MiR-885-5p Negatively Regulates Warburg Effect by Silencing Hexokinase 2 in Liver Cancer

Abstract Growing tumor cells possess a distinct metabolic phenomenon that allows them to preferentially utilize glucose through aerobic glycolysis, which is referred to as the “Warburg effect.” Accumulating evidences suggest microRNAs (miRNAs) could regulate such metabolic reprogramming. Our microarray analysis and quantitative PCR validation revealed miR-885-5p was strongly down-regulated in hepatocellular carcinoma (HCC) tissues and cell lines. To investigate miR-885-5p’s biological functions in HCC progression, malignant phenotypes were performed in different types of hypoxic model and indicated that overexpression of miR-885-5p significantly inhibited HCC cells proliferation, migration and induced apoptosis in vitro and tumor growth in vivo. Subsequent investigations of whether miR-885-5p regulated the glycometabolic activity of cancer cells demonstrated that forced expression of miR-885-5p in SMMC-7721 cells significantly reduced glucose uptake and lactate production by repressing several key enzymes related to glycolysis. Particularly, miR-885-5p directly targets the 3’-untranslated region of hexokinase 2 (HK2), which is a key enzyme catalyzes the irreversible first step of glycolysis and associates with poor patient outcomes. MiR-885-5p/HK2 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising therapeutic target and prognostic predictor for HCC patients.