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Cell Cycle, Cell Death, and Senescence

Mitotic Aberration Coupled With Centrosome Amplification Is Induced by Hepatitis B Virus X Oncoprotein via the Ras-Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Pathway¹

¹ Department of Biochemistry and Molecular Biology, Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, South Korea;
² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; and
³ Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

Requests for reprints: Hyeseong Cho, Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 5 Wonchon-dong, Paldal-gu, Suwon 442-741, Korea. Phone: 82-31-219-5052; Fax: 82-31-219-5059. E-mail: hscho{at}ajou.ac.kr

Multinucleated cells have been noted in pathophysiological states of the liver including infection with hepatitis B virus (HBV), the status of which is also closely associated with genomic instability in liver cancer. Here, we showed that hepatitis B virus X oncoprotein (HBx) expression in Chang cells results in a multinuclear phenotype and an abnormal number of centrosomes (n   3). Regulation of centrosome duplication in HBx-expressing ChangX-34 cells was defective and uncoupled from the cell cycle. HBx induced amplification of centrosomes, multipolar spindle formation, and chromosomal missegregation during mitosis and subsequently increased the generation of multinucleated cells and micronuclei formation. Treatment with PD98059, a mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2 inhibitor, significantly reduced the number of cells with hyperamplified centrosomes and decreased the multinucleated cells and micronuclei formation. Consistently, the phospho-ERK level during cell progression was substantially higher in ChangX-34 cells than that of Chang cells. In contrast, neither wortmannin, an inhibitor of phosphoinositide-3 kinase, nor SB203589, an inhibitor of p38 mitogen-activated protein kinase (MAPK), showed any effects. Introduction of Ras dominant-negative (D/N) and MEK2 D/N genes into ChangX-34 cells significantly alleviated centrosome amplification, whereas introduction of the PKC D/N and PKB D/N genes did not. Thus, our results demonstrate that the HBx induced centrosome hyperamplification and mitotic aberration by activation of the Ras-MEK-MAPK. Intervention of this signaling pathway could suppress the centrosome amplification as well as mitotic aberration. These findings may provide a possible mechanism by which HBx promotes phenotypic progression by predisposing chromosomal alteration in HBV-infected liver.

Key Words: HBx • centrosome • genomic instability • Ras-MEK-MAPK pathway

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