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SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development

2016; Impact Journals LLC; Volume: 7; Issue: 40 Linguagem: Inglês

10.18632/oncotarget.11601

1949-2553

Jessica Gagné‐Sansfaçon, Geneviève Coulombe, Marie-Josée Langlois, Ariane Langlois, Marilène Paquet, Julie Carrier, Gen‐Sheng Feng, Cheng‐Kui Qu, Nathalie Rivard,

Cytokine Signaling Pathways and Interactions

// Jessica Gagné-Sansfaçon 1 , Geneviève Coulombe 1 , Marie-Josée Langlois 1 , Ariane Langlois 1 , Marilene Paquet 2 , Julie Carrier 3 , Gen-Sheng Feng 4 , Cheng-Kui Qu 5 , Nathalie Rivard 1 1 Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada 2 Département de microbiologie et pathologie, Université de Montréal, St-Hyacinthe, QC, Canada 3 Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada 4 Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA 5 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Correspondence to: 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 ABSTRACT 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-2 E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the Apc Min/+ 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 Apc Min/+ 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.