Hepatitis C virus-NS3P in relation to p53, p21waf, mdm2, p21-ras and c-erbB2 in hepatocarcinogenesis

Background: The non-structural protein 3 (NS3P) of hepatitis C virus (HCV) genome was linked to the neoplastic transformation of normal hepatocytes in chronically infected patients. However, the exact mechanisms involved in this process are unidentified yet, especially in the Egyptian population where the commonest type is genotype 4. Methods: We investigated 32 HCV reverse transcriptase-polymerase chain reaction (RT-PCR) positive hepatocellular carcinoma (HCC) cases and 18 morphologically normal hepatic tissues distant to tumors (MNT) for the correlation between HCV-NS3P, p53, p21(waf), mdm2, p21ras and c-erbB2 and DNA content by immunohistochemistry and image analysis. Results: The NS3P expression was lower in HCC (65.6%) than in MNT (94.4%) patients. The expression level of studied genes in HCC was: p53 (56.25%), p21(waf) (43.7%), mdm2 (59.4%), p21-ras (73.3%) and c-erbB2 (75%). Whereas in MNT, it was 22.2, 61.1, 44.4, 41.2 and 77.8%, respectively. The NS3P expression showed a significant correlation with the presence of cirrhosis, chronic active hepatitis (CAH) and tumor grade (P < 0.05). c-erbB2 overexpression and p21(waf) loss were higher in MNT than in HCC patients, however, this did not reach a statistically significant level. There was a statistically significant correlation between NS3P, c-erbB2 and p21(waf) (P < 0.01). There was also a significant correlation between p21(waf) loss and CAH (P = 0.01) as well as between mdm2, c-erbB2 and cirrhosis (P = 0.025 and 0.001) in HCC cases. There was a statistically significant difference in the ploidy status between HCC and MNT, but there was no significant relationship between the ploidy status and other clinicopathological features. Conclusion: The carcinogenic effect of NS3P is probably exerted at an early stage of HCC possibly through a pathway involving c-erbB2 and p21(waf) alterations. In contrast, p53, p21ras and mdm2 alterations are late events in hepatocarcinogenesis and are usually associated with an aggressive phenotype. (C) 2005 Blackwell Publishing Asia Pty Ltd.