miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1

• Published in: Oncogene 2018-03, Vol.37 (12), p.1624-1636
• Main Authors: Hua, Shengni, Lei, Ling, Deng, Ling, Weng, Xie, Liu, Chengdong, Qi, Xiaolong, Wang, Shuang, Zhang, Dongyan, Zou, Xuejing, Cao, Chuanhui, Liu, Li, Wu, Dehua
• Format: Article
• Language: English
• Subjects: 13/109; 13/51; 38/77; 38/90; 6-Phosphofructo-2-kinase; 631/337/384; 631/67/1504/1610; 631/80/83; 64/60; 82/80; Apoptosis; Cancer; Cancer cells; Cancer metastasis; Cancer research; Carcinoma; Care and treatment; Cell Biology; Cell growth; Cell migration; Cell proliferation; Chromosome 5; Ets-1 protein; Fructose; Gene expression; Gene regulation; Genetic aspects; Genomes; Genomics; Glucose; Glucose metabolism; Glycolysis; Hepatocellular carcinoma; Hexokinase; Human Genetics; Hydrolases; Internal Medicine; Kinases; Liver cancer; Medicine; Medicine & Public Health; Metabolism; Metastases; MicroRNA; MicroRNAs; miRNA; Oncology; Post-transcription; Transcription (Genetics); Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-017-0057-3

Cancer cells have metabolic features that allow them to preferentially metabolize glucose through aerobic glycolysis, providing them with a progression advantage. However, microRNA (miRNA) regulation of aerobic glycolysis in cancer cells has not been extensively investigated. We addressed this in the present study by examining the regulation of miR-139-5p on aerobic glycolysis of hepatocellular carcinoma (HCC) using clinical specimens, HCC cells, and a mouse xenograft model. We found that overexpressing miR-139-5p restrained aerobic glycolysis, suppressing proliferation, migration, and invasion in HCC cells. miR-139-5p regulated hexokinase 1 (HK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression by directly targeting the transcription factor ETS1, which bound to the promoters of the HK1 and PFKFB3 genes. miR-139-5p-induced aerobic glycolysis, proliferation, migration, and invasion were reversed by ETS1 overexpression, while ETS1 silencing induced the expression of miR-139-5p via a post-transcriptional regulation mode involving Drosha. miR-139-5p expression was reduced in HCC compared to para-carcinoma tissue, which was confirmed in The Cancer Genome Atlas and GSE54751 HCC cohorts. Notably, the lower expression of mir-139 was correlated with worse prognosis. These outcomes indicate that reciprocal regulatory interactions between miR-139-5p and ETS1 modulate aerobic glycolysis, proliferation, and metastasis in HCC cells, suggesting new targets for HCC treatment.