Influence of plasminogen activator inhibitor-1 (SERPINE1) 4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection.
Hepatocarcinogenesis is heavily influenced by chronic hepatitis B (HBV) and C (HCV) infection. Elevated levels of plasminogen activator inhibitor-1 (SERPINE1/PAI-1) have been reported in patients with hepatocellular carcinoma (HCC) associated with viral infection. The gene encoding SERPINE1 is highly polymorphic and the frequently associated 4/5 guanosine (4G/5G) polymorphism in the gene promoter may influence its expression. Here, we investigated the distribution of genotypes and the frequency of alleles of the 4G/5G polymorphism in patients with HCC, the influence of the 4G/5G polymorphism on plasma SERPINE1 levels and its association with viral infection. A total of 75 patients with HCC were enrolled: 32 (42.6%) were HBV(+)/HCV(+), 11 (14.6%) were only HCV(+), and 32 (42.6%) were negative for both viruses. A control group of healthy donors was also enrolled (n=50). SERPINE1 plasma concentrations were determined by ELISA and the detection of the promoter 4G/5G polymorphism was performed by an allele-specific PCR analysis. We found that the frequency of both the 4G/4G genotype (p=0.02) and the 4G allele (p=0.006) were significantly higher in patients with HCC compared to the control group, and particularly higher in patients with HCC co-infected with HBV(+)/HCV(+) than in those with no viral infection. We also found that patients with the 4G/4G genotype had significantly higher plasma SERPINE1 protein levels when compared with patients with the 4G/5G or 5G/5G genotype (p<0.001). Differences in frequency of 4G allele and genetic variability of 4G/5G SERPINE1 polymorphism with a higher level of SERPINE1 protein in patients with HCC with HBV(+)/HCV(+) than those without infection, suggest the presence of two distinct pathogenic mechanisms in hepatocarcinogenesis, depending on the etiology.
Department of Experimantal Oncology, Clinical Pathology Laboratory National Cancer Institute Giovanni Paolo II, Viale Orazio Flacco, 65, 70100, Bari, Italy. rosadive@inwind.it
Rosa
R
Divella
Antonio
A
Mazzocca
Cosimo
C
Gadaleta
Giovanni
G
Simone
Angelo
A
Paradiso
Michele
M
Quaranta
Antonella
A
Daniele
D000368:Aged; D000369:Aged, 80 and over; D000941:Antigens / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000821:virology; D060085:Coinfection / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D019694:Hepatitis B, Chronic / Q000097:blood / Q000235:genetics / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000097:blood / Q000235:genetics / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
D000941:Antigens; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human