한빛사논문
- 조회472
Yoona Seo 1 2, Yura Kang 1 2, Youngwook Ham 3 4, Mi-Hwa Kim 5, Seong-Jun Kim 5, Seung Kew Yoon 6, Sung Key Jang 7, Jong Bae Park 2, Sungchan Cho 3 4, Jong Heon Kim 1 2
1Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea.
2Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.
3Nucleic Acid Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea.
4Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea.
5Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
6The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
7Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea.
To whom correspondence may be addressed: Sungchan Cho, Jong Heon Kim
Abstract
The liver-specific microRNA, miR-122, plays an essential role in the propagation of hepatitis C virus (HCV) by binding directly to the 5'-end of its genomic RNA. Despite its significance for HCV proliferation, the host factors responsible for regulating miR-122 remain largely unknown. In this study, we identified the cellular RNA-binding protein, ELAVL1/HuR (embryonic lethal-abnormal vision-like 1/human antigen R), as critically contributing to miR-122 biogenesis by strong binding to the 3'-end of miR-122. The availability of ELAVL1/HuR was highly correlated with HCV proliferation in replicon, infectious, and chronically infected patient conditions. Furthermore, by screening a kinase inhibitor library, we identified rigosertib, an anticancer agent under clinical trials, as having both miR-122-modulating and anti-HCV activities that were mediated by its ability to target polo-like kinase 1 (PLK1) and subsequently modulate ELAVL1/HuR-miR-122 signaling. The expression of PLK1 was also highly correlated with HCV proliferation and the HCV positivity of HCC patients. ELAVL1/HuR-miR-122 signaling and its mediation of PLK1-dependent HCV proliferation were demonstrated by performing various rescue experiments and utilizing an HCV mutant with low dependency on miR-122. In addition, the HCV-inhibitory effectiveness of rigosertib was validated in various HCV-relevant conditions, including replicons, infected cells, and replicon-harboring mice. Rigosertib was highly effective in inhibiting the proliferation of not only wild-type HCVs, but also sofosbuvir resistance-associated substitution-bearing HCVs. Our study identifies PLK1-ELAVL1/HuR-miR-122 signaling as a regulatory axis that is critical for HCV proliferation, and suggests that a therapeutic approach targeting this host cell signaling pathway could be useful for treating HCV and HCV-associated diseases.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2022-12-28)
- 국내 연구진
- 생명과학 > 분자생물학
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