Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma.
Human APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3) cytidine deaminases have been shown to be potent inhibitors of diverse retroviruses including Vif-deficient human immunodeficiency virus 1 (HIV-1), hepatitis virus B (HBV), adeno-associated virus, and endogenous retroelements. Despite the fact that these enzymes are known to be potential DNA mutators and to target retroviral DNA for cytidine deamination, the pathological effects of their deregulated expression in human diseases are not yet clear. Mutants of the viral HBx protein have been implicated in the carcinogenesis of hepatocellular carcinoma (HCC); however, little is known about how or why such mutants are generated in the human liver. Here, we report that a number of APOBEC3 deaminases preferentially edit the HBx region of HBV DNA and generate C-terminally truncated HBx mutants. Our functional studies indicated that APOBEC3-mediated HBx mutants, especially the C-terminally truncated mutants, cause a gain of function that enhances the colony-forming ability and proliferative capacity of neoplastic cells. Furthermore, we detected G-to-A hypermutation-mediated HBx mutants in preneoplastic liver tissues of selected patients with active chronic HBV infections. We also observed that the APOBEC3B (A3B) cytidine deaminase was widely up-regulated in HCC tumor tissues; it also promoted the growth of neoplastic human HepG2 liver cells and up-regulated heat shock transcription factor1 (HSF1) expression.


CONCLUSIONS
These findings suggest that some of the APOBEC3 deaminases play a role in the carcinogenesis of HCC through the generation of HBx mutants, providing preneoplastic and neoplastic hepatocytes with a selective clonal growth advantage. Deregulated expression of A3B in liver tissues may also have the potential to promote genetic instability and tumorigenesis.
Xu
Rongzhen
R
Second Affiliated Hospital, Cancer Institute, School of Medicine, Zhejiang University, Hangzhou, China.
Zhang
Xuzhao
X
Zhang
Wei
W
Fang
Yongmin
Y
Zheng
Shu
S
Yu
Xiao-Fang
XF
D000071478:APOBEC Deaminases; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000503:physiopathology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism*; D006511:Hepatitis B Antigens / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D006511:Hepatitis B Antigens; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase