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.

The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration

“…The complete mating information is available in supplementary material, Supplementary materials and methods. In brief, to express an active Shp‐2 protein in IEC, knock‐in Ptpn11 E76KNeo/+ mice were crossed with Villin‐Cre mice to generate double heterozygous experimental mice ( Shp‐2 IEC‐E76K ) and control littermates . The Shp‐2 deletion model was previously described ( Shp‐2 IEC‐KO ) .…”

“…Colons and ileums were fixed, sectioned and stained as described previously . Immunohistochemistry was performed using a DAKO EnVision+ System kit (Lexington, MA, USA).…”

The gain‐of‐function mutation E76K in SHP2 promotes CAC tumorigenesis and induces EMT via the Wnt/β‐catenin signaling pathway

“…However, Kim et al suggested that SHP2 acts as a negative regulator of the JAK‐STAT signaling pathway, inhibiting inflammation in small glial cells. It has also been reported that IEC‐specific knockout of SHP2 (SHP2IEC‐KO) causes inflammation in mice and that this can result in spontaneous CRC after 15 months. However, in another in vitro experiments, the authors silenced SHP2 expression in IECs transfected with KRAS (IEC‐6/KRAIG) and in colon cancer cell lines and observed that this inhibited the malignant behavior of the cells.…”

PTPN11 hypomethylation is associated with gastric cancer progression

“…PTPN11 mutations have been extensively investigated in the past years. Germline mutations in PTPN11 cause Noonan syndrome (9)(10)(11) and its clinically related Leopard syndrome (12), whereas somatic mutations of PTPN11 contribute to leukemogenesis (13)(14)(15)(16)(17), as well as in the development of specific solid tumors, including neuroblastoma (18,19), metachondromatosis (20,21), brain tumors (22)(23)(24), neurofibromatosis (25), optic nerve pilomyxoid astrocytoma (26), breast carcinoma (27,28), colorectal cancer (29,30) and Ewing sarcoma (31). However, oncogenic mutations of PTPN11 are rare in the majority of solid tumors including GC (32,33).…”