Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway.
Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and probably also non-Hodgkin's B-cell lymphoma. The molecular mechanisms of HCV-associated carcinogenesis are unknown. Here we demonstrated that peripheral blood mononuclear cells obtained from hepatitis C patients and hepatocytes infected with HCV in vitro showed frequent chromosomal polyploidy. HCV infection or the expression of viral core protein alone in hepatocyte culture or transgenic mice inhibited mitotic spindle checkpoint function because of reduced Rb transcription and enhanced E2F-1 and Mad2 expression. The silencing of E2F-1 by RNA interference technology restored the function of mitotic checkpoint in core-expressing cells. Taken together, these data suggest that HCV infection may inhibit the mitotic checkpoint to induce polyploidy, which likely contributes to neoplastic transformation.
Machida
Keigo
K
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Liu
Jian-Chang
JC
McNamara
George
G
Levine
Alexandra
A
Duan
Lewei
L
Lai
Michael M C
MM
D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D064246:Mad2 Proteins; D051379:Mice; D008822:Mice, Transgenic; D011123:Polyploidy; D012097:Repressor Proteins / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D014779:Virus Replication
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein