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Hepatitis C virus and its protein NS4B activate the cancer-related STAT3 pathway via the endoplasmic reticulum overload response

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Abstract

Oxidative stress induces the activation of signal transducer and activator of transcription 3 (STAT3), which plays an important role in hepatocellular carcinoma (HCC). We have previously reported that hepatitis C virus (HCV) and its protein NS4B induce the production of reactive oxygen species (ROS) via the endoplasmic reticulum overload response (EOR) in human hepatocytes. Here, we found that NS4B and HCV induce STAT3 activation and stimulate the expression of cancer-related STAT3 target genes, including VEGF, c-myc, MMP-9 and Mcl-1, by EOR in human hepatocytes. Moreover, the cancer-related STAT3 pathway activated by NS4B and HCV via EOR were found to promote human hepatocyte viability. Taken together, these findings revealed that HCV NS4B might contribute to HCC by activating the EOR-mediated cancer-related STAT3 pathway, and this could provide novel insights into HCV-induced HCC.

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Acknowledgments

This work was funded by grants from National Nature Science Foundation of China (No. 31160034 and 31460667) to L. Kong, and Jiangxi Province (Nos. 20133ACG70005, 2010GZY0059 and GJJ12219) to L. Kong.

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    Authors and Affiliations

    1. College of Bioscience and Engineering, Jiangxi Agricultural University, Nanchang, Jiangxi, China

      Lingbao Kong, Ahui Xu, Mingjie Huang, Xiaoyu Wu, Yunli Guo, Fenglin Guo & Jin Xu

    2. Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China

      Shanshan Li & Xilan Yu

    3. Department of Plant Pathology and Microbiology, Iowa State University, Ames, IA, USA

      Shanshan Li

    4. Department of Immunology and Pathogen Biology, Tongji University School of Medicine, 1239 Siping Rd, Shanghai, China

      Xiaonan Fang

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    1. Lingbao Kong
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    L. Kong and S. Li contributed equally.

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    Kong, L., Li, S., Yu, X. et al. Hepatitis C virus and its protein NS4B activate the cancer-related STAT3 pathway via the endoplasmic reticulum overload response. Arch Virol 161, 2149–2159 (2016). https://doi.org/10.1007/s00705-016-2892-x

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