruits of Melia toosendan Sieb et Zucc, suppresses gastric cancer proliferation, invasion, and migration by targeting miR-200a to downregulate β-catenin (162). In addition, another study demonstrated that Garcinol exerts antineoplastic effects on aggressive breast cancer due to reversal of the mesenchymal phenotype, which is mediated by miR-200s and let-7s targeting NF-κB and Wnt signaling (163). Moreover, Du et al showed that propofol can inhibit the proliferation and EMT of MCF-7 cells by targeting miR-21 to regulate the PI3K/Akt and Wnt/β-catenin pathway (164). These findings not only provide promising compounds against EMT but also reveal the mechanism of miRNAs as targets in Wnt signaling regulation.
Results and Discussion
As shown in Fig. 1, Wnt/β-catenin signaling is under solid regulation by miRNAs to prevent EMT prior to tumor metastasis. Dysregulation of miRNAs is involved in multiple types of invasive cancer due to their effects on gene expression at the post-transcriptional level (59). A single miRNA can target many genes, similarly a specific gene is regulated by multiple miRNAs, indicating the complex biological effects caused by a small change of miRNA (15,84,85). In this review, we divided miRNAs into two classes including EMT suppressors or stimulators; however, certain miRNAs may play dual roles in different types or different stages of cancer. For example, miR-374a acts as an EMT suppressor in early-stage NSCLC (stages I and II) by targeting cyclin D1 but switches to an EMT promoter in more advanced stages by targeting PTEN (165). Another study demonstrated the paradoxical effects of miR-145 on SW480 and SW620. Ectopic expression of miR-145 suppresses the proliferation, migration and invasion in SW480 but enhances these traits in its metastatic counterpart, SW620, which may be mediated through the downregulation of SIP1 but differential tuning of Wnt signaling and EMT-mediators (166). Interestingly, the dual effects of Wnt/β-catenin signaling also add to the complexity of EMT regulation. Li et al reported miR-630 inhibits EMT of gastric cancer by activating the Wnt/β-catenin pathway (167). Moreover, there is an exceptional case where a high level of Wnt3A suppresses melanoma growth and metastasis although β-catenin is active (168), indicating the opposite effects of activated Wnt/β-catenin signaling in response to different Wnt ligands. These results suggest that miRNAs and Wnt signaling may act as double-edged swords, and the level of miRNA affects gene expression in a cell and tissue context-dependent manner (169). Therefore, the dual functions of miRNA and the strategies of using miRNA targeting Wnt to overcome EMT need further investigation. We should take cancer type, clinical stage, tissue context, and tumor microenvironment into consideration. Additionally, recent studies have elucidated the regulatory effects of miRNAs on EMT-induced cancer drug resistance. For example, Wang et al found that miR-200c-3p suppression contributes to the acquired resistance of NSCLC to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors via a mediating EMT process (170). Cochrane et al reported that miR-200c could inhibit EMT and reinstate sensitivity to chemotherapeutic drugs in endometrial, breast, and ovarian cancer cells (171). These results indicated that regulation of EMT by miRNAs also plays a role in drug sensitivity, and comprehensive studies of miRNA's effects in all respects are required to combat cancer.
There are numerous studies demonstrating the upstream regulators of miRNA including key proteins, circular RNA (circRNA), and long non-coding RNA (lncRNA) (Fig. 2). For example, Forkhead box-O 3a (FOXO3a) inhibits β-catenin through transactivating miR-34b/c (93). As mentioned above, Ascl2 negatively regulates the miR-200 family which belongs to tumor suppressors, making Ascl2 a potential target to reverse EMT (75). Hsa_circ_0007059 blocks the Wnt/β-catenin and ERK1/2 pathways by targeting miR-378 in A549 and H1975 cells (172). MiR-106a-3p is a direct target of lncRNA LINC01133 which suppresses gastric cancer metastasis by acting as a competitive endogenous RNA (ceRNA) for miR-106a-3p to regulate APC in Wnt/β-catenin signaling (173). Furthermore, LncRNA H19 (174), lncRNA HOXD-AS1 (175), lncRNA SNHG5 (176) and lncRNA UCA1 (177) were confirmed to regulate the Wnt signaling pathway by targeting miRNAs. All the evidence indicate that multiple miRNA-mediated signal transductions participate in the regulation of EMT. Revealing the connections of miRNAs and their upstream regulators may give us new prospective therapeutic strategies for cancer treatment.
Since miRNA has established its role in EMT, the strategy of utilizing miRNA to overcome cancer metastasis has increasingly gained attention. Although the complex mechanism of EMT regulation by miRNA has not been fully defined, miRNAs are still regarded as potential therapeutic implements in cancer (Fig. 2). On the one hand, various methods of directly switching the level of miRNA by miRNA mimics, miRNA sponges, or anti-miRNA oligonucleotides, which are under study for different phases, have been shown to be effective. On the other hand, indirect regulation of miRNAs by affecting upstream regulators (protein, circRNA, lncRNA) or crosstalk with other signaling pathways are also useful approaches to inhibit EMT. Currently, a number of miRNA-based therapies are in clinical trials to treat cancer or other diseases. However, safety concerns regarding miRNA therapy always exist. Off-target side-effects, toxicity, and carcinogenicity of miRNA are important challenges in the development of miRNA therapy. Seeking effective delivery systems for miRNA is also a dilemma, so further research may focus on these issues to improve the utilization value of miRNA therapy.
Conclusion
In conclusion, miRNAs regulate Wnt/β-catenin signaling through targeting transcription factors and key proteins of Wnt signaling or crosstalk with other signaling pathways. However, the complicated role of miRNA as either a tumor suppressor or an oncogene and its underlying mechanism need further exploration. This review, not only provides potential applications of miRNAs as molecular targets in invasive tumor treatment, but also helps us gain a better understanding of the complexity of the EMT process and crosstalk between Wnt/β-catenin and other signaling pathways.
Acknowledgements
The authors would like to thank Professor Dong-Mei Zhang (College of Pharmacy, Jinan University) and Jun-Shan Liu (Traditional Chinese Medicine, Southern Medical University) for their guidance.
Funding
This review was supported by the National Natural Science Foundation of China (grant nos. 81803790, 81573918, and 81703975), National Natural Science Foundation of Guangdong (grant no. 2020A1515011090), Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (grant no. 20181069), the Fundamental Research Funds for the Central Universities (grant no. 21618336), and Public Health Research Projects of Futian District, Shenzhen (grant no. FTWS2019064)
Availability of data and materials
Not applicable.
