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Sci Rep. 2019 Dec 5;9(1):18440. doi: 10.1038/s41598-019-54890-9.

β-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers.

Kim WK1,2,3, Kwon Y1,2,3,4, Jang M2, Park M1,2, Kim J5, Cho S3,4, Jang DG1,6, Lee WB3, Jung SH3,4, Choi HJ7, Min BS8, Il Kim T7, Hong SP9, Paik YK10, Kim H11,12.

Author information

1
Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
2
Departments of Pathology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
3
Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung, 25451, Korea.
4
Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Daejeon, 34113, Korea.
5
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
6
Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, Korea.
7
Department of Internal medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, 120-752, Korea.
8
Department of Surgery, Yonsei University College of Medicine, Seoul, 120-752, Korea.
9
Department of Surgery and Cancer, Imperial College London, London, W120NN, UK.
10
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752, Korea.
11
Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea. hkyonsei@yuhs.ac.
12
Departments of Pathology, Yonsei University College of Medicine, Seoul, 120-752, Korea. hkyonsei@yuhs.ac.

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 epithelial-to-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic differences 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 significantly correlated with overall survival of CRC patients (P = 0.009). Our findings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness.

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