ACTIVATION OF FETAL PROMOTERS OF INSULIN-LIKE GROWTH-FACTOR-II GENE IN HEPATITIS-C VIRUS-RELATED CHRONIC HEPATITIS, CIRRHOSIS, AND HEPATOCELLULAR-CARCINOMA

Increased prevalence of hepatitis C virus (HCV) infection has been fou nd in patients with hepatocellular carcinoma (HCC). The expression of insulinlike growth factor II (IGF-II) has been linked to hepatocarcino genesis in the experimental animal and in humans. Since reactivation o f fetal IGF-II transcripts has been observed in human HCC, we have ana lyzed the levels of adult P1 and fetal P3 and P4 IGF-II promoter-deriv ed transcripts in the Liver of patients with HCV-related chronic activ e hepatitis (CAH), cirrhosis, and HCC by means of a semiquantitative r everse-transcription polymerase chain reaction (RT-PCR) assay. Transcr ipts derived from adult P1 promoter were increasingly expressed from n ormals to patients with CAH and cirrhosis, but were undetectable in th e tumorous area of 5 of 7 HCC patients and present at low levels in th e nontumorous area of all HCC patients. Transcripts derived from fetal P3 promoter were not detectable in normal subjects, while they were e xpressed abundantly in most CAH and all cirrhotic patients. Transcript s from fetal P4 promoter were detected at high levels in 3 of 9 CAH pa tients and in the majority of cirrhotic patients. Increased expression of fetal promoter-derived transcripts was also found in the liver of HCC patients, although levels were lower than in cirrhosis. Also, the activity of fetal P3 and P4 promoters was higher in the nontumorous th an in the tumorous area of the liver of HCC patients, The expression o f IGF-II transcripts was correlated with the rate of cell mitotic acti vity by measuring the expression of the proliferating cell nuclear ant igen (PCNA) gene. PCNA messenger RNA (mRNA) levels progressively incre ased from normals to CAN and to cirrhotic patients, and persisted at a high level in the tumorous and in the nontumorous area of HCC subject s, thus showing that the increase of IGF-II transcripts in CAH and cir rhosis is accompanied by an activation of cell mitosis in these sample s. These data suggest that the activation of IGF-II gene expression fr om adult and fetal promoters may play a role in premalignant prolifera tion observed in HCV-related chronic liver disease.