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beta-catenin activation leads to Epithelial-mesenchymal transition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Increases in cellular reactive oxygen species and chronic reactive oxygen species leading to human treatment-resistant gastric cancer||adjacent||Moderate||Moderate||Shihori Tanabe (send email)||Open for comment. Do not cite||EAGMST Under Review|
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induce the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; Yang et al., 2019).
EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 2014). The transcription factors such as Snail, ZEB and Twist bind to E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).
Evidence Collection Strategy
Evidence Supporting this KER
The treatment of human gastric cancer cells with INC280, which inhibits c-MET overexpressed in diffuse-type gastric cancer with poor prognosis, shows downregulation in beta-catenin and Snail expression,(Sohn et al., 2019).
The treatment with garcinol, a polyisoprenylated benzophenone derivative that is obtained from Garcinia indica extract, induced ZEB1 and ZEB2 down-regulation, increase in phosphorylated beta-catenin, and decrease in nuclear beta-catenin in human breast cancer cells (Ahmad et al., 2012).
Sortilin, a member of the Vps10p sorting receptor family which is highly expressed in high-grade malignant glioma, positively regulates GSK-3beta/beta-catenin/Twist signaling pathway in glioblastoma (Yang et al., 2019).
TM4SF1 promotes EMT via Wnt/beta-catenin/SOX2 pathway in colorectal cancer (Yang et al., 2020).
The transcription factors such as Snail, Zeb, and Twist inhibit the CDH1 expression through their binding towards the promoter of CDH1, which leads to inhibition of cell adhesion and EMT (Diaz et al., 2014)
Uncertainties and Inconsistencies
It is possible that the inhibition of ZEB1 and ZEB2 by garcinol treatment is caused by down-regulation of NFkappaB and Wnt/beta-catenin signaling (Ahmad et al., 2012).
The EMT is induced different transcription factors other than Zeb, Twist, and Snail, which includes E47 and KLF8 (Diaz et al., 2014).
Zeb, Twist, and Snail may activate or inactivate different genes or molecules to induce phenomena related to EMT and other phenomena other than EMT (Li & Balazsi, 2018).
Known modulating factors
The proto-oncogene MET regulates beta-catenin and Snail expression (Sohn et al., 2019).
The inhibition of GSK3beta by SB216763 induced expression of beta-catenin and Twist, as well as mesenchymal markers such as N-cadherin, vimentin, and MMP9 (Yang et al., 2019).
The decrease in E-cadherin (CDH1), a cell adhesion molecule, is related to EMT (Diaz et al., 2014).
Methyltransferase-like 3 (METTL3) modulates methylation of Snail (SNAI1) mRNA and EMT (Lin et al., 2019).
The binding of beta-catenin to members of the TCF/LEF family transcription factors increase gene expression related to EMT such as Twist and decrease E-cadherin protein expression (Qualtrough, Rees, Speight, Williams, & Paraskeva, 2015).
The treatment with AF38469, a sortilin inhibitor, in 0, 100, 200, 400, 800, and 1600 nM concentration inhibited beta-catenin and Twist (EMT regulator) expression dose-dependently in human glioblastoma cells (Yang et al., 2019).
Snail (SNAI1, a key transcription factor of EMT induced by beta-catenin) mRNA is methylated, and N6-methyladenosine (m6A) in its coding region (CDS) and 3’ untranslated region (3’UTR) are significantly enriched during EMT progression (Lin et al., 2019). The m6A enrichment fold of SNAI1 mRNA in EMT cells is about 2.3-fold greater than in control cells (Lin et al., 2019).
Nuclear accumulation of beta-catenin induces endogenous ZEB1 in 15 and 30 min (Sanchez-Tillo E et al., 2011).
The treatment with 25 uM of garcinol for 48 hours induced an increase in phosphorylated beta-catenin and decreased nuclear beta-catenin protein and ZEB1/ZEB2 mRNA in human breast cancer cells (Ahmad et al., 2012).
The treatment with AF38469, a sortilin inhibitor, for 0, 2, 4, 8, 16, or 24 hours shows that the expression of beta-catenin and Twist decrease in 8 hours followed by the subsequent decrease in 16 and 24 hours in human glioblastoma cells (Yang et al., 2019).
Snail (SNAI1) transfection for 48 hours induces the repression of E-cadherin (CDH1) protein expression (Lin et al., 2019).
SNAI1 mRNA in polysome is up-regulated in EMT-undergoing HeLa cells treated with 10 ng/ml of TGF-beta for 3 days compared with control cells (Lin et al., 2019).
Known Feedforward/Feedback loops influencing this KER
The inhibited expression of phosphorylated GSK3beta, beta-catenin, and Twist by sortilin inhibition is reversed by GSK3beta inhibition. Furthermore, twist overexpression by lentivirus increased the inhibited expression of N-cadherin, MMP9, and vimentin and reverses the inhibitory effect of AF38469 on sortilin, which suggests that sortilin induces glioblastoma invasion mainly via GSK3beta/beta-catenin/Twist induced mesenchymal transition (Yang et al., 2019).
The inhibition of Hedgehog signaling pathway with cyclopamine reduces beta-catenin-TCF transcriptional activity, decreases the Twist expression, induces E-cadherin expression, and inhibits EMT (Qualtrough et al., 2015).
