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.

Cell‐cycle‐dependent localization of human cytomegalovirus UL83 phosphoprotein in the nucleolus and modulation of viral gene expression in human embryo fibroblasts in vitro

“…Targeting the nucleolus in order to take over control of the cell cycle may represent an important strategy for many viruses, crucial for the infection outcome [Dittmer and Mocarsky, 1997; Fortunato et al, 2002; Hiscox, 2002, 2007; Bain and Sinclair, 2007; Cawood et al, 2007; Galati and Bocchino, 2007; Sarfraz et al, 2008; Chang et al, 2009; Hamid et al, 2009].…”

Durability of Sustained Virological Response and Long Term Follow Up to Pegylated Interferon and Ribavirin in Treated Patients with Chronic Hepatitis C

“…No patient developed liver cancer during the period of follow up, but these data must not assure us that our treated patients are protected from acquiring HCC. Japanese authors (27,28) have reported a HCC rate of 0.02%-0.5% per year, also Maria Trapero-Marugan et al (12) reported incidence of 0.65% of HCC, Sang Bu Choi et al rated an incidence of 0.68% of HCC, (13) Chavalitdhamrong et al rated an incidence of 1.7% of HCC (10) and George et al had an incidence of 1.3%. (8) These data raise up that the risk of late development of HCC after a SVR is a real problem, and we must continue the followup of these patients for a long time.…”

Pleural fluid analysis of lung cancer vs benign inflammatory disease patients

“…We decided to analyse these markers as they belong to three different marker groups that may be related to cancer and/or to inflammatory diseases. p27, Skp2, Cox2, CycD1 and Ki67 are considered as tumour and/or proliferation markers (Huang et al, 2003;Siggelkow et al, 2004;Adjei, 2005;Vig-Varga et al, 2006;Garg et al, 2008;Park et al, 2008;Chang et al, 2009;Meeran et al, 2009;Mukhopadhyay et al, 2009), ImAnOx and carbonyls are oxidative markers (Nyström, 2005;Bahar et al, 2007) and MMP-9, -3 and -2 are MMPs that are expressed in various pathological processes such as inflammation and cancer and also in response to infections (Korpos et al, 2009;Oikonomidi et al, 2009;Vanlaere and Libert, 2009). Enhanced oxidative stress characterises both inflammation and cancer; all other markers analysed were also shown previously to be associated with inflammation, as well as with oxidative stress, presumably mediated through the activation of NF-kB (Huang et al, 2003;Vig-Varga et al, 2006;Park et al, 2008;Gonda et al, 2009;Karalis et al, 2009;Ku et al, 2009;Perricone et al, 2009;Víctor et al, 2009).…”