Pseudogene KRT17P3 Drives Cisplatin Resistance of Human NSCLC Cells by Modulating miR-497-5p/mTOR

Abstract

Background: Chemoresistance is a major obstacle in non-small-cell lung cancer (NSCLC) treatment. The pseudogene KRT17P3 has been shown to be up-regulated in lung cancer tissues from patients with cisplatin resistance. However, its molecular mechanism in promoting chemoresistance has not been elucidated.Methods: Real-time PCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin-resistance patients and 32 cisplatin-sensitive patients. KRT17P3 was overexpressed or knocked down in A549 and SK-MES-1 NSCLC cells to evaluate the effects of KRT17P3 on the in vitro and in vivo resistance of NSCLC to cisplatin. Cell Counting Kit 8, Annexin V/propidium iodide staining, and PARP-1 cleavage assays were performed to evaluate cell viability and apoptosis. Dual luciferase reporter, RNA immunoprecipitation, Western blot assays, and rescue experiments were used to evaluate the functional interaction of KRT17P3, miR-497-5p and mTOR.Results: Our results demonstrate that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment, while KRT17P3 knockdown has the opposite effect. KRT17P3 overexpression promotes NSCLC tumor growth upon in cisplatin-treated xenografted mice. Mechanistically, KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR. Rescue experiments validated the functional interaction among KRT17P3, miR497-5p, and mTOR. Moreover, the plasma level of KRT17P3 is up-regulated in cisplatin-resistance patients.Conclusions: Our findings indicate that KRT17P3/miR497-5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin-resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin.