MicroRNA-375 inhibits the proliferation, migration and invasion of kidney cancer cells by triggering apoptosis and modulation of PDK1 expression

Abstract

Kidney cancer is one of the deadly cancers and is the cause of significant number of deaths worldwide. The treatments used for the treatment of kidney cancer are limited and associated with number of side effects. Therefore, there is need for the development of new drug options or to identify novel therapeutic targets for the treatment of kidney cancer. In this study we investigated the potential of miR-375 as the therapeutic target for the treatment of Kidney cancer. The results revealed that miR-375 is significantly downregulated in the Kidney cancer cells. To investigate the role therapeutic potential of miR-375, one kidney cancer cell line (A-498) was selected for further experimentation. It was observed that overexpression of miR-375 inhibits A-498 kidney cancer proliferation by induction of apoptosis. In addition, overexpression of miR-375 causes suppression of migration and invasion of the A-498 kidney cancers cells. Bioinformatic analysis revealed PDK1 to be putative target of miR-375 in Kidney cancer cells. The western blot analysis revealed the expression of PDK1 to be significantly upregulated in Kidney cancer cells and overexpression of miR-375 in A-498 cells caused inhibition of PDK1 preventing the phosphorylation of AKT (Thr308 and Ser473). Additionally, inhibition of PDK1 had similar effects as that of miR-375 overexpression on cell proliferation of A-498 kidney cancer cells. The inhibition of miR-375 expression could not rescue the effects of PDK-1 suppression on A-498 cell proliferation. In contrary, overexpression of PKD1 in A-498 cells transfected with miR-375 mimics could nullify the effects of miR-375 on proliferation of the A-498 cells. Taken together, we conclude that miR-375 regulates cell proliferation, migration and invasion of A-498 kidney cancer cells and may prove to be an important therapeutic target.