title: SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development.
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.
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Jessica
authors: J
authors: Gagné-Sansfaçon
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Geneviève
authors: G
authors: Coulombe
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Marie-Josée
authors: MJ
authors: Langlois
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Ariane
authors: A
authors: Langlois
authors: Département de microbiologie et pathologie, Université de Montréal, St-Hyacinthe, QC, Canada.
authors: Marilene
authors: M
authors: Paquet
authors: Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Julie
authors: J
authors: Carrier
authors: Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
authors: Gen-Sheng
authors: GS
authors: Feng
authors: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Cheng-Kui
authors: CK
authors: Qu
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors: Nathalie
authors: N
authors: Rivard
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis; D049109:Cell Proliferation; D003092:Colitis / Q000150:complications* / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011379:Prognosis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: SHP-2; colitis-associated cancer; colorectal cancer; mitogen-activated protein kinase; oncogene