Authors' contributions
EXZ and LJD designed the study and revised the manuscript. YHL, LC and GZ searched the literature and drafted the manuscript. AYS, BL, JYS and CFZ were also involved in the conception of the study. JW, XL, CFY and YYC assisted with the critical revision of the manuscript. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
ReferencesPasquierJAbu-KaoudNAl ThaniHRafiiAEpithelial to mesenchymal transition in a clinical perspective2015792182201510.1155/2015/79218226425122YilmazMChristoforiGEMT, the cytoskeleton, and cancer cell invasion281533200910.1007/s10555-008-9169-019169796OkumuraNKagamiTFujiiKNakaharaMKoizumiNInvolvement of nectin-afadin in the adherens junctions of the corneal endothelium37633640201810.1097/ICO.000000000000152629384809TsukitaSFuruseMItohMMultifunctional strands in tight junctions2285293200110.1038/3506708811283726TakaiYMiyoshiJIkedaWOgitaHNectins and nectin-like molecules: Roles in contact inhibition of cell movement and proliferation9603615200810.1038/nrm245718648374InagakiMIrieKIshizakiHTanaka-OkamotoMMiyoshiJTakaiYRole of cell adhesion molecule nectin-3 in spermatid development1111251132200610.1111/j.1365-2443.2006.01006.x16923130OkabeNShimizuKOzaki-KurodaKNakanishiHMorimotoKTakeuchiMKatsumaruHMurakamiFTakaiYContacts between the commissural axons and the floor plate cells are mediated by nectins273244256200410.1016/j.ydbio.2004.05.03415328010HeubergerJBirchmeierWInterplay of cadherin-mediated cell adhesion and canonical Wnt signaling2a002915201010.1101/cshperspect.a00291520182623CoopmanPDjianeAAdherens Junction and E-Cadherin complex regulation by epithelial polarity7335353553201610.1007/s00018-016-2260-827151512GuoFParker KerriganBCYangDHuLShmulevichISoodAKXueFZhangWPost-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions719201410.1186/1756-8722-7-1924598126ThieryJPAcloqueHHuangRYNietoMAEpithelial-mesenchymal transitions in development and disease139871890200910.1016/j.cell.2009.11.00719945376DongCWuYWangYWangCKangTRychahouPGChiYIEversBMZhouBPInteraction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer3213511362201310.1038/onc.2012.16922562246GuoQQinWDKK3 blocked translocation of β-catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc-3 cell1928322841201510.1111/jcmm.1267526395974ZhaoJHLuoYJiangYGHeDLWuCTKnockdown of β-Catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1α29377382201110.3109/07357907.2010.51259521649463CaiJGuanHFangLYangYZhuXYuanJWuJLiMMicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis123566579201323321667KrolJLoedigeIFilipowiczWThe widespread regulation of microRNA biogenesis, function and decay11597610201010.1038/nrg284320661255WuCZhuangYJiangSLiuSZhouJWuJTengYXiaBWangRZouXInteraction between Wnt/beta-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)4822362246201610.3892/ijo.2016.348027082441ZaravinosAThe Regulatory Role of MicroRNAs in EMT and Cancer2015865816201510.1155/2015/86581625883654KimDHXingTYangZDudekRLuQChenYHEpithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview71201710.3390/jcm7010001ZhangRRGuiYHWangXRole of the canonical Wnt signaling pathway in heart valve development177577622015(In Chinese)26182289AhsanKSinghNRochaMHuangCPrinceVEPrickle1 is required for EMT and migration of zebrafish cranial neural crest4481635201910.1016/j.ydbio.2019.01.01830721665KalluriRWeinbergRAThe basics of epithelial-mesenchymal transition11914201428200910.1172/JCI3910419487818PaolilloMSerraMSchinelliSIntegrins in glioblastoma: Still an attractive target?1135561201610.1016/j.phrs.2016.08.00427498157SantoroRZanottoMCarboneCPiroGTortoraGMelisiDMEKK3 sustains EMT and stemness in pancreatic cancer by regulating YAP and TAZ transcriptional activity3819371946201829599309HuBTianXLiYYangTHanZAnJKongLLiYEpithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1926862697202010.1002/cam4.287132077634KangHKimHLeeSYounHYounBRole of Metabolic Reprogramming in Epithelial-Mesenchymal Transition (EMT)202042201910.3390/ijms20082042GargMEpithelial plasticity, autophagy and metastasis: Potential modifiers of the crosstalk to overcome therapeutic resistance202010.1007/s12015-019-09945-932125607ChenLMaiWChenMHuJZhuoZLeiXDengLLiuJYaoNHuangMArenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin123130142201710.1016/j.phrs.2017.07.00928712972DerynckRMuthusamyBPSaeteurnKYSignaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition315666201410.1016/j.ceb.2014.09.00125240174CreightonCJLiXLandisMDixonJMNeumeisterVMSjolundARimmDLWongHRodriguezAHerschkowitzJIResidual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features1061382013825200910.1073/pnas.090571810619666588PeinadoHOlmedaDCanoASnail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype?7415428200710.1038/nrc213117508028AstudilloPWnt5a Signaling in Gastric Cancer8110202010.3389/fcell.2020.0011032195251WangMMarcoPCapraVKibarZUpdate on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects81198201910.3390/cells8101198CiciDCorradoARotondoCCantatoreFPWnt signaling and biological therapy in rheumatoid arthritis and spondyloarthritis205552201910.3390/ijms20225552HuangGRWeiSJHuangYQXingWWangLYLiangLLMechanism of combined use of vitamin D and puerarin in anti-hepatic fibrosis by regulating the Wnt/β-catenin signalling pathway2441784185201810.3748/wjg.v24.i36.417830271082GayATowlerDAWnt signaling in cardiovascular disease: Opportunities and challenges28387396201710.1097/MOL.000000000000044528723729VillarroelADel Valle-PerezBFuertesGCurtoJOntiverosNGarcia de HerrerosADuñachMSrc and Fyn define a new signaling cascade activated by canonical and non-canonical Wnt ligands and required for gene transcription and cell invasion77919935202010.1007/s00018-019-03221-231312879RaoTPKuhlMAn updated overview on Wnt signaling