Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes.
Naturally occurring mutants with a deletion in the pre-S2 region of the large surface protein (Delta S2-LHBs) are prevalent in serum and livers of patients with chronic hepatitis B virus (HBV) infection associated with cirrhosis. The Delta S2-LHBs protein is retained in the endoplasmic reticulum (ER) and may induce ER stress. One interesting observation is the consistently clustered distribution of hepatocytes expressing Delta S2-LHBs. In this study, complementary DNA microarray analysis identified cyclin A and several groups of genes as being significantly upregulated by Delta S2-LHBs in the HuH-7 cell line. This observation was confirmed in liver tissues. The induction of cyclin A expression may occur via the specific transactivator function of Delta S2-LHBs independent of ER stress. In the presence of Delta S2-LHBs, hepatocytes sustained cyclin A expression and cell cycle progression under ER stress and displayed increased BrdU incorporation with multinuclear formation. Furthermore, Delta S2-LHBs could enhance anchorage-independent cell growth in a nontransformed human hepatocyte line and induced nodular proliferation of hepatocytes in transgenic mice. In conclusion, these in vitro and in vivo data support a role for Delta S2-LHBs in the hepatocyte hyperplasia and a likely role in the process of HBV-related tumorigenesis.
Wang
Hui-Ching
HC
Division of Clinical Research, National Health Research Institutes, Tainan, Taiwan.
Chang
Wen-Tsan
WT
Chang
Wen-Wei
WW
Wu
Han-Chieh
HC
Huang
Wenya
W
Lei
Huan-Yao
HY
Lai
Ming-Derg
MD
Fausto
Nelson
N
Su
Ih-Jen
IJ
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015854:Up-Regulation
D019925:Cyclin A; D006514:Hepatitis B Surface Antigens; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine