Tissue-Specific Effects of Reduced β-catenin Expression on Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium

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Enhanced Wnt signaling contributes to colorectal and other cancers. β-catenin functions in Wnt signaling as a T cell factor (TCF) transcriptional co-activator. Previous studies showed specific β-catenin dosage favors Wnt signaling-dependent tumorigenesis for some tumor types. However, earlier studies emphasized the role of constitutional Ctnnb1 and Apc gene variations, rather than somatic gene targeting, and the work focused on small intestine tumors and no effects on colon tumor phenotypes were described. Furthermore, definitive insights were lacking into how reduced Ctnnb1 gene dosage affected Apc mutation-dependent tumorigenesis. Here, we show somatic inactivation of one Ctnnb1 allele dramatically inhibits mouse colon adenomatous polyposis induced by somatic bi-allelic Apc inactivation. In contrast, Ctnnb1 hemizygous inactivation does not affect mouse ovarian endometrioid adenocarcinoma development arising from Apc- and Pten-inactivation. Ctnnb1 hemizygous gene dose dramatically reduces the active pool of β-catenin, leading to the significant inhibition of β-catenin/TCF-regulated target gene expression, including those encoding key stem cell regulatory and crypt compartmentalization factors in colon epithelium. Tissue-specific differences for expression of selected β-catenin/TCF-regulated genes, such as Myc, may contribute to the context-dependent effects of Ctnnb1 gene dosage in Apc mutation-driven colon and ovarian tumors.

Vyšlo v časopise: Tissue-Specific Effects of Reduced β-catenin Expression on Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium. PLoS Genet 11(11): e32767. doi:10.1371/journal.pgen.1005638
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005638

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