pathways: A prelude for more10617981806201010.1161/CIRCRESAHA.110.21984020576942MacDonaldBTTamaiKHeXWnt/beta-catenin signaling: Components, mechanisms, and diseases17926200910.1016/j.devcel.2009.06.01619619488CleversHNusseRWnt/beta-catenin signaling and disease14911921205201210.1016/j.cell.2012.05.01222682243KawanoYKyptaRSecreted antagonists of the Wnt signalling pathway11626272634200310.1242/jcs.0062312775774BaficoALiuGYanivAGazitAAaronsonSANovel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow3683686200110.1038/3508308111433302BrottBKSokolSYRegulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins2261006110200210.1128/MCB.22.17.6100-6110.200212167704WuWGlinkaADeliusHNiehrsCMutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling1016111614200010.1016/S0960-9822(00)00868-X11137016MaoBNiehrsCKremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling302179183200310.1016/S0378-1119(02)01106-X12527209CruciatCMNiehrsCSecreted and transmembrane wnt inhibitors and activators5a015081201310.1101/cshperspect.a01508123085770PiccoloSAgiusELeynsLBhattacharyyaSGrunzHBouwmeesterTDe RobertisEMThe head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals397707710199910.1038/1782010067895ItasakiNJonesCMMercurioSRoweADomingosPMSmithJCKrumlaufRWise, a context-dependent activator and inhibitor of Wnt signalling13042954305200310.1242/dev.0067412900447SchmalhoferOBrabletzSBrabletzTE-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer28151166200910.1007/s10555-008-9179-y19153669TalbotLJBhattacharyaSDKuoPCEpithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies3117136201222773954GhahhariNMBabashahSInterplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer5116381649201510.1016/j.ejca.2015.04.02126025765GuoYXiaoLSunLLiuFWnt/beta-catenin signaling: A promising new target for fibrosis diseases61337346201210.33549/physiolres.93228922670697GebertLFRMacRaeIJRegulation of microRNA function in animals202137201910.1038/s41580-018-0045-730108335FilipowiczWBhattacharyyaSNSonenbergNMechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight?9102114200810.1038/nrg229018197166LeeYKimMHanJYeomKHLeeSBaekSHKimVNMicroRNA genes are transcribed by RNA polymerase II2340514060200410.1038/sj.emboj.760038515372072OkadaCYamashitaELeeSJShibataSKatahiraJNakagawaAYonedaYTsukiharaTA high-resolution structure of the pre-microRNA nuclear export machinery32612751279200910.1126/science.117870519965479DalmayTMechanism of miRNA-mediated repression of mRNA translation542938201310.1042/bse054002923829525ThomsonJMNewmanMParkerJSMorin-KensickiEMWrightTHammondSMExtensive post-transcriptional regulation of microRNAs and its implications for cancer2022022207200610.1101/gad.144440616882971Moyret-LalleCRuizEPuisieuxAEpithelial-mesenchymal transition transcription factors and miRNAs: ‘Plastic surgeons’ of breast cancer5311322201410.5306/wjco.v5.i3.31125114847ZengMZhuLLiLKangCmiR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD12212201710.1186/s11658-017-0041-528725241TianLZhaoZXieLZhuJMiR-361-5p inhibits the mobility of gastric cancer cells through suppressing epithelial-mesenchymal transition via the Wnt/β-catenin pathway675102109201810.1016/j.gene.2018.06.09529960070GuoRWuZWangJLiQShenSWangWZhouLWangWCaoZGuoYDevelopment of a Non-Coding-RNA-based EMT/CSC Inhibitory Nanomedicine for In Vivo Treatment and Monitoring of HCC61801885201910.1002/advs.20180188531065520TeagueEMPrintCGHullMLThe role of microRNAs in endometriosis and associated reproductive conditions16142165201010.1093/humupd/dmp03419773286WiklundEDBramsenJBHulfTDyrskjøtLRamanathanRHansenTBVilladsenSBGaoSOstenfeldMSBorreMCoordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer12813271334201110.1002/ijc.2546120473948TryndyakVPBelandFAPogribnyIPE-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells12625752583201019839049Elson-SchwabILorentzenAMarshallCJMicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion5e13176201010.1371/journal.pone.001317620957176HuXMacdonaldDMHuettnerPCFengZEl NaqaIMSchwarzJKMutchDGGrigsbyPWPowellSNWangXA miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer114457464200910.1016/j.ygyno.2009.05.02219501389ShinozakiASakataniTUshikuTHinoRIsogaiMIshikawaSUozakiHTakadaKFukayamaMDownregulation of microRNA-200 in EBV-associated gastric carcinoma7047194727201010.1158/0008-5472.CAN-09-462020484038KongDLiYWangZBanerjeeSAhmadAKimHRSarkarFHmiR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells2717121721200910.1002/stem.10119544444GregoryPABertAGPatersonELBarrySCTsykinAFarshidGVadasMAKhew-GoodallYGoodallGJThe miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP110593601200810.1038/ncb172218376396SaydamOShenYWurdingerTSenolOBokeEJamesMFTannousBAStemmer-RachamimovAOYiMStephensRMDownregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway2959235940200910.1128/MCB.00332-0919703993Sanchez-TilloELazaroATorrentRCuatrecasasMVaqueroECCastellsAEngelPPostigoAZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG12934903500201010.1038/onc.2010.10220418909CongNDuPZhangAShenFSuJPuPWangTZjangJKangCZhangQDownregulated microRNA-200a promotes EMT and tumor growth through the wnt/β-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma2915791587201310.3892/or.2013.226723381389SuJZhangAShiZMaFPuPWangTZhangJKangCZhangQMicroRNA-200a suppresses the Wnt/β-catenin signaling pathway by interacting with β-catenin4011621170201222211245TianYPanQShangYZhuRYeJLiuYZhongXLiSHeYChenLMicroRNA-200 (miR-200) cluster regulation by achaete scute-like 2 (Ascl2): Impact on the epithelial-mesenchymal transition in colon cancer cells2893610136115201410.1074/jbc.M114.59838325371200LiuJRuanBYouNHuangQLiuWDangZXuWZhouTJiRCaoYDownregulation of miR-200a induces EMT phenotypes and CSC-like signatures through targeting