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

• Authors: Jessica Gagné-Sansfaçon, University of Sherbrooke; Geneviève Coulombe, University of Sherbrooke; Marie-Josée Langlois, University of Sherbrooke; Ariane Langlois, University of Sherbrooke; Marilene Paquet, University of Montreal; Julie Carrier, University of Sherbrooke; Gen-Sheng Feng, University of California San Diego; Cheng-Kui Qu, Emory University; Nathalie Rivard, University of Sherbrooke
• Journal Title: Oncotarget
• Volume: Volume 7, Number 40
• Publisher: Impact Journals | 2016-10-04, Pages 65676-65695
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.18632/oncotarget.11601
• Subjects: Health Sciences, Oncology; Biology, Cell; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Cell Biology; SHP-2; colorectal cancer; colitis-associated cancer; oncogene; mitogen-activated protein kinase; PROTEIN-TYROSINE-PHOSPHATASE; CELL-CYCLE PROGRESSION; COLORECTAL-CANCER; ULCERATIVE-COLITIS; OXIDATIVE STRESS; EPITHELIAL-CELLS; APC(MIN/+) MICE; SOLID TUMORS; PTPN11 SHP2; MUTATIONS

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-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.