Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma. Several lines of evidence suggest that the core protein of HCV may play a role in the development of this cancer. The authors examined regulation of the cell cycle in stable cell lines derived from Chinese hamster ovary (CHO-K1) cells that constitutively expressed one or more of the structural proteins of HCV. In media containing low concentrations of serum (serum starvation), cell lines expressing the core protein showed a significantly lower population of viable cells than noncore-expressing cells. The low viability of the core-expressing cells was a result of the increased population of cells undergoing apoptosis. Interestingly, the cell cycle analysis revealed that the arresting function at G(0) was impaired, and the cell cycle was accelerated in core-expressing cell lines even under serum starvation. Thus, the HCV core protein sensitizes the apoptosis to serum starvation, although it promotes the cell cycle in CHO-K1 cells. To explain these findings, the authors examined the expression of revival apoptosis and cell-cycle-related genes. Expression of the c-myc genes was significantly induced in core-expressing cells in response to serum starvation. Other apoptosis-inducing genes downstream of c-myc, p53, p21WAF1/CIP1 and Bax were significantly highly induced, although there was no induction of Bcl-2, which prevents apoptosis in core-expressing cells. Thus, the HCV core protein induced apoptosis and impaired the regulation of the cell cycle by activating c-myc expression, whereas the p53 and Bax pathways play a role in the induction of apoptosis.

Translation of the hepatitis C virus (HCV) polyprotein is mediated by an internal ribosome entry site (IRES) that is located within the 5 -nontranslated region (5 NTR)H epatitis C virus (HCV), a positive-strand, enveloped RNA virus, is classified within the genus Hepacivirus of the family Flaviviridae. 1 HCV infects the human liver, leading to the development of chronic hepatitis, cirrhosis, and, in some instances, hepatocellular carcinoma. [2][3][4] The treatment of chronic hepatitis C aims to eliminate viremia, and currently, the antiviral agent interferon alfa (IFN-␣) is commonly used worldwide. [5][6][7] It is known that the antiviral action mechanisms of IFN-␣ chiefly include the transcriptional activation of 2Ј,5Ј-oligoadenylate synthetase (2Ј,5ЈAS) that catalyzes 2Ј,5Ј-oligoadenylate (2Ј,5ЈA) synthesis, 8 thereby activating the endonuclease, RNase L, which degrades viral and cellular RNA (2Ј,5ЈA/RNase L system), and also activating the double-stranded RNA-activated protein kinase (PKR), 9,10 which phosphorylates the initiation factor elF2 and leads to the inhibition of translation. 11,12 However, because IFN is used in various intracellular signal transduction pathways, we speculate that mechanisms of antiviral action by IFN-␣ other than that involving the 2Ј,5ЈA/RNase L system and PKR may exist.It is known that the translation of the HCV-RNA genome is initiated by a highly structured RNA segment, 13,14 the internal ribosome entry site (IRES) that occupies most of the 5Ј nontranslated (5ЈNTR) RNA. [15][16][17] The IRES activity is highly dependent on both the primary sequence of this segment and its ability to form complex secondary and tertiary RNA structures. 18-22 A number of in vitro studies have suggested that several cellular proteins, including both conventional translation initiation factors such as eukaryotic initiation factor 3 (eIF3) 23,24 and noncanonical translation initiation factors such as the nuclear La protein [25][26][27][28][29] or polypyrimidine tract binding protein (PTB), 30-32 may stimulate HCV translation. We previously reported that HCV translation is regulated in a cell-cycle-dependent manner and that cellular proteins that vary in abundance during the cell cycle may be involved in this process, 33 but to date, the mechanism by which HCV translation is regulated in vivo is not well understood.

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