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  • br Introduction Epidemiological studies have


    Introduction Epidemiological studies have shown that viral infections such as hepatitis C virus (HCV) and hepatitis B virus (HBV) are important factors contributing to hepatocellular carcinoma (HCC) development. Chronic HCV leads to cirrhosis in approximately 20% of patients over a 10–20 year period, and approximately 10–20% of cirrhotic patients will develop HCC within 5 years. Viral hepatitis is a major etiological agent of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Fas-mediated apoptosis is the major cause of hepatocyte damage during liver disease. Although molecular events of HCC carcinogenesis have been studied extensively, the mechanism remains largely elusive. In patients with HBV infection, the HBx gene encodes a protein called HBV X protein and its interaction with proteasome subunits might be responsible for HCC carcinogenesis. In patients infected with HCV, the mechanisms causing viral evasion of cell-mediated immune responses leading to apoptotic death of hepatocytes might contribute to viral persistence. Such a mechanism might also contribute to the development of liver cancer. Progressive liver damage from viral hepatitis may be the results of repeated attempts by cytotoxic T lymphocytes (CTL) to clear infected hepatocytes. Histological necroinflammation is a well-recognized phenomenon in chronic HCV infection. Reports have shown that altered regulation of apoptosis was associated with the pathogenesis of HCC and dysplasia, primary biliary cirrhosis, viral hepatitis and liver disease induced by ethanol, bile salts, toxins and drugs. Indeed, both HBxAg and the HCV core protein have been reported to induce the kisspeptin of FasL on HCC cells, which counter-attack CTL for immune evasion. Fas/FasL, a transmembrane receptor, is a member of the tumor necrosis factor receptor superfamily, which play an important role in embryogenesis, autoimmunity, liver cirrhosis and tumorigenesis. Engagement of the Fas ligand (FasL) triggers programmed cell death, which is important in apoptosis mediated by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Genetic polymorphisms with functional differences of Fas/FasL genes were recently reported to be associated with autoimmune diseases including cervix cancer, HCV related liver cirrhosis, lung cancer, and esophageal cancer. The present study was intended to test the hypothesis that genetic polymorphisms of Fas/FasL promoter may be associated with individual susceptibility to virus hepatitis, and the prognosis of HCC in a Taiwanese population.
    Materials and methods
    Result The gender distributions (M/F) in the cirrhosis group and the HCC group were 106/51 and 100/42, respectively. Overall, there was no real difference between these distributions and the control group (200/100). The clinical characteristics were summarized in Table 1. The mean patient age in the cirrhotic group was 59.3 ± 13.4 years, and in the HCC group was 58.9 ± 13.3 years; similarly, there was no difference from the control group\'s mean patient age. There were 107 patients of the cirrhotic group that had a history of HBV infection, and 50 patients with a history of HCV infection. In the HCC group, there were 100 patients with HBV infection and 35 patients with HCV infection, again showing little difference in distribution between the two groups. One of the exclusion criteria for the control group was hepatitis virus infection, so all patients in the control group had no history of hepatitis virus infection.
    Discussion Our results showed an association between the Fas genotype and HCV-associated cirrhosis of the liver. The FasL genotype was also associated with CLIP stages of HCC, where AFP is detrimental associated with polymorphism and the risk of severe cirrhosis with chronic HCV infection. The major SNPs in the Fas promoter region were not associated with HCC patients. When factoring in the clinical parameters of the CLIP staging system, Child classification, tumor numbers, AFP levels and portal invasion for HCC patients, only patients with AFP level ≥400 ng/dL had an association with FasL −844 T/C polymorphyism.