Upstream eventβ-catenin activation
Snail, Zeb, Twist activation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy||adjacent||High||Moderate|
|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; W. Yang et al., 2019).
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-glade malignant glioma, positively regulates GSK-3beta/beta-catenin/Twist signaling pathway in glioblastoma (W. Yang et al., 2019).
The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced increase in phosphorylated beta-catenin, decrease in beta-catenin and Snail (Sohn et al., 2019).
The garcinol, that has anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibit EMT (Ahmad et al., 2012).
The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in decrease in beta-catenin and Twist expression in human glioblastoma cells (W. Yang et al., 2019).
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).
Quantitative Understanding of the Linkage
The treatment with AF38469, a sortilin inhibitor, in 0, 100, 200, 400, 800, and 1600 nM concentration inhibited beta-catenin and Twist expression dose-depenently in human glioblastoma cells (W. Yang et al., 2019).
The treatment with 25 mM of garcinol for 48 hours induced 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 gliobastoma cells (W. Yang et al., 2019).
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 (W. Yang 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 (W. Yang et al., 2019).
Domain of Applicability
The inhibition of c-MET decreases the expression of beta-catenin and Snail in human diffuse-type gastric cancer (Sohn et al., 2019).
The treatment with garcinol decreases the expression of beta-catenin and ZEB1/ZEB2 in human breast cancer cells (Ahmad et al., 2012).
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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22821148. doi:10.1158/1535-7163.MCT-12-0232-T
Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22682243. doi:10.1016/j.cell.2012.05.012
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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28131904. doi:10.1016/j.canlet.2017.01.029
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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30871613. doi:10.1186/s13104-019-4163-x
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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30814514. doi:10.1038/s41419-019-1449-9