Gene expression analysis in HBV transgenic mouse liver: a model to study early events related to hepatocarcinogenesis.
Hepatitis B virus (HBV) is one of the major etiological factors responsible for the development of hepatocellular carcinoma (HCC). We used a transgenic mouse, containing HBV sequences, as a model system to unravel the molecular mechanisms of hepatocarcinogenesis induced by HBV. We chose this animal model because it consistently develops liver cancer after intermediate steps that mimic the natural history of HBV infection in humans. In this study, we focus our attention on the early events leading to liver cancer. We compared the gene expression profile of 3-month-old transgenic mice with that of 3-month-old wild-type (wt) animals. In the transgenic mouse, microarray data analysis showed a total of 45 significantly differentially expressed genes, 25 highly expressed (fold change > or =2; P = 0.0025), and 20 downregulated (fold change < or =0.5; P = 0.0025). These genes belong to several different functional categories such as the regulation of immunological response, transcription, intracellular calcium ion mobilization, regulation of cell cycle and proliferation, NF-kappab signal transduction cascades, and apoptosis. In particular, the upregulation of the antiapoptotic gene NuprI and the downregulation of the proapoptotic gene Bnip3 were found. This observation was supported by an in vitro apoptosis assay that showed downregulation of apoptosis in hepatocytes of HBV transgenic mouse compared with wt mice treated with staurosporine. In conclusion, our experimental approach allowed identification of new genes modulated by HBV and showed that the apoptotic process was deregulated in transgenic mouse hepatocytes. These data shed light on one possible mechanism by which HBV induces hepatocarcinogenesis.
Barone
Michele
M
Sezione di Gastroenterologia, Dipartimento di Emergenza e di Trapianto d'Organo, Università di Bari, Bari, Italia.
Spano
Daniela
D
D'Apolito
Maria
M
Centra
Marta
M
Lasalandra
Carla
C
Capasso
Mario
M
Di Leo
Alfredo
A
Volinia
Stefano
S
Arcelli
Diego
D
Rosso
Natalia
N
Francavilla
Antonio
A
Tiribelli
Claudio
C
Iolascon
Achille
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology
D019311:Staurosporine