Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis.
Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development.
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Gastroenterology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
Ranxu
R
Zhu
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Myth T S
MT
Mok
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Wei
W
Kang
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Suki S K
SS
Lau
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Wing-Kit
WK
Yip
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Yangchao
Y
Chen
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Paul B S
PB
Lai
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Vincent W S
VW
Wong
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Ka-Fai
KF
To
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Joseph J Y
JJ
Sung
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Alfred S L
AS
Cheng
Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Henry L Y
HL
Chan
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002453:Cell Cycle; D002472:Cell Transformation, Viral; D016922:Cellular Senescence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
C490936:GAS2 protein, human; D008840:Microfilament Proteins; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
GAS2; HBV; apoptosis; cell cycle; hepatocellular carcinoma; senescence; truncated HBx