the beta-catenin pathway in hepatic oval cells8e79409201310.1371/journal.pone.007940924260215ParkSMGaurABLengyelEPeterMEThe miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB222894907200810.1101/gad.164060818381893SulimanMAZhangZNaHRibeiroALZhangYNiangBHamidASZhangHXuLZuoYNiclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family38776784201610.3892/ijmm.2016.268927460529FengBWangRSongHZChenLBMicroRNA-200b reverses chemoresistance of docetaxel-resistant human lung adenocarcinoma cells by targeting E2F311833653376201210.1002/cncr.2656022139708QuJLiMAnJZhaoBZhongWGuQCaoLYangHHuCMicroRNA-33b inhibits lung adenocarcinoma cell growth, invasion, and epithelial-mesenchymal transition by suppressing Wnt/β-catenin/ZEB1 signaling4721412152201510.3892/ijo.2015.318726459797ZhangXXuXGeGZangXShaoMZouSZhangYMaoZZhangJMaoFmiR498 inhibits the growth and metastasis of liver cancer by targeting ZEB24116381648201930592286YueHTangBZhaoYNiuYYinPYangWZhangZYuPMIR-519d suppresses the gastric cancer epithelial-mesenchymal transition via Twist1 and inhibits Wnt/β-catenin signaling pathway936543664201728861156JinYWangJHanJLuoDSunZMiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Snail1 and Snail2 and suppressing WNT/β-cadherin signaling pathway360210217201710.1016/j.yexcr.2017.09.01028890291SongXFWangQHHuoREffects of microRNA-708 on epithelial-mesenchymal transition, cell proliferation and apoptosis in melanoma cells by targeting lef1 through the wnt signaling pathway25377389201910.1007/s12253-017-0334-z29138985LiangJLiYDanielsGSfanosKDe MarzoAWeiJLiXChenWWangJZhongXLEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a13681688201510.1158/1541-7786.MCR-14-050325587085ChenJLuoQYuanYHuangXCaiWLiCWeiTZhangLYangMLiuQPygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion3056215635201010.1128/MCB.00465-1020937768ChiYWangFZhangTXuHZhangYShanZWuSFanQSunYmiR-516a-3p inhibits breast cancer cell growth and EMT by blocking the Pygo2/Wnt signalling pathway2362956307201910.1111/jcmm.1451531273950ZhengHEWangGSongJLiuYLiYMDuWPMicroRNA-495 inhibits the progression of non-small-cell lung cancer by targeting TCF4 and inactivating Wnt/beta-catenin pathway2277507759201830536319XuZYuZTanQWeiCTangQWangLHongYMiR-876-5p regulates gastric cancer cell proliferation, apoptosis and migration through targeting WNT5A and MITF39BSR20190066201910.1042/BSR2019006631171711ZhangYZhangXWangXGanLYuGChenYLiuKLiPPanJWangJQinSInhibition of LDH-A by lentivirus-mediated small interfering RNA suppresses intestinal-type gastric cancer tumorigenicity through the downregulation of Oct43214554201210.1016/j.canlet.2012.03.01322429998IidaHSuzukiMGoitsukaRUenoHHypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2407179201221947321LingDJChenZSZhangYDLiaoQDFengJXZhangXYShiTSMicroRNA-145 inhibits lung cancer cell metastasis1131083114201510.3892/mmr.2014.303625483817LiuHYinJWangHJiangGDengMZhangGBuXCaiSDuJHeZFOXO3a modulates WNT/beta-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells27510518201510.1016/j.cellsig.2015.01.00125578861ZhangQMiaoSHanXLiCZhangMCuiKXiongTChenZWangCXuHMicroRNA-3619-5p suppresses bladder carcinoma progression by directly targeting β-catenin and CDK2 and activating p219960201810.1038/s41419-018-0986-y30237499LiangCWangZLiYYYuBHZhangFLiHYmiR-33a suppresses the nuclear translocation of beta-catenin to enhance gemcitabine sensitivity in human pancreatic cancer cells3693959403201510.1007/s13277-015-3679-526113407WangNWangQShenDSunXCaoXWuDDownregulation of microRNA-122 promotes proliferation, migration, and invasion of human hepatocellular carcinoma cells by activating epithelial-mesenchymal transition920352047201610.2147/OTT.S9237827103830YanHDongXZhongXYeJZhouYYangXShenJZhangJInhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma53960969201410.1002/mc.2206423861222PengLLiuZXiaoJTuYWanZXiongHLiYXiaoWMicroRNA-148a suppresses epithelial-mesenchymal transition and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/beta-catenin signaling pathway38301308201710.3892/or.2017.570528586066HuangXZhuHGaoZLiJZhuangJDongYShenBLiMZhouHGuoHHuangRYanJWnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p29366936706201810.1074/jbc.RA118.00168929549123YangYSunYWuYTangDDingXXuWSuBGaoWDownregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/β-catenin signaling in non-small-cell lung cancer57842853201810.1002/mc.2280529566281LiuQGuanYLiZWangYLiuYCuiRWangYmiR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt-β-catenin pathway38358201910.1186/s13046-019-1370-131419987JinRLiuWMenezesSYueFZhengMKovacevicZRichardsonDRThe metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK412731163130201410.1242/jcs.14783524829151ZhengKZhouXYuJLiQWangHLiMShaoZZhangFLuoYShenZEpigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway376178187201610.1016/j.canlet.2016.03.02427037061CuiYYangYRenLYangJWangBXingTChenHChenMmiR-15a-3p Suppresses Prostate Cancer Cell Proliferation and Invasion by Targeting SLC39A7 Via Downregulating Wnt/β-Catenin Signaling Pathway34472479201910.1089/cbr.2018.272231135177NimmanonTZiliottoSMorrisSFlanaganLTaylorKMPhosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling9471481201710.1039/C6MT00286B28205653ZhaoXLuYNieYFanDMicroRNAs as critical regulators involved in regulating epithelial- mesenchymal transition13935944201310.2174/1568009611313666009924168189HuangHWangCLiuFLiHZPengGGaoXDongKQWangHRKongDPQuMReciprocal network between cancer stem-like cells and macrophages facilitates the progression and androgen deprivation therapy resistance of prostate cancer2446124626201810.1158/1078-0432.CCR-18-046129691294AraiKEguchiTRahmanMMSakamotoRMasudaNNakatsuraTCalderwoodSKKozakiKItohMA Novel high-throughput 3D screening system for EMT inhibitors: A pilot screening discovered