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

SHP2 is encoded by the protein tyrosine phosphatase 11 (Ptpn11) gene. Several gain‐of‐function (GOF) mutations in Ptpn11 have been identified in human hematopoietic malignancies and solid tumors. In addition, the mutation rate for SHP2 is the highest for colorectal cancer (CRC) among solid tumors. The E76K GOF mutation is the most common and active SHP2 mutation; however, the pathogenic effects and function of this mutation in CRC tumor progression have not been well characterized. The Wnt/β‐catenin (CTNNB1) signaling pathway is crucial for CRC, and excessive activation of this pathway has been observed in several tumors. We used Ptpn11E76K conditional knock‐in mice to study this GOF mutation in colitis‐associated CRC (CAC) and used the CRC cell lines HT29 and HCT116 to determine the relationship between SHP2 and Wnt/β‐catenin signaling. Ptpn11E76K conditional knock‐in mice exhibited aggravated inflammation and increased CAC tumorigenesis. In vitro, SHP2E76K and SHP2WT promoted malignant biological behaviors of CRC cells and induced epithelial‐mesenchymal transition (EMT) via the Wnt/β‐catenin signaling pathway. Together, our results showed that SHP2E76K acts as an oncogene that promotes the tumorigenesis and metastasis of CRC.