PTPN3 Inhibits the Growth and Metastasis of Clear Cell Renal Cell Carcinoma via Inhibition of PI3K/AKT Signaling

Abstract

The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase non-receptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. Immunohistochemical analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) 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. 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. Overexpressing PTPN3 inhibited 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 renal cell carcinoma 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. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. ImplicationsPTPN3 is an independent favorable prognostic factor for ccRCC patients and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.

SPRR3, a novel miR‑338‑3p target, regulates the malignant progression of clear cell renal cell carcinoma in vitro via the PI3K/Akt signaling pathway

“…The aberrant activation of the PI3K/Akt signaling pathway promotes the proliferation, migration and invasion of ccRCC cells ( 15 ). SPRR3 activates the PI3K/Akt pathway in colorectal and breast cancer cells ( 4 , 5 ).…”

“…miR-338-3p inhibits the proliferation, migration and invasion of ccRCC cells (12)(13)(14); however, the underlying mechanism remains unclear, and to the best of our knowledge no study has reported the association between miR-338-3p and SPRR3. Activation of the PI3K/Akt signaling pathway promotes ccRCC progression (15). Furthermore, this pathway mediates the regulation of RCC cells by miR-338-3p (16).…”

Exosomal microRNA‐15a from ACHN cells aggravates clear cell renal cell carcinoma via the BTG2/PI3K/AKT axis

“…35 In contrast, PI3K/AKT inhibition suppresses the metastasis and growth of ccRCC. 36 Therefore, we inferred that exosomal miR-15a from RCC cells accelerates cell viability by downregulating BTG2 and promoting PI3K/AKT signaling pathway activity.…”

Silent information regulator 2 promotes clear cell renal cell carcinoma progression through deacetylation and small ubiquitin‐related modifier 1 modification of glucose 6‐phosphate dehydrogenase

“…Clear cell renal cell carcinoma, the predominant histologic subtype in RCC, has a high degree of malignancy. 1 , 2 However, molecular mechanisms underlying ccRCC tumorigenesis are still unclear, and new therapies targeting ccRCC are still challenging. 2 …”

“… 1 , 2 However, molecular mechanisms underlying ccRCC tumorigenesis are still unclear, and new therapies targeting ccRCC are still challenging. 2 …”