title: Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation.
abstract: Hepatocellular carcinoma (HCC) is a common primary cancer associated with high incidences of genetic variations including chromosome instability. Moreover, it has been demonstrated that hepatitis C virus (HCV) is one of the major causes of HCC. However, no previous work has assessed whether HCV proteins are associated with the induction of chromosome instability. Here, we found that liver cell lines constitutively expressing full-length or truncated versions of the HCV genome show a high incidence of chromosome instability. In particular, the overexpression of HCV NS5A protein in cultured liver cells was found to promote chromosome instability and aneuploidy. Further experiments showed that NS5A-induced chromosome instability is associated with aberrant mitotic regulations, such as, an unscheduled delay in mitotic exit and other mitotic impairments (e.g. multi-polar spindles). Thus, our results indicate that HCV NS5A protein may be directly involved in the induction of chromosome instability via mitotic cell cycle dysregulation, and provide novel insights into the molecular mechanisms of HCV-associated hepatocarcinogenesis.
authors.affiliation: Research Institute, National Cancer Center, Goyang, South Korea.
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Park
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sook-Jung
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Hong
authors.forename: Joong-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Kim
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Lee
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology; D008938:Mitosis / Q000502:physiology*; D008941:Spindle Apparatus / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase