Molecular Mechanism Underlying the Suppression of CPB2 Expression Caused by Persistent Hepatitis C Virus RNA Replication.
The mechanisms of hepatitis C virus (HCV)-associated hepatocarcinogenesis and disease progression are unclear. We previously observed that the expression level of carboxypeptidase B2 (CPB2) gene was remarkably suppressed by persistent HCV RNA replication in human hepatoma cell line Li23- derived cells. The results of the present study demonstrated that the CPB2 expression in patients with chronic hepatitis C was inversely correlated with several risk factors of hepatic fibrosis or steatosis, although ectopic CPB2 expression did not suppress the expression of fibrogenic or lipogenic genes. The suppressed CPB2 expression was restored by treatment with 5-azacytidine. To clarify the mechanism underlying this phenomenon, we analyzed the CPB2 promoter, and the results revealed that (1) hepatocyte nuclear factor 1 (HNF1), especially HNF1α, was essential for the CPB2 promoter, and (2) CPB2 promoter was not methylated by persistent HCV RNA replication. The expression levels of HNF1α and HNF1β were also not changed by persistent HCV RNA replication. These results suggest the existence of 5-azacytidine-inducible or -reducible unknown factor(s) that can control the CPB2 expression. To evaluate this idea we performed a microarray analysis, and several gene candidates corresponding to the suggested factor(s) were identified.
Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Hiroe
H
Sejima
Shinya
S
Satoh
Hiromichi
H
Dansako
Masao
M
Honda
Shuichi
S
Kaneko
Masanori
M
Ikeda
Nobuyuki
N
Kato
D001374:Azacitidine / Q000494:pharmacology; D025901:Carboxypeptidase B2 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
D004791:Enzyme Inhibitors; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D035683:MicroRNAs; D012367:RNA, Viral; D051539:Hepatocyte Nuclear Factor 1-beta; C585364:CPB2 protein, human; D025901:Carboxypeptidase B2; D001374:Azacitidine