MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect

Glucose metabolic reprogramming from oxidative to aerobic glycolysis, referred as the Warburg effect, is a hallmark of tumor cells Accumulating evidence suggests that a subset of microRNAs play pivotal roles in modulating such reprogramming of glucose metabolism in cancer cells miR-3662 has been implicated previously in both pro tumorigenic and anti tumorigenic effects in several types of cancer The expression level of miR -3662 is downregulated in acute myeloid leukemia, whereas increased miR-3662 expression is observed in lung adenocarcinoma. However, the roles and underlying mechanisms of miR-3662 in hepatocellular carcinoma (HCC) metabolic reprogramming remain unclear Our present study revealed that miR-3662 was frequently downregulated in HCC tissues and cell lines The low expression level of miR-3662 was associated with tumor size, tumor multiplicity, Edmondson grade, and tumor node metastasis stage Gain of function and loss of function assays showed that miR -3662 dampened glycolysis by reducing lactate production, glucose consumption, cellular glucose 6 phosphate level, ATP generation, and extracellular acidification rate, and increasing oxygen consumption rate in HCC cells after treatment with the hypoxia mimetic CoCl2 Moreover, miR-3662 suppressed cell growth in vitro and in vivo, and induced G1/S cell cycle arrest miR-3662 inhibited the activation of ERK and JNK signaling pathways in HCC By combined computational and experimental approaches, hypoxia inducible factor la (HIF l alpha) was determined as a direct target of miR -3662 After treatment with the hypoxia mimetic CoCl2, miR-3662 regulated the Warburg effect and HCC progression via decreasing HIF 1-alpha expression Our findings uncover a mechanistic role for miR 3662/HIF 1-1 alpha axis in HCC metabolic reprogramming, providing a potential therapeutic strategy in liver cancer.