All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated.

Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G 1 /S and G 2 /M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G 1 /S and the G 2 /M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G 1 /S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G 2 /M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G 1 /S and the G 2 /M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway. The hepatitis C virus (HCV)3 infection is a rapidly increasing public health problem, with millions of chronically infected patients to date. It is well known that patients with chronic disease have an increased risk of developing hepatocellular carcinoma (HCC) (1). Despite the research already done in this field, HCV-related mechanisms inducing cell transformation are still incompletely understood. Clinical observations indicate that the increased proliferation rate of hepatocytes is a major risk factor for the development of HCC (2). Several in vivo studies on hepatic biopsies reported an imbalance between the G 1 and the S phases of the cell cycle in liver cells obtained from chronic hepatitis C patients (3). Moreover, some studies revealed a G 2 /M dysfunction in hepatocarcinoma-derived cells (4). A large body of evidence has pointed to the possibility that HCV pathogenesis is due to virus-mediated disruption of several signal transduction pathways that normally regulate cell proliferation (5-7). However, the lack of appropriate cell culture systems and of suitable animal models that mimic viral propagation in humans has hampered the full understanding of HCV-dependent pathogenic mechanisms. The analysis of HCV gene product(s), responsible for the impairment of cell cycle regulation, has already suggested a main role of HCV core protein in regulating hepatocyte proliferation, making cells susceptible to cellular transforma...

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