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Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT
  1. Fang luan (luanfang2004{at}126.com)
  1. Institute of Immunology, Shandong University School of Medicine, China
    1. Hua Liu (liuhuagreen{at}126.com)
    1. Institute of Immunology, Shandong University School of Medicine, China
      1. Lifen Gao (lfgglf{at}sdu.edu.cn)
      1. Institute of Immunology, Shandong University School of Medicine, China
        1. Jun Liu (dr_liujun{at}hotmail.com)
        1. Department of Surgery, Shandong Provincial Hospital, China
          1. Zhaohui Sun Sun (szhsd68{at}126.com)
          1. The Second Hospital of Shandong University, Shandong, China
            1. Ying Ju (juying2003{at}126.com)
            1. Institute of Immunology, Shandong University School of Medicine, China
              1. Nan Hou (hounan2006{at}yahoo.com.cn)
              1. Institute of Immunology, Shandong University School of Medicine, China
                1. Chun Guo (guochun{at}sdu.edu.cn)
                1. Institute of Immunology, Shandong University School of Medicine, China
                  1. Xiaohong Liang (liangxiaohong{at}sdu.edu.cn)
                  1. Institute of Immunology, Shandong University School of Medicine, China
                    1. Lining Zhang (immuno{at}sdu.edu.cn)
                    1. Institute of Immunology, Shandong University School of Medicine, China
                      1. Wensheng Sun (wsw{at}sdu.edu.cn)
                      1. Institute of Immunology, Shandong University School of Medicine, China
                        1. Chunhong Ma (machunhong{at}sdu.edu.cn)
                        1. The Key Laboratory for Experimental Teratology of the Ministry of Education. Institute of Immunology, China

                          Abstract

                          Backgrounds and aims: Telomerase is significantly reactivated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Our previous studies showed that the transactivation unit of HBV surface (S) gene, preS2, could upregulate human telomerase reverse transcriptase (hTERT) expression and telomerase activity of HepG2 cells. Here, we aim to explore the functions, and the underlying mechanisms, of this preS2-mediated hTERT upregulation during HCC development.

                          Methods: Antisense blocking assay was performed on HBV-integrated HepG2.2.15 cells. The expression of hTERT was examined in clinical samples to test the role of the preS2-mediated hTERT upregulation in HCC development in vivo. In order to explore the mechanisms of preS2-mediated hTERT upregulation, co-transfection, reporter assay and electrophoretic mobility shift assays (EMSA) were performed.

                          Results: Blocking preS2 expression reduced hTERT expression, telomerase activity, cell proliferation and tumorigenicity of HepG2.2.15. A region located between -349 and -329 bp upstream of the transcription initiation site was identified to be responsible for the preS2-mediated effect. preS2 interacted with the preS2-responsible region (PRR) and activated hTERT promoter. Importantly, hTERT was also highly expressed in preS2-positive human HCC samples. All these findings strongly suggest that preS2 may promote HCC development via hTERT activation.

                          Conclusions: HBV protein preS2 upregulates hTERT via the PRR element in promoting HCC development.

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