CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression
Menée à l'aide d'échantillons tumoraux et d'échantillons tissulaires normaux issus de patients atteints d'un cancer colorectal et menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel le facteur de transcription CDX2 inhibe la transition épithélio-mésenchymateuse en réduisant l'expression du gène Snail et la stabilisation de la bêta-caténine via la transactivation de l'expression du gène PTEN
Background : Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC). Methods : Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. Results : CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3
β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Conclusions
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Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression.