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APC loss promotes intestinal transformation though B-CATENIN-independent dysregulation of a GSK3-AJUBA-YAP signaling axis

ABSTRACT: The majority of colorectal cancer (CRC) cases are believed to be initiated by the genetic inactivation of the APC tumor suppressor, which negatively regulates the Wnt effector beta-catenin. This has led to the prevailing view that loss of APC drives tumorigenesis through constitutive activation of the Wnt/beta-catenin pathway. Although activation of beta-catenin is necessary for tumor initiation, activating mutations in beta-catenin are rare in CRC. Instead, CRC typically exhibits poorly understood mechanisms that favor the genetic inactivation of APC over activating mutations in beta-catenin or other Wnt pathway components, which are more commonly seen in other types of carcinoma. In this study, we profiled single cells isolated from organoids with floxed alleles of Apc (Apc f/f), beta-catenin (beta-Catenin Exon3 f/f), or organoids expressing a dominant-negative form of Tcf4 with floxed alleles of Apc (Apc f/f).

ORGANISM(S): Mus musculus

PROVIDER: GSE266579 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Purpose: WNT signaling activation in colorectal cancers (CRCs) occurs mainly through APC inactivation or, more uncommonly, β-catenin activation. Both processes promote β-catenin nuclear accumulation, which transcriptionally up-regulates epithelial-to-mesenchymal transition (EMT)-related genes. Experimental Design: We investigated β-catenin localization, downstream gene expression, and phenotypic alterations in 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 localization and associated phenotypes in CRC tissues. Results: Wild-type β-catenin mainly localized at the cell membrane, whereas mutant showed predominantly nuclear localization; membranous, cytoplasmic, and nuclear localization was observed in HCT116-P cells. Microarray analysis revealed significant down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT cells. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT cells, although E-cadherin expression was unaffected. Altered expression of cell-cell junction-related molecules led to tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased migration and invasion activities of HCT116-WT, whereas AJ loss was required to further up-regulate these activities in HCT116-P. Immunohistochemistry analysis of 101 stage III CRC tissues revealed high nuclear β-catenin expression (≥30% of tumor cells) in 15 (14.9%) samples, low nuclear expression (1-29%) in 53 (52.5%) samples, and undetectable nuclear expression in 33 (32.6%) samples, with a trend toward more frequent down-regulation of Claudin-7 and E-cadherin, and increased metastasis in CRCs with high vs. low nuclear β-catenin. Conclusions: β-catenin activation and nuclear translocation induce EMT progression by modifying cell-cell junctions, and are associated with aggressive behaviors of CRCs.

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APC loss promotes intestinal transformation though B-CATENIN-independent dysregulation of a GSK3-AJUBA-YAP signaling axis

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