the EMT inhibitory activity of CDK2 Inhibitor SU951611e0162394201610.1371/journal.pone.016239427622654WangXChenZKnockdown of CUL4B Suppresses the Proliferation and Invasion in Non-Small Cell Lung Cancer Cells24271277201610.3727/096504016X1466699034747327656838ZhangJQChenSGuJNZhuYZhanQChengDFChenHDengXXShenBYPengCHMicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells11910271040201810.1002/jcb.2627028685847YuRCaiLChiYDingXWuXmiR377 targets CUL4A and regulates metastatic capability in ovarian cancer4131473156201829512715ParaisoKHDas ThakurMFangBKoomenJMFedorenkoIVJohnJKTsaoHFlahertyKTSondakVKMessinaJLLigand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype5264273201510.1158/2159-8290.CD-14-029325542447HuangJHeYMcLeodHLXieYXiaoDHuHChenPShenLZengSYinXmiR-302b inhibits tumorigenesis by targeting EphA2 via Wnt/β-catenin/EMT signaling cascade in gastric cancer17886201710.1186/s12885-017-3875-329273006SongBLinHXDongLLMaJJJiangZGMicroRNA-338 inhibits proliferation, migration, and invasion of gastric cancer cells by the Wnt/β-catenin signaling pathway2212901296201829565486ZhouFGouSXiongJWuHWangCLiuTOncogenicity of LHX2 in pancreatic ductal adenocarcinoma4181638167201410.1007/s11033-014-3716-225324171LiangTSZhengYJWangJZhaoJYYangDKLiuZSMicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/β-catenin signaling pathway by down-regulating LHX23897201910.1186/s13046-019-1023-430791932ChenJRajasekaranMXiaHZhangXKongSNSekarKSeshachalamVPDeivasigamaniAGohBKOoiLLThe microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway6515221534201610.1136/gutjnl-2015-31062526941395TangHZhaoHYuZYFengXFuBSQiuCHZhangJWMicroRNA-194 inhibits cell invasion and migration in hepatocellular carcinoma through PRC1-mediated inhibition of Wnt/β-catenin signaling pathway5113141322201910.1016/j.dld.2019.02.01230948333ChenCHChuangSMYangMFLiaoJWYuSLChenJJA novel function of YWHAZ/beta-catenin axis in promoting epithelial-mesenchymal transition and lung cancer metastasis1013191331201210.1158/1541-7786.MCR-12-018922912335GuoFGaoYSuiGJiaoDSunLFuQJinCmiR-375-3p/YWHAZ/β-catenin axis regulates migration, invasion, EMT in gastric cancer cells46144152201910.1111/1440-1681.1304730353914ShiLHuoJWChenSSXueJXGaoWYLiXYSongYHXuHTZhuXWChenKMicroRNA-22 targets FMNL2 to inhibit melanoma progression via the regulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition2353325342201931298385WangJJLiZFLiXJHanZZhangLLiuZJEffects of microRNA-136 on melanoma cell proliferation, apoptosis, and epithelial-mesenchymal transition by targetting PMEL through the Wnt signaling pathway37BSR20170743201710.1042/BSR2017074328724603ZhangJXMaiSJHuangXXWangFWLiaoYJLinMCKungHFZengYXXieDMiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling2521962204201410.1093/annonc/mdu43925193986ZhangZYangYZhangXMiR-770 inhibits tumorigenesis and EMT by targeting JMJD6 and regulating WNT/β-catenin pathway in non-small cell lung cancer188163171201710.1016/j.lfs.2017.09.00228882645YanakaYMuramatsuTUetakeHKozakiKInazawaJmiR-544a induces epithelial-mesenchymal transition through the activation of WNT signaling pathway in gastric cancer3613631371201510.1093/carcin/bgv10626264654HuZWangPLinJZhengXYangFZhangGChenDXieJGaoZPengLXieCMicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling51470486201810.1159/00049524230453289GebertLFRebhanMACrivelliSEDenzlerRStoffelMHallJMiravirsen (SPC3649) can inhibit the biogenesis of miR-12242609621201410.1093/nar/gkt85224068553PetrovaYISchectersonLGumbinerBMRoles for E-cadherin cell surface regulation in cancer2732333244201610.1091/mbc.E16-01-005827582386XuXZLiXALuoYLiuJFWuHWHuangGMiR-9 promotes synovial sarcoma cell migration and invasion by directly targeting CDH11126171201910.1016/j.biocel.2019.04.00130959202MaFLiWLiuCLiWYuHLeiBRenYLiZPangDQianCMiR-23a promotes TGF-β1-induced EMT and tumor metastasis in breast cancer cells by directly targeting CDH1 and activating Wnt/β-catenin signaling86953869550201710.18632/oncotarget.1842229050223ZhaoXHeLLiTLuYMiaoYLiangSGuoHBaiMXieHLuoGSRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer2119001913201410.1038/cdd.2014.10925080937ZhangZLiuSShiRZhaoGmiR-27 promotes human gastric cancer cell metastasis by inducing epithelial-to-mesenchymal transition204486491201110.1016/j.cancergen.2011.07.00422018270MaoXWXiaoJQLiZYZhengYCZhangNEffects of microRNA-135a on the epithelial-mesenchymal transition, migration and invasion of bladder cancer cells by targeting GSK3β through the Wnt/β-catenin signaling pathway50e429201810.1038/emm.2017.23929350680YangFXiongHDuanLLiQLiXZhouYMiR-1246 Promotes Metastasis and Invasion of A549 cells by Targeting GSK-3betaMediated Wnt/β-Catenin Pathway5114201429201910.4143/crt.2018.63830913872HoeflichKPLuoJRubieEATsaoMSJinOWoodgettJRRequirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation4068690200010.1038/3501757410894547LiuWYYangZSunQYangXHuYXieHGaoHJGuoLMYiJYLiuMTangHmiR-377-3p drives malignancy characteristics via upregulating GSK-3β expression and activating NF-κB pathway in hCRC cells11921242134201810.1002/jcb.2637428857252NieJJiangHCZhouYCJiangBHeWJWangYFDongJMiR-125b regulates the proliferation and metastasis of triple negative breast cancer cells via the Wnt/β-catenin pathway and EMT8310621071201910.1080/09168451.2019.158452130950326Barrantes IdelBMontero-PedrazuelaAGuadano-FerrazAObregonMJMartinez de MenaRGailus-DurnerVFuchsHFranzTJKalaydjievSKlemptMGeneration and characterization of dickkopf3 mutant mice2623172326200610.1128/MCB.26.6.2317-2326.200616508007HoangBHKuboTHealeyJHYangRNathanSSKolbEAMazzaBMeyersPAGorlickRDickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway6427342739200410.1158/0008-5472.CAN-03-195215087387XiMChengLHuaWZhouYLGaoQLYangJXQiSYMicroRNA-95-3p promoted the development of