β-catenin activation downregulates cell-cell junction-related genes and induces epithelialto- mesenchymal transition in colorectal cancers

Title
β-catenin activation downregulates cell-cell junction-related genes and induces epithelialto- mesenchymal transition in colorectal cancers
Authors
정상훈이욱빈김원규조수연권유진장미박민희김지윤장동건최혜진민병소김태일홍성필백융기김호근
Issue Date
2019-12
Publisher
Scientific Reports
Citation
VOL 9-18440-15
Abstract
WNT signaling activation in colorectal cancers (CRCs) occurs through APC inactivation or β-catenin mutations. Both processes promote β-catenin nuclear accumulation, which up-regulates epithelialto-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic diferences of HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin expression and associated phenotypes in CRC tissues. Wild-type β-catenin showed membranous localization, whereas mutant showed nuclear localization; both nuclear and non-nuclear localization were observed in HCT116-P. Microarray analysis revealed down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT without E-cadherin dysregulation. We found that ZEB1 is a critical EMT factor for mutant β-catenin-mediated loss of E-cadherin and Claudin-7 in HCT116-P and HCT116-MT cells. We also demonstrated that E-cadherin binds to both WT and mutant β-catenin, and loss of E-cadherin releases β-catenin from the cell membrane and leads to its degradation. Alteration of Claudin-7, as well as both Claudin-7 and E-cadherin respectively caused tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased cell motility, and subsequent AJ loss further up-regulated that. Immunohistochemistry analysis of 101 CRCs revealed high (14.9%), low (52.5%), and undetectable (32.6%) β-catenin nuclear expression, and high β-catenin nuclear expression was signifcantly correlated with overall survival of CRC patients (P=0.009). Our fndings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness.
URI
http://pubs.kist.re.kr/handle/201004/70811
ISSN
2045-2322
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