Domain of Applicability
- The inhibition of c-MET decreases the expression of beta-catenin and Snail in human diffuse-type gastric cancer (Homo sapiens) (Sohn et al., 2019).
- The treatment with garcinol decreases the expression of beta-catenin and ZEB1/ZEB2 in human breast cancer cells (Homo sapiens) (Ahmad et al., 2012).
- Zeb1 activation leads to EMT via Prex1 activation in NCH421k, NCH441, and NCH644 human glioblastoma model cells (Homo sapiens) (Rosmaninho et al., 2018).
- Zeb1 siRNA induced the suppression of EMT in SGC-7901 human gastric cancer cell line (Homo sapiens) (Xue et al., 2019). Snail induces EMT in SAS and HSC-4 human head and neck squamous cancer cells (Homo sapiens) (Ota et al., 2016).
- Snail induces EMT in B16-F10 murine melanoma cells (Mus musculus) (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009; Wang, Shi, Chai, Ying, & Zhou, 2013).
- Twist1 is related to EMT in MCF-7 and MDA-MB-231 human breast cancer cell lines (Homo sapiens) (Menendez-Menendez et al., 2019).
- Twist induces EMT in Huh7 human hepatocellular carcinoma cell lines (Homo sapiens) (Hu et al., 2019).
Ahmad, A., Sarkar, S. H., Bitar, B., Ali, S., Aboukameel, A., Sethi, S., . . . Sarkar, F. H. (2012). Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther, 11(10), 2193-2201. doi:10.1158/1535-7163.MCT-12-0232-T
Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., & García de Herreros, A. (2000). The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84-89. doi:10.1038/35000034
Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. doi:10.1016/j.cell.2012.05.012
Diaz, V. M., Vinas-Castells, R., & Garcia de Herreros, A. (2014). Regulation of the protein stability of EMT transcription factors. Cell Adh Migr, 8(4), 418-428. doi:10.4161/19336918.2014.969998
Hu, B., Cheng, J. W., Hu, J. W., Li, H., Ma, X. L., Tang, W. G., . . . Yang, X. R. (2019). KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition. Journal of Cancer, 10(17), 3914-3925. doi:10.7150/jca.31448
Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. Cancer Cell, 15(3), 195-206. doi:10.1016/j.ccr.2009.01.023
Li, C., & Balazsi, G. (2018). A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst Biol Appl, 4, 34. doi:10.1038/s41540-018-0068-x
Lin, X., Chai, G., Wu, Y., Li, J., Chen, F., Liu, J., . . . Wang, H. (2019). RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun, 10(1), 2065. doi:10.1038/s41467-019-09865-9
Menendez-Menendez, J., Hermida-Prado, F., Granda-Diaz, R., Gonzalez, A., Garcia-Pedrero, J. M., Del-Rio-Ibisate, N., . . . Martinez-Campa, C. (2019). Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin. Cancers (Basel), 11(7). doi:10.3390/cancers11071011
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Pearlman, R. L., Montes de Oca, M. K., Pal, H. C., & Afaq, F. (2017). Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. Cancer Lett, 391, 125-140. doi:10.1016/j.canlet.2017.01.029
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Qualtrough, D., Rees, P., Speight, B., Williams, A. C., & Paraskeva, C. (2015). The Hedgehog Inhibitor Cyclopamine Reduces beta-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells. Cancers (Basel), 7(3), 1885-1899. doi:10.3390/cancers7030867
Rosmaninho, P., Mükusch, S., Piscopo, V., Teixeira, V., Raposo, A. A., Warta, R., . . . Castro, D. S. (2018). Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. The EMBO Journal, 37(15), e97115. doi:10.15252/embj.201797115
Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. beta-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci U S A, 2011;108(48):19204-9.
Sohn, S. H., Kim, B., Sul, H. J., Kim, Y. J., Kim, H. S., Kim, H., . . . Zang, D. Y. (2019). INC280 inhibits Wnt/beta-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification. BMC Res Notes, 12(1), 125. doi:10.1186/s13104-019-4163-x
Tang Q, Chen J, Di Z, Yuan W, Zhou Z, Liu Z, Han S, Liu Y, Ying G, Shu X, Di M. TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer. J Exp Clin Cancer Res. 2020 Nov 5;39(1):232. doi: 10.1186/s13046-020-01690-z. PMID: 33153498; PMCID: PMC7643364.
Wang, Y., Shi, J., Chai, K., Ying, X., & Zhou, B. P. (2013). The Role of Snail in EMT and Tumorigenesis. Current cancer drug targets, 13(9), 963-972. doi: 10.2174/15680096113136660102
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Xue, Y., Zhang, L., Zhu, Y., Ke, X., Wang, Q., & Min, H. (2019). Regulation of Proliferation and Epithelial-to-Mesenchymal Transition (EMT) of Gastric Cancer by ZEB1 via Modulating Wnt5a and Related Mechanisms. Medical science monitor : international medical journal of experimental and clinical research, 25, 1663-1670. doi:10.12659/MSM.912338
Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. Cell Death Dis, 10(3), 208. doi:10.1038/s41419-019-1449-9