prostatic cancer via regulating DKK3 and activating Wnt/β-catenin pathway2310021011201930779066WengJZhangHWangCLiangJChenGLiWTangHHouJmiR-373-3p Targets DKK1 to promote EMT-induced metastasis via the Wnt/β-catenin pathway in tongue squamous cell carcinoma20176010926201710.1155/2017/601092628337453ElziDJSongMHakalaKWeintraubSTShiioYWnt antagonist SFRP1 functions as a secreted mediator of senescence3243884399201210.1128/MCB.06023-1122927647QiaoBHeBXCaiJHTaoQKing-Yin LamAMicroRNA-27a-3p modulates the Wnt/β-catenin signaling pathway to promote epithelial-mesenchymal transition in oral squamous carcinoma stem cells by targeting SFRP1744688201710.1038/srep4468828425477ZebischMXuYKrastevCMacDonaldBTChenMGilbertRJHeXJonesEYStructural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin42787201310.1038/ncomms378724225776QiaoGDaiCHeYShiJXuCEffects of miR106b3p on cell proliferation and epithelialmesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma4318171829201930816445DengXWuBXiaoKKangJXieJZhangXFanYMiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3357182201510.1159/00036967625547151ZhangWChenXKatoYEvansPMYuanSYangJRychahouPGYangVWHeXEversBMLiuCNovel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression2620552064200610.1128/MCB.26.6.2055-2064.200616507986ChenELiQWangHYangFMinLYangJMiR-92a promotes tumorigenesis of colorectal cancer, a transcriptomic and functional based study10613701377201810.1016/j.biopha.2018.07.09830119209ParentiSMontorsiLFantiniSMammoliFGemelliCAteneCGLosiLFrassinetiCCalabrettaBTagliaficoEKLF4 Mediates the Effect of 5-ASA on the β-Catenin Pathway in Colon Cancer Cells11503510201810.1158/1940-6207.CAPR-17-038229794245FanDLinXZhangFZhongWHuJChenYCaiZZouYHeXChenXMicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A109354362201810.1111/cas.1345129160937TanMWuJCaiYSuppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer438673679201310.1016/j.bbrc.2013.07.12323939044TokarzPBlasiakJThe role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment59467474201210.18388/abp.2012_207923173124GarzonRMarcucciGCroceCMTargeting microRNAs in cancer: Rationale, strategies and challenges9775789201010.1038/nrd317920885409BaderAGmiR-34-a microRNA replacement therapy is headed to the clinic3120201210.3389/fgene.2012.0012022783274SlabyOLagaRSedlacekOTherapeutic targeting of non-coding RNAs in cancer47442194251201710.1042/BCJ2017007929242381TrangPWigginsJFDaigeCLChoCOmotolaMBrownDWeidhaasJBBaderAGSlackFJSystemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice1911161122201110.1038/mt.2011.4821427705LiuCKelnarKLiuBChenXCalhoun-DavisTLiHPatrawalaLYanHJeterCHonorioSThe microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD4417211215201110.1038/nm.228421240262ZhangLLiaoYTangLMicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer3853201910.1186/s13046-019-1059-530717802Gallant-BehmCLPiperJDickinsonBADalbyCMPestanoLAJacksonALA synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds26311323201810.1111/wrr.1266030118158RupaimooleRSlackFJMicroRNA therapeutics: Towards a new era for the management of cancer and other diseases16203222201710.1038/nrd.2016.24628209991QiYLiJTriptolide inhibits the growth and migration of colon carcinoma cells by down-regulation of miR-1911072331201910.1016/j.yexmp.2019.01.00830684462WangGHuangYXZhangRHouLDLiuHChenXYZhuJSZhangJToosendanin suppresses oncogenic phenotypes of human gastric carcinoma SGC7901 cells partly via miR200amediated downregulation of β-catenin pathway5115631573201710.3892/ijo.2017.413929048657AhmadASarkarSHBitarBAliSAboukameelASethiSLiYBaoBKongDBanerjeeSGarcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells1121932201201210.1158/1535-7163.MCT-12-0232-T22821148DuQZhangXZhangXWeiMXuHWangSPropofol inhibits proliferation and epithelial-mesenchymal transition of MCF-7 cells by suppressing miR-21 expression4712651271201910.1080/21691401.2019.159400030942630ZhaoMXuPLiuZZhenYChenYLiuYFuQDengXLiangZLiYDual roles of miR-374a by modulated c-Jun respectively targets CCND1-inducing PI3K/AKT signal and PTEN-suppressing Wnt/β-catenin signaling in non-small-cell lung cancer978201810.1038/s41419-017-0103-729362431SathyanarayananAChandrasekaranKSKarunagaranDmicroRNA-145 downregulates SIP1-expression but differentially regulates proliferation, migration, invasion and Wnt signaling in SW480 and SW620 cells11920222035201810.1002/jcb.2636528833449LiDTianBJinXmiR-630 Inhibits Epithelial-to-Mesenchymal Transition (EMT) by Regulating the Wnt/β-Catenin Pathway in Gastric Cancer Cells27917201810.3727/096504018X1517873262547929422112ChienAJMooreECLonsdorfASKulikauskasRMRothbergBGBergerAJMajorMBHwangSTRimmDLMoonRTActivated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model10611931198200910.1073/pnas.081190210619144919HaTYMicroRNAs in human diseases: From cancer to cardiovascular disease11135154201110.4110/in.2011.11.3.13521860607WangHYLiuYNWuSGHsuCLChangTHTsaiMFLinYTShihJYMiR-200c-3p suppression is associated with development of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer via a mediating epithelial-to-mesenchymal transition (EMT) process28351363202010.3233/CBM-19111932417760CochraneDRSpoelstraNSHoweENNordeenSKRicherJKMicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents810551066200910.1158/1535-7163.MCT-08-104619435871GaoSYuYLiuLMengJLiGCircular RNA hsa_circ_0007059 restrains proliferation and epithelial-mesenchymal transition in lung cancer cells via inhibiting microRNA-378233116692201910.1016/j.lfs.2019.11669231351967YangXZChengTTHeQJLeiZYChiJTangZLiaoQXZhangHZengLSCuiSZLINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/beta-catenin pathway17126201810.1186/s12943-018-0874-130134915DingDLiCZhaoTLiDYangLZhangBLncRNA H19/miR-29b-3p/PGRN axis promoted epithelial-mesenchymal