title: Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53.
abstract: OBJECTIVE
  Hepatitis B virus core promoter (CP) mutations can increase risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been associated with hepatocarcinogenesis. The cyclin kinase inhibitor P53 is an important regulator of cell cycle progression. We determined whether HBx mutants that result from mutations in the CP deregulate P53.
  
  
  METHODS
  A HBx combination (combo) mutant with changes in the CP region that corresponded to A1762T/G1764A (TA), T1753A, and T1768A was constructed and expressed in L-02 and Hep3B cells. The effects of CP mutations on expression and degradation of P53, and the effects on cell cycle progression and proliferation were analyzed.
  
  
  RESULTS
  The combo mutant decreased levels of P53 and increased cyclin D1 expression, accelerated P53 degradation in L-02 cells, accelerated cell cycle progression, and increased expression of S-phase kinase-associated protein 2 (Skp2) in L-02 and Hep3B cells. Silencing of Skp2 abrogated the effects of CP mutations on P53 expression. The kinetics of P53 expression correlated with changes in cell cycle distribution.
  
  
  CONCLUSIONS
  The HBx mutant with a combination of CP mutations can up-regulate Skp2, which then down-regulates P53 via ubiquitin-mediated proteasomal degradation, increasing the risk of hepatocellular carcinoma.
authors.affiliation: Hepatobiliary Surgery Department, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, TianHe Road, TianHe District, Guangzhou City, 510630, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Yao
authors.forename: Kunpeng
authors.initials: K
authors.lastname: Hu
authors.forename: Yuesi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Mingliang
authors.initials: M
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Xiong
authors.forename: Meihai
authors.initials: M
authors.lastname: Deng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D009154:Mutation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014758:Viral Core Proteins / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C530104:CCND1 protein, human; D044786:S-Phase Kinase-Associated Proteins; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex