MicroRNA-100 Enhances Autophagy and Suppresses Migration and Invasion of Renal Cell Carcinoma Cells via Disruption of NOX4-Dependent mTOR Pathway

Clin Transl Sci. 2020 May 1. doi: 10.1111/cts.12798. Online ahead of print.

Abstract

Renal cell carcinoma (RCC) is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy. Recently, microRNAs (miRNAs or miRs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. In the present study, we aim to explore the potential role of miR-100 in RCC by targeting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) through the mammalian target of rapamycin (mTOR) pathway. Initially, microarray-based gene expression profiling of RCC was used to identify differentially expressed genes. Next, the expression of miR-100 and NOX4 was examined in RCC tissues and cell lines. Then, the interaction between miR-100 and NOX4 was identified using bioinformatics analysis and dual-luciferase reporter assay. Gain-of-function or loss-of-function approaches were adopted to manipulate miR-100 and NOX4 in order to explore the functional roles in RCC. The results revealed the presence of an upregulated NOX4 and a downregulated miR-100 in both RCC tissues and cell lines. NOX4 was verified as a target of miR-100 in cells. In addition, overexpression of miR-100 or NOX4 silencing could increase autophagy while decreasing the expression of mTOR pathway-related genes and migration and invasion. Conjointly, upregulated miR-100 can potentially increase the autophagy and inhibit the invasion and migration of RCC cells by targeting NOX4 and inactivating the mTOR pathway, which contributes to an extensive understanding of RCC and may provide novel therapeutic options for this disease.