MicroRNA 21 induces carcinogenesis in hepatic cells by modulating mitochondrial metabolism

Abstract

AbstractMitochondria plays crucial role in cell’s survivability and normal functioning. But in the case of cancer, the mitochondrial machinery (ETC) is altered and glycolytic pathway is activated as an alternate source of energy. The main reason behind the reprogramming of mitochondrial machinery could be mutations in mitochondrial genes or suppression of genes involved in normal functioning of the mitochondria. MicroRNAs could be a key player in modulating the mitochondrial metabolism, as they have targets on various important mitochondrial genes involved in the Electron Transport Chain of the mitochondria. Any alteration in the expression pattern of the mitochondrial genes would directly contribute to the modulation of normal functioning of the mitochondrial machinery. Micro RNA 21 is an oncomiR, located at q arm of the 17thchromosome. MiR 21 has been reported to be involved in many types of cancer. MiR 21 is reported to have targets on many important genes, crucial for cell survivability and proliferation, most of which falls in the category of tumor suppressor genes. With our bioinformatics analysis, we found that miR 21 has targets on important mitochondrial genes involved in the ETC. So, we tried to elucidate the role of miR 21 in modulation of the mitochondrial machinery and role of this alteration in the mitochondrial mechanism in carcinogenesis. Our results revealed that miR 21 have targets on the Cytochrome C Oxidase 1 (Cox1), which is directly involved in the Complex 4 of the electron transport chain. Next we checked the phenotypic effects of this down regulation of Cox1 by measuring the oxygen consumption by the mitochondria and found that O2 consumption goes significantly down in miR 21 over expressing cells. Along with this, we also checked if exosomes from miR 21 overexpressing cancer cells could induce the carcinogenesis in the normal hepatic cells and found that miR 21 accelerates the rate of cellular migration and enhances the colony formation. The results together suggest that miR 21 posses carcinogenic property, possibly by modulating mitochondrial machinery.