transition of colorectal cancer cells by acting on wnt signaling41423435201829754471ZhangYDunYZhouSHuangXHLncRNA HOXD-AS1 promotes epithelial ovarian cancer cells proliferation and invasion by targeting miR-133a-3p and activating Wnt/β-catenin signaling pathway9612161221201710.1016/j.biopha.2017.11.09629239819LiYGuoDZhaoYRenMLuGWangYZhangJMiCHeSLuXLong non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3β signal pathway9888201810.1038/s41419-018-0882-530166525ChenXGaoJYuYZhaoZPanYLong non-coding RNA UCA1 targets miR-185-5p and regulates cell mobility by affecting epithelial-mesenchymal transition in melanoma via Wnt/β-catenin signaling pathway676298305201810.1016/j.gene.2018.08.06530144501TaubeJHMaloufGGLuESphyrisNVijayVRamachandranPPUenoKRGaurSNicolosoMSRossiSEpigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties32687201310.1038/srep0268724045437StrillacciAValeriiMCSansonePCaggianoCSgromoAVittoriLFiorentinoMPoggioliGRizzelloFCampieriMSpisniELoss of miR-101 expression promotes Wnt/β-catenin signalling pathway activation and malignancy in colon cancer cells229379389201310.1002/path.409722930392HuangZLiQLuoKZhangQGengJZhouXXuYQianMZhangJAJiLWuJmiR-340-FHL2 axis inhibits cell growth and metastasis in ovarian cancer10372201910.1038/s41419-019-1604-331068580LiuPChenBGuYLiuQPNMA1, regulated by miR-33a-5p, promotes proliferation and EMT in hepatocellular carcinoma by activating the Wnt/β-catenin pathway108492499201810.1016/j.biopha.2018.09.05930243081HanSCaoCTangTLuCXuJWangSXueLZhangXLiMROBO3 promotes growth and metastasis of pancreatic carcinoma3666170201510.1016/j.canlet.2015.06.00426070964LiYLvZHeGWangJZhangXLuGRenXWangFZhuXDingYThe SOX17/miR-371-5p/SOX2 axis inhibits EMT, stem cell properties and metastasis in colorectal cancer690999112201510.18632/oncotarget.360325868860XuWJiJXuYLiuYShiLLiuYLuXZhaoYLuoFWangBMicroRNA-191, by promoting the EMT and increasing CSC-like properties, is involved in neoplastic and metastatic properties of transformed human bronchial epithelial cells54(Suppl 1)E148161201510.1002/mc.2222125252218LiYSunDGaoJShiZChiPMengYZouCWangYMicroRNA-373 promotes the development of endometrial cancer by targeting LATS2 and activating the Wnt/β-Catenin pathway2018YangZWangXLBaiRLiuWYLiXLiuMTangHmiR-23a promotes IKKα expression but suppresses ST7L expression to contribute to the malignancy of epithelial ovarian cancer cells115731740201610.1038/bjc.2016.24427537390WangCWangXSuZFeiHLiuXPanQMiR-25 promotes hepatocellular carcinoma cell growth, migration and invasion by inhibiting RhoGDI163623136244201510.18632/oncotarget.474026460549HaoJJinXShiYZhangHmiR-93-5p enhance lacrimal gland adenoid cystic carcinoma cell tumorigenesis by targeting BRMS1L1872201810.1186/s12935-018-0552-929760585TangJLiLHuangWSuiCYangYLinXHouGChenXFuJYuanSMiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition3643343201510.1016/j.canlet.2015.04.02325931210SongQXuYYangCChenZJiaCChenJZhangYLaiPFanXZhouXmiR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM7430313042201410.1158/0008-5472.CAN-13-219324710410WangHYanBZhangPLiuSLiQYangJYangFChenEMiR-496 promotes migration and epithelial-mesenchymal transition by targeting RASSF6 in colorectal cancer23514691479202010.1002/jcp.2906631273789LiuLTianYCMaoGZhangYGHanLMiR-675 is frequently overexpressed in gastric cancer and enhances cell proliferation and invasion via targeting a potent anti-tumor gene PITX162109352201910.1016/j.cellsig.2019.10935231260797ZhangXPengYHuangYYangMYanRZhaoYChengYLiuXDengSFengXSMG-1 inhibition by miR-192/-215 causes epithelial-mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling7146156201810.1002/cam4.123729239144PeiYFYinXMLiuXQTOP2A induces malignant character of pancreatic cancer through activating β-catenin signaling pathway1864197207201810.1016/j.bbadis.2017.10.01929045811GuoYHWangLQLiBXuHYangJHZhengLSYuPZhouADZhangYXieSJWnt/β-catenin pathway transactivates microRNA-150 that promotes EMT of colorectal cancer cells by suppressing CREB signaling74251342526201610.18632/oncotarget.989327285761LiangHWangCGaoKLiJJiaRMuicroRNA-421 promotes the progression of nonsmall cell lung cancer by targeting HOPX and regulating the Wnt/β-catenin signaling pathway20151161201931115507ListingHMardinWAWohlfrommSMeesSTHaierJMiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer112131139201510.1038/bjc.2014.58725422915
Regulation of Wnt/β-catenin signaling by miRNAs. Left panel: miRNAs targeting inactive Wnt/β-catenin signaling to initiate EMT. In the absence of Wnt ligands, β-catenin is phosphorylated by GSK3β by forming a destruction complex with Axin, APC, CKIα and GSK3β, forming β-catenin degradation by ubiquitin. MiRNAs facilitate EMT by targeting Wnt/β-catenin suppressors. Right panel: miRNAs targeting activated Wnt/β-catenin signaling to inhibit EMT. When receptors received Wnt ligands, the phosphorylation of β-catenin by GSK3β was inhibited, followed by β-catenin disassembly from the destruction complex and accumulation in cytoplasm. Then, β-catenin translocated to the nucleus and formed a complex with TCF/LEF, which promoted transcription of Wnt target genes such as Twist and Snail, thus facilitating EMT. MiRNAs block EMT by targeting various components of the Wnt/β-catenin signaling pathway.
Use of miRNAs to combat EMT. MiRNAs regulate Wnt/β-catenin signaling by targeting downstream transcription factors and key proteins of Wnt signaling or crosstalk with other signaling pathways. The strategies of using miRNAs to combat EMT include delivering miRNA mimic, anti-miRNA oligonucleotides or small molecule inhibitors. In addition, circRNA as miRNA sponge, lncRNA as ceRNA, and targeting regulatory proteins may constitute new prospective therapeutic strategies for cancer treatment.
