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microRNA-9-5p regulates the mitochondrial function of hepatocellular carcinoma cells through suppressing PDK4

Cancer Gene Therapy volume 28, pages 706–718 (2021)Cite this article

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Abstract

Due to the lack of early diagnostic and effective treatment modalities, hepatocellular carcinoma (HCC) is still the most lethal cancer with a high mortality on a global scale. Recent studies have highlighted the key roles of microRNAs (miRs) in HCC development. In the study, we attempted to investigate the potential role of miR-9-5p in the progression of HCC. Expression of pyruvate dehydrogenase kinase 4 (PDK4) and miR-9-5p was examined in HCC tissues collected from HCC patients and cell lines. The proliferation, migration, invasion, and apoptosis of HCC cells, and levels of oxygen consumption rate, extracellular acidification rate and reactive oxygen species (ROS) as well as the tumorigenicity of transfected cells in vivo were measured after gain- and loss-of-function experiments in HCC cells. It was revealed that miR-9-5p was upregulated, while PDK4 was poorly expressed in HCC tissues and cells, associating with a poor prognosis of HCC patients. miR-9-5p directly targeted PDK4 and could downregulate its expression, thus leading to promoted cell proliferation, invasion and migration, enhanced mitochondrial activity and energy metabolism, and suppressed apoptosis in HCC cells, along with increased tumorigenicity in mouse xenograft models. Altogether, miR-9-5p facilitated mitochondrial energy metabolism of HCC cells by downregulating PDK4, promoting the development of HCC. miR-9-5p and PDK4 may serve as potential therapeutic targets for preventing recurrence and metastasis of HCC.

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Fig. 1: The expression of PDK4 mRNA and protein in hepatocellular carcinoma tissues.
Fig. 2: PDK4 inhibits proliferation, migration, and invasion but promotes apoptosis of HCC cells in vitro.
Fig. 3: PDK4 suppresses mitochondrial function and energy metabolism in HCC cells.
Fig. 4: miR-9-5p is highly expressed in HCC tissues and targets PDK4 in HCC cells.
Fig. 5: miR-9-5p downregulation suppresses proliferation, migration, and invasion and induces apoptosis in HCC cells by elevating PDK4.
Fig. 6: miR-9-5p downregulation decreases mitochondrial function to suppress the tumor growth by upregulating PDK4.
Fig. 7: The potential role of miR-9-5p in the progression of hepatocellular carcinoma.

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Acknowledgements

We would like to express our sincere appreciation to our colleagues for their valuable suggestions on this study.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 82060856) and the Natural Science Foundation of Guangxi (Grant No. 2020JJA140194).

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Authors and Affiliations

  1. Integrative Cancer Centre, Guangzhou University of Chinese Medicine First Affiliated Hospital, 510405, Guangzhou, China

    Tao Si, Hongwei Zhao & Lizhu Lin

  2. Department of Oncology, Liuzhou Traditional Chinese Medical Hospital, 545001, Liuzhou, China

    Tao Si, Xuejian Ning, Ping Huang, Zhengguo Hu & Liu Yang

  3. Guangxi University of Chinese Medicine, 530000, Nanning, China

    Mingmin Zhang

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  1. Tao Si
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Correspondence to Lizhu Lin.

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Si, T., Ning, X., Zhao, H. et al. microRNA-9-5p regulates the mitochondrial function of hepatocellular carcinoma cells through suppressing PDK4. Cancer Gene Ther 28, 706–718 (2021). https://doi.org/10.1038/s41417-020-00253-w

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