Abstract
BackgroundWe previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. Enhanced PLAGL2 expression was observed in several malignant tumours. However, the exact function of PLAGL2 and its underlying mechanism in colorectal cancer (CRC) remain largely unknown.MethodsImmunohistochemical analysis of PLAGL2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of PLAGL2 in the progression of CRC.ResultsEnhanced PLAGL2 expression was significantly associated with EMT-related proteins in CRC. The data revealed that PLAGL2 promotes CRC cell proliferation, migration, invasion and EMT both in vitro and in vivo. Mechanistically, PLAGL2 promoted the expression of ZEB1. PLAGL2 enhanced the expression and nuclear translocation of β-catenin by decreasing its phosphorylation. The depletion of β-catenin neutralised the regulation of ZEB1 that was caused by enhanced PLAGL2 expression. The small-molecule inhibitor PNU-74654, also impaired the enhancement of ZEB1 that resulted from the modified PLAGL2 expression. The depletion of ZEB1 could block the biological function of PLAGL2 in CRC cells.ConclusionsCollectively, our findings suggest that PLAGL2 mediates EMT to promote colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1.
Highlights
We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease
Enhanced PLAGL2 expression was significantly associated with epithelial–mesenchymal transition (EMT)-related proteins in colorectal cancer (CRC)
PLAGL2 promoted the expression of ZEB1
Summary
We previously demonstrated that the pleomorphic adenoma gene like-2 (PLAGL2) is involved in the pathogenesis of Hirschsprung disease. The molecular characteristics of EMT include the suppression of epithelial markers, including E-cadherin, and the concomitant promotion of mesenchymal markers such as Ncadherin and vimentin.[7] In the initiation of EMT, E-cadherin depletion is a crucial initial step.[4] Various EMT-inducing transcription factors, including Snail, Twist and ZEB protein families, and corresponding intracellular signalling pathways can initiate the EMT process.[8] There are the most consistent negative correlations between the expression levels of ZEB1 and E-cadherin in various cancers.[9] In EMT activation, ZEB1 suppresses epithelial gene expression and upregulates mesenchymal markers such as N-cadherin. ZEB1 expression is associated with worse clinical outcomes across different types of tumours
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