Cell cycle perturbation in the hepatocytes of HCV core transgenic mice following common bile duct ligation is associated with enhanced p21 expression

Abstract

Hepatitis C virus (HCV) core protein has been reported to alter the cell cycle in vitro, but the data remain inconclusive, and in vitro experiments do not represent precisely events that occur in vivo, which may involve hepatic inflammation or regeneration. A group of double-transgenic mice carrying tetracycline transactivator (tTA) and HCV core that express conditionally the HCV core in the mature liver, and single-transgenic mice carrying only tTA were subjected to sham laparotomy, 43% partial hepatectomy, or common bile duct ligation. The cell cycle markers, including cyclin A, B1, D, E1, Mcm-2, phosphorylated histone 3 protein, Ki67, and p21Waf1/Cip1/Sdi1 (p21), were evaluated in liver samples obtained 3 days after the operation. No significant differences in the levels of any markers were observed between the double- and single-transgenic mice following sham laparotomy. Among the mice that underwent common bile duct ligation, the double-transgenic mice had lower levels of Ki67 (P = 0.0001), higher levels of cyclin D1 (P = 0.0001), and higher levels of p21 expression than the single-transgenic mice. Among those that underwent partial hepatectomy, the double-transgenic mice had higher p21 expression levels, but no significant differences in the levels of any other markers were observed between the double- and single-transgenic mice. It is concluded that the HCV core alters the hepatocyte cell cycle in addition to inducing G1 arrest in vivo after common bile duct ligation, and is associated with enhanced p21 expression. This may account at least partially for the strong association between HCV-related hepatocarcinogenesis and hepatic inflammation/ fibrosis.