Mitochondrial miR-181a-5p promotes glucose metabolism reprogramming in liver cancer by regulating the electron transport chain.

Abstract

Liver cancer and other malignant tumor cells rely on the glycolytic pathway to obtain energy (i.e. the Warburg effect); however, the underlying mechanism is unclear. Mitochondria are sites of oxidative phosphorylation and adenosine triphosphate (ATP) production. The 13 constituent respiratory chain proteins encoded by the mitochondrial genome (namely, mtDNA) play essential roles. We found that in human hepatocellular carcinoma (HCC) tissues, 11 out of the 13 mtDNA-encoded genes exhibited decreased mRNA levels and 5 genes displayed decreased protein levels, including the cytochrome B (mt-CYB) and cytochrome C oxidase II (mt-CO2) genes. Mitochondrial gene sequencing revealed abnormalities in the levels of a large number of mitochondrial miRNAs (mitomiRs). MicroRNA-181a-5p (mir-181a-5p), which potentially targets genes encoding mt-CYB and mt-CO2 protein, was screened out from 549 downregulated mitomiRs via bioinformatic analysis. After overexpression of mitomiR-181a-5p, mt-CYB and mt-CO2 levels were reduced in HCC cells, and the mitochondrial membrane potential (MMP) maintained by the electron transport chain (ETC) was decreased. Furthermore, the expression of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1) was upregulated, accompanied by elevated glucose, lactic acid release, and activity of lactate dehydrogenase (LDH). In vivo experiments confirmed that constitutive mitomiR-181a-5p expression caused reprogramming of glucose metabolism and promoted tumor growth and early lung metastasis in liver cancer. In summary, the present study reveals the important role of mitomiRs in glucose metabolism reprogramming in liver cancer, which is of considerable value in exploring new therapeutic targets for HCC.