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Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferation of hepatoma cells

Oncogene volume 33, pages 449–460 (2014)Cite this article

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Abstract

Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt −235/−66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.

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Acknowledgements

We thank Dr Xiao Yang (from the Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, People’s Republic of China) for kindly providing the HBx transgenic mice. This work was supported in part by National Basic Research Program of China (973 Program, No. 2009CB521702) and National Natural Science Foundation of China (No. 81071624, 81272218).

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Authors and Affiliations

  1. Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, College of Life Sciences, Nankai University, Tianjin, People’s Republic of China

    X You, T Zhang, N Lv, C Shan, Y Du, G Kong, T Wang & X Zhang

  2. Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, People’s Republic of China

    F Liu, Q Liu & L Ye

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You, X., Liu, F., Zhang, T. et al. Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferation of hepatoma cells. Oncogene 33, 449–460 (2014). https://doi.org/10.1038/onc.2012.618

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