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The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression

Abstract : We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis.
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https://hal.sorbonne-universite.fr/hal-03071333
Contributor : Gestionnaire Hal-Su <>
Submitted on : Wednesday, December 16, 2020 - 9:21:41 AM
Last modification on : Friday, December 18, 2020 - 2:05:40 PM

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Larissa Kotelevets, Francine Walker, Godefroy Mamadou, Thérèse Lehy, Peter Jordan, et al.. The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression. Oncogene, Nature Publishing Group, 2018, 37 (46), pp.6054-6068. ⟨10.1038/s41388-018-0389-7⟩. ⟨hal-03071333⟩

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