Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT.
OBJECTIVE
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.
Luan
F
F
Institute of Immunology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Shandong, 250012 PR China.
Liu
H
H
Gao
L
L
Liu
J
J
Sun
Z
Z
Ju
Y
Y
Hou
N
N
Guo
C
C
Liang
X
X
Zhang
L
L
Sun
W
W
Ma
C
C
D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016372:RNA, Antisense / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D016372:RNA, Antisense; C050807:presurface protein 2, hepatitis B surface antigen; D019098:Telomerase