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

Oncogene volume 37, pages 6054–6068 (2018)Cite this article

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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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Acknowledgements

The authors acknowledge Dr. Sylvie Robine (Institut Curie, Paris, France) for her donation of the villin-Cre (B6-Tg(Vil-cre)20Sy/Nci) mice. The authors greatly thank Valérie Gratio of the CRI cytometry facility. The authors are indebted to Dr. Samira Benadda (INSERM U1149) for her assistance in confocal microscopy, and Olivier Thibaudeau (INSERM U1152) for help in histologic experiments. This work was supported by French minister of higher education and research, INSERM, and University Paris Diderot.

Author contributions

LK and EC conceived the study; LK, PJ, and EC designed the experiments; LK, EC, and GM performed the experiments; TL and FW performed the histologic analyses; LK, FW, GM, TL, PJ, and EC analyzed and interpreted the data; LK and EC wrote the manuscript with comments from PJ, TL, and FW.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, UMR S 938, Centre de Recherche Saint-Antoine, Paris, France

    Larissa Kotelevets & Eric Chastre

  2. Université Pierre-et-Marie-Curie Paris 6, Hôpital Saint-Antoine, Site Bâtiment Kourilsky, Paris, France

    Larissa Kotelevets & Eric Chastre

  3. Institut National de la Santé et de la Recherche Médicale, U1149, Centre National de la Recherche Scientifique-ERL8252, Centre de Recherche sur l’Inflammation, Paris, France

    Francine Walker & Thérèse Lehy

  4. Assistance publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val de Seine Bichat-Claude Bernard, Department of Pathology, Paris, France

    Francine Walker

  5. TransCell-Lab Laboratory, Faculty of Medicine Xavier Bichat, University of Paris Diderot – Paris7, Paris, France

    Godefroy Mamadou

  6. Department of Human Genetics, National Health Institute, Doctor Ricardo Jorge, Lisbon, Portugal

    Peter Jordan

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  1. Larissa Kotelevets
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Correspondence to Larissa Kotelevets or Eric Chastre.

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Kotelevets, L., Walker, F., Mamadou, G. et al. The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression. Oncogene 37, 6054–6068 (2018). https://doi.org/10.1038/s41388-018-0389-7

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