SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development
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Jessica Gagné-Sansfaçon1, Geneviève Coulombe1, Marie-Josée Langlois1, Ariane Langlois1, Marilene Paquet2, Julie Carrier3, Gen-Sheng Feng4, Cheng-Kui Qu5, Nathalie Rivard1
1Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
2Département de microbiologie et pathologie, Université de Montréal, St-Hyacinthe, QC, Canada
3Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada
4Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA
5Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
Nathalie Rivard, email: Nathalie.Rivard@USherbrooke.ca
Keywords: SHP-2, colorectal cancer, colitis-associated cancer, oncogene, mitogen-activated protein kinase
Received: May 06, 2016 Accepted: August 13, 2016 Published: August 25, 2016
A major risk factor of developing colorectal cancer (CRC) is the presence of chronic inflammation in the colon. In order to understand how inflammation contributes to CRC development, the present study focused on SHP-2, a tyrosine phosphatase encoded by PTPN11 gene in which polymorphisms have been shown to be markers of colitis susceptibility. Conversely, gain-of-function mutations in PTPN11 gene (E76 residue) have been found in certain sporadic CRC. Results shown herein demonstrate that SHP-2 expression was markedly increased in sporadic human adenomas but not in advanced colorectal tumors. SHP-2 silencing inhibited proliferative, invasive and tumoral properties of both intestinal epithelial cells (IECs) transformed by oncogenic KRAS and of human CRC cells. IEC-specific expression of a SHP-2E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background. Conversely, mice with a conditional deletion of SHP-2 in IECs developed colitis-associated adenocarcinomas with age, associated with sustained activation of Wnt/β-catenin, NFκB and STAT3 signalings in the colonic mucosae. Moreover, SHP-2 epithelial deficiency considerably increased tumor load in ApcMin/+ mice, shifting tumor incidence toward the colon. Overall, these results reveal that SHP-2 can exert opposing functions in the large intestine: it can promote or inhibit tumorigenesis depending of the inflammatory context.
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