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.


CONCLUSIONS
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.
Bahnassi
Abeer A
AA
Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Zekri
Abdel-Rahman N
AR
El-Houssini
Soumaya
S
Mokhtar
Nadia M
NM
Abdel-Aziz
Asraf O
AO
Sherif
Ghada M
GM
El-Mishad
Abla M
AM
Khaled
Hussein M
HM
D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics; D002648:Child; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011003:Ploidies; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D012697:Serine Endopeptidases; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; C493956:CDKN1A protein, human; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C497206:MDM2 protein, human