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MicroRNA let-7g cooperates with interferon/ribavirin to repress hepatitis C virus replication

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Abstract

MicroRNAs (miRNA) have been implicated in HCV infection. The present study analyzed the effects of let-7g on HCV infection in vitro, in clinical tissue and serum samples. Here, we show that the expression of let-7g in serum and liver tissue is significantly higher in patients with sustained virologic response (SVR). We show that interferon (IFN)/ribavirin (RBV) induces let-7g expression through p38/AP-1 signaling. Overexpression of let-7g reduced HCV gene or core protein level and inhibited the HCV viral load. The let-7g and IFN/RBV have additively inhibitory effect on HCV replication. These data implicate let-7g as a new therapeutic drug to additively cooperate with IFN/RBV to repress HCV replication.

Key messages

  • let-7g expression is increased in serum and liver tissue of patients with SVR.

  • Interferon/ribavirin induces let-7g expression through p38/AP-1 signaling.

  • Overexpression of let-7g can repress HCV replication.

  • Let-7g additively cooperates with interferon/ribavirin to repress HCV replication.

  • Lin28B silencing can reverse let-7g expression and repress HCV replication.

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Acknowledgments

We would like to thank Dr. Takaji Wakita of Tokyo Metropolitan Institute of Neuroscience for kindly providing the HCV strain JFH-1; Dr. Wei-Lun Tsai of the Kaohsiung Veterans General Hospital for kindly providing the Huh7.5.1 cell line; Apath, LLC for the gift of the Ava.5, J6/JFH and Con1 replicon cells. This work was supported by grants from the National Science Council of Taiwan (grant number NSC101-2314-B-037-063-MY3) and Kaohsiung Medical University Hospital (grant number KMUH101-1R06) and grants partially from Kaohsiung Medical University “Aim for the Top Universities Grant, grant no. KMU-TP103D12, KMU-TP103D13, KMU-TP103D14, and KMU-KMU-TP103E07.” We appreciate the help from the Taiwan Liver Research Function.

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Authors and Affiliations

  1. Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan

    Wen-Wen Chou, Chung-Feng Huang, Ming-Lun Yeh, Yi-Shan Tsai, Ming-Yen Hsieh, Ching-I Huang, Jee-Fu Huang, Pei-Chien Tsai, Wan-Long Chuang, Ming-Lung Yu & Chia-Yen Dai

  2. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Edward Hsi & Suh-Hang Hank Juo

  3. Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Chia-Yen Dai

  4. Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chung-Feng Huang, Jee-Fu Huang, Wan-Long Chuang, Ming-Lung Yu & Chia-Yen Dai

  5. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ming-Lun Yeh, Edward Hsi & Chia-Yen Dai

  6. Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Edward Hsi & Suh-Hang Hank Juo

  7. Center for Infectious Disease and Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Wan-Long Chuang, Ming-Lung Yu & Chia-Yen Dai

  8. Center for Lipid Science and Aging Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Wan-Long Chuang, Ming-Lung Yu & Chia-Yen Dai

  9. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ming-Lung Yu & Chia-Yen Dai

  10. Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Wei-Lun Tsai

  11. School of Medicine, National Yang Ming University, Taipei, Taiwan

    Wei-Lun Tsai

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  1. Wen-Wen Chou
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  2. Chung-Feng Huang
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Correspondence to Chia-Yen Dai.

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Summary statement

Let-7g reduces the HCV expression, and the level of let-7g in serum and liver tissue is significantly higher in patients with sustained virologic response in HCV infection. Let-7g may be developed as target drug and predictor for HCV therapy.

Author contributions

Conceived and designed the experiments: Wen-Wen Chou, Suh-Hang Hank Juo, Chia-Yen Dai, Ming-Lung Yu. Performed the experiments: Wen-Wen Chou, Yi-Shan Tsai, Chung-Feng Huang, Ming-Lun Yeh, Ming-Yen Hsieh, Ching-I Huang, Jee-Fu Huang. Analyzed the data: Wen-Wen Chou, Pei-Chien Tsai, Edward Hsi. Contributed reagents/materials/analysis tools: Wen-Wen Chou, Chung-Feng Huang, Ming-Lun Yeh, Ming-Yen Hsieh, Ching-I Huang, Jee-Fu Huang, Suh-Hang Hank Juo, Wei-Lun Tsai, Wan-Long Chuang, Chia-Yen Dai, Ming-Lung Yu. Wrote the paper: Wen-Wen Chou, Chia-Yen Dai, Ming-Lung Yu.

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Chou, WW., Huang, CF., Yeh, ML. et al. MicroRNA let-7g cooperates with interferon/ribavirin to repress hepatitis C virus replication. J Mol Med 94, 311–320 (2016). https://doi.org/10.1007/s00109-015-1348-1

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  • DOI: https://doi.org/10.1007/s00109-015-1348-1

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