title: Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus pre-S2 mutants and its implication in hepatocarcinogenesis.
abstract: Ground glass hepatocytes harboring hepatitis B virus (HBV) pre-S2 mutants have been recognized as pre-neoplastic lesions of hepatocellular carcinoma (HCC). The pre-S2 mutants accumulated in endoplasmic reticulum (ER) can induce ER stress, upregulate cyclin A and promote hepatocyte proliferation. Notably, cyclin A was aberrantly detected in the cytoplasm, instead of nucleus, of pre-S2 mutant-transgenic mice livers, thereby raising the potential role of cytoplasmic cyclin A in HBV hepatocarcinogenesis. In this study, we confirmed that cyclin A was detected in the cytoplasm in the majority of HBV-related HCC tissues. In vitro, the pre-S2 mutant-initiated ER stress could induce cytoplasmic cyclin A mediated via cleavage by the calcium-dependent protease μ-calpain, resulting in an N-terminal truncated product which was preferentially located in the cytoplasm. The aberrant cyclin A expression subsequently induced centrosome overduplication, and this effect was abolished by calpain-specific inhibitors or RNA interference targeting to cyclin A. Overall, our data indicate that HBV pre-S2 mutant may elicit aberrant cyclin A expression and centrosome overduplication through ER stress induction and thereby represent a potential mechanism for the chromosome instability in HBV hepatocarcinogenesis.
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Lily Hui-Ching
authors.initials: LH
authors.lastname: Wang
authors.forename: Wenya
authors.initials: W
authors.lastname: Huang
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
mesh_terms: D000818:Animals; D016466:CHO Cells; D002154:Calpain / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018385:Centrosome / Q000378:metabolism*; D043171:Chromosomal Instability / Q000235:genetics*; D006224:Cricetinae; D019925:Cyclin A / Q000096:biosynthesis* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics*; D034622:RNA Interference; D014407:Tumor Cells, Cultured
chemical_list: D019925:Cyclin A; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; C050807:presurface protein 2, hepatitis B surface antigen; D002154:Calpain