Journal
DIGESTIVE DISEASES AND SCIENCES
Volume 60, Issue 5, Pages 1315-1324Publisher
SPRINGER
DOI: 10.1007/s10620-014-3492-9
Keywords
Core promoter (CP); Hepatitis B virus (HBV); Mutation; Hepatocarcinogenesis
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Funding
- National Natural Science Foundation of Guangdong Province [S2013010016015]
- National Natural Science Fund for Young Scholars of China [81000177]
- Projects on Science and Technology plan of Guangzhou City [2013J410061-1955]
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Background and Aim 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.
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