PTPN3 inhibits the growth and metastasis of clear cell renal cell carcinoma via inhibition of PI3K/AKT signaling

Abstract Background: The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is not fully understood. The significant downregulation of protein tyrosine phosphatase non-receptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. Methods: Immunohistochemical analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 expression was an independent, favorable prognostic factor for overall survival ( P = 0.0343) and distant metastasis-free survival ( P = 0.0166) of patients. The ccRCC cell lines SN12C, 1932, ACHN and Caki-1 were used to evaluate, both in vitro and in vivo , the biological roles of PTPN3. Results: We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. PTPN3 overexpression suppressed xenograft tumor growth and lung metastasis in vivo mice models. PTN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of ccRCC cells. Further, the inhibition of phospho-AKT Thr308 and phospho-AKT Ser473 reversed PTPN3 induced-silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in ccRCC patients. Conclusions: Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.