Inhibition of EMT by miRNAs.
miRNA
Cancer type
Molecular targets
(Refs.)
miR-125b-5p
Hepatocellular carcinoma
STAT3
(62)
miR-200 family
Gastric adenocarcinoma
ZEB1/2, β-catenin
(73,74)
Hepatocellular carcinoma
β-catenin
(76)
Colonic adenocarcinoma
ZEB1/2
(75)
miR-122
Hepatocellular carcinoma
Wnt1, Snail1/2
(83,96)
miR-3127-5p
Non-small-cell lung cancer
FZD4
(100)
miR-136
Melanoma
PMEL
(122)
miR-708
Melanoma
LEF1
(84)
miR-203
Breast cancer
DKK1
(178)
miR-490-3p
Colorectal cancer
FRAT1
(103)
miR-34b/c
Prostate cancer
β-catenin
(93)
miR-148a
Hepatocellular carcinoma
Wnt1
(97)
Pancreatic cancer
Wnt10b
(98)
miR-34a
Prostate cancer
LEF1
(85)
miR-101
Colon cancer
EZH2
(179)
miR-22
Melanoma
FMNL2
(121)
miR-33b
Lung adenocarcinoma
ZEB1
(80)
miR-145
Lung cancer
Oct4
(92)
miR-194
Hepatocellular carcinoma
PRC1
(118)
miR-300
Pancreatic cancer
CUL4B
(110)
miR-338
Gastric cancer
EphA2
(114)
miR-495
Non-small-cell lung cancer
TCF4
(88)
miR-506
Nasopharyngeal carcinoma
LHX2
(116)
miR-3619-5p
Bladder carcinoma
β-catenin, CDK2, p21
(94)
miR-15a-3p
Prostate cancer
SLC39A7
(104)
miR-29c
Colorectal carcinoma
GNA13, PTP4A
(123)
miR-33a
Pancreatic cancer
β-catenin
(95)
miR-302b
Gastric cancer
EphA2
(113)
miR-340
Ovarian cancer
FHL2
(180)
miR-375
Gastric cancer
YWHAZ
(120)
miR-377
Ovarian cancer
CUL4A
(111)
miR-378
Colon cancer
SDAD1
(60)
miR-498
Liver cancer
ZEB2
(81)
miR-504
Glioblastoma
FZD7
(101)
miR-516a-3p
Breast cancer
Pygo2
(87)
miR-519d
Gastric cancer
Twist1
(82)
miR-770
Non-small-cell lung cancer
JMJD6
(124)
miR-876-5p
Gastric cancer
Wnt5A and MITF
(89)
miR-33a-5p
Hepatocellular carcinoma
PNMA1
(181)
miR-383
Pancreatic carcinoma
ROBO3
(182)
miR-371-5p
Colorectal cancer
SOX2
(183)
miR-370-3p
Bladder cancer
Wnt7a
(99)
STAT3, signal transducer and activator of transcription 3; ZEB, zinc finger E-box-binding homeobox; FZD, Frizzled; PMEL, Premelanosome Protein; LEF1, lymphoid enhancer factor 1; DKK1, Dickkopf 1; FRAT1, frequently rearranged in advanced T-cell lymphomas 1; EZH2, enhancer of zeste homolog 2; FMNL2, formin like 2; Oct4, octamer-binding protein 4; PRC1, protein regulator of cytokinesis 1; CUL4B, cullin 4B; EphA2, EPH receptor A2; TCF4, T-cell factor 4; LHX2, LIM homeobox 2; CDK2, cyclin-dependent kinase 2; PTP4A, protein tyrosine phosphatase 4A2; GNA13, G protein subunit alpha 13; FHL2, four and a half LIM domains 2; CUL4A, Cullin 4A; SDAD1, SDA1 Domain Containing 1; Pygo2, Pygopus2; JMJD6, Jumonji Domain Containing 6; MITF, melanogenesis-associated transcription factor; PNMA1, paraneoplastic ma sntigen 1; ROBO3, roundabout guidance receptor 3; SOX2, SRY-box transcription factor 2.
Promotion of EMT by miRNAs.
MiRNA
Cancer type
Molecular targets
(Refs.)
miR-135
Bladder cancer
GSK3β
(133)
miR-106b-3p
Esophageal squamous cell carcinoma
ZNRF3
(145)
miR-26b
Colorectal cancer
PTEN, Wnt5A
(150)
miR-27a-3p
Oral squamous carcinoma stem cells
SFRP1
(143)
miR-95-3p
Prostatic cancer
DKK3
(140)
miR-191
Lung cancer
BASP1
(184)
miR-197
Hepatocellular carcinoma
AXIN2, NKD1, DKK2
(126)
miR-373
Endometrial cancer
LATS2
(185)
miR-374a
Breast cancer
WIF1, PTEN, Wnt5A
(15)
miR-9
Synovial sarcoma
E-cadherin
(129)
miR-23a
Epithelial ovarian cancer
ST7L
(186)
Breast cancer
E-cadherin
(130)
miR-25
Hepatocellular carcinoma
RhoGDI1
(187)
miR-27
Gastric cancer
APC
(132)
miR-93-5p
Lacrimal gland adenoid cystic carcinoma
BRMS1L
(188)
miR-125b
Triple negative breast cancer
APC
(137)
miR-146b-5p
Thyroid cancer
ZNRF3
(146)
miR-373-3p
Tongue squamous cell carcinoma
DKK1
(141)
miR-429
Hepatocellular carcinoma
PTEN
(189)
miR-483-5p
Lung adenocarcinoma
RhoGDI1, ALCAM
(190)
miR-496
Colorectal cancer
RASSF6
(191)
miR-544a
Gastric cancer
E-cadherin, AXIN2
(125)
miR-675
Gastric cancer
PITX1
(192)
miR-1246
Lung cancer
GSK3β
(134)
miR-192/215
Gastric cancer
SMG-1
(193)
miR-199a-5p
Gastric cancer
E-cadherin
(131)
miR-139
Pancreatic cancer
TOP2A
(194)
miR-150
Colorectal cancer
CREB1, EP300
(195)
miR-421
Non-small cell lung cancer
HOPX
(196)
miR-23a/24
Pancreatic ductal adenocarcinoma
FZD5, TMEM92, HNF1B
(197)
miR-92a
Colorectal cancer
KLF4
(148)
GSK3β, glycogen synthase kinase 3β; ZNRF3, zinc and ring finger 3; PTEN, phosphatase and tensin homologue; SFRP1, secreted frizzled-related protein 1; BASP1, brain abundant membrane attached signal protein 1; LATS2, large tumor suppressor kinase 2; WIF1, Wnt inhibitory factor 1; APC, adenomatous polyposis coli; ALCAM, activated leukocyte cell adhesion molecule; RASSF6, Ras association domain family member 6; PITX1, paired-like homeodomain 1; TOP2A, DNA Topoisomerase II Alpha; CREB1, CAMP responsive element binding protein 1; EP300, E1A binding protein P300; HOPX, homeodomain only protein x; HNF1B, HNF1 homeobox B; KLF4, Kruppel-like factor 4.