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

• Type of Material: Article
• 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
• Language: English
• Date: 2016-10-04
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Gagné-Sansfaçon et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.11601
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 7
• Issue: 40
• Start Page: 65676
• End Page: 65695
• Grant/Funding Information: Nathalie Rivard is a recipient of a Canadian Research Chair in colorectal cancer and inflammatory cell signaling.; This research was supported by grants from the Cancer Research Society and Canadian Institutes of Health Research to NR.; The biobank of colorectal cancer specimens was supported by a Team grant on digestive epithelium from the Canadian Institutes of Health Research.; Jessica Gagné-Sansfaçon is student scholar from the Fonds de la Recherche en Santé du Québec (FRSQ).; Nathalie Rivard and Julie C Carrier are members of the FRSQ-Funded Centre de Recherche du CHUS.
• Keywords: PTPN11 SHP2; SHP-2; Oncology; SOLID TUMORS; oncogene; MUTATIONS; Science & Technology; colorectal cancer; CELL-CYCLE PROGRESSION; OXIDATIVE STRESS; ULCERATIVE-COLITIS; PROTEIN-TYROSINE-PHOSPHATASE; EPITHELIAL-CELLS; mitogen-activated protein kinase; COLORECTAL-CANCER; APC(MIN/+) MICE; colitis-associated cancer; Life Sciences & Biomedicine; Cell Biology
• Research Categories: Biology, Cell; Health Sciences, Pathology; Health Sciences, Oncology

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.