Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation.
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.
Baek
Kwan-Hyuck
KH
Research Institute, National Cancer Center, Goyang, South Korea.
Park
Hye-Young
HY
Kang
Chang-Mo
CM
Kim
So-Jung
SJ
Jeong
Sook-Jung
SJ
Hong
Eun-Kyung
EK
Park
Joong-Won
JW
Sung
Young-Chul
YC
Suzuki
Tetsuro
T
Kim
Chang-Min
CM
Lee
Chang-Woo
CW
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
D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase