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: An 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 assays 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 of hTERT was identified as responsible for the preS2-mediated effect. preS2 interacted with the preS2-responsible region (PRR) and activated the 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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Funding This work was supported, in part, by grants from the National Science Foundation of China (No. 30471525 and No. 30670966), the National Basic Research Program (No. 2009CB521900), the Cultivation Fund of the Key Scientific and Technical Innovation Project, Ministry of Education of China (No. 704030), and the Scientific Foundation of Innovative Research Team in Shandong University.
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed
Ethics approval This work was done with the approval of the Medical Ethics Committee of Shandong University. The mice used in this study were cared for and handled according to animal protocols approved by the Shandong University Animal Care Committee.