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

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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.

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This work was supported by Nation’s Nature Science Foundation of China (Grant nos. 81472711, 91540111, 81672756, 81401180, and 81372283) and the Guangdong Province Nature Science Foundation (Grant no. 2014A030311013).

Author information


  1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    • Shengni Hua
    • , Ling Lei
    • , Ling Deng
    • , Chengdong Liu
    • , Dongyan Zhang
    • , Chuanhui Cao
    •  & Dehua Wu
  2. Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    • Xie Weng
    • , Xuejing Zou
    •  & Li Liu
  3. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

    • Xiaolong Qi
  4. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    • Shuang Wang


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Conflict of interest

The authors declare they have no competing interests.

Corresponding authors

Correspondence to Li Liu or Dehua Wu.

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