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

ABSTRACT: 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-1? (HIF-1?) 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? expression. Our findings uncover a mechanistic role for miR-3662/HIF-1? axis in HCC metabolic reprogramming, providing a potential therapeutic strategy in liver cancer.

SUBMITTER: Chen Z 

PROVIDER: S-EPMC5945826 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other