Differential promoter usage for insulin-like growth factor-II gene in Chinese hepatocellular carcinoma with hepatitis B virus infection

Background: Human insulin-like growth factor-II (IGF-II) gene contains nine exons and four different promoters (P1–P4). Expression of the gene is elevated in the preneoplastic hepatic foci and hepatocellular carcinoma (HCC) of experimental animals and humans. To gain insight into transcriptional regulation of the gene in HCC, we analyzed the relative usage of the P1–P4 promoters and its correlation with the clinical and pathological characteristics in Chinese hepatocellular carcinoma with hepatitis B virus (HBV) infection. Methods: P1–P4 usage levels of the gene in tumorous and matched adjacent nontumorous tissues from 23 HCC patients and 7 normal liver tissues were evaluated using a semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) assay. The mutation status of p53 gene in HCC tissues was analyzed by PCR and sequencing. Results: Transcripts from P1 were not detectable in 65.2% HCC tissues, and were expressed at low levels or not expressed in all nontumorous tissues compared with normals, but P2 usage levels showed no differences. P3 and P4 expression was significantly increased in most of HCC and almost all adjacent nontumorous tissues. There was a positive association of expression levels of both P3 and P4 transcripts in HCC tissues with the p53 mutation and presence of tumor embolus of portal vein, and expression of P3 were negatively related to differentiation of HCC. However, expression of both P3 and P4 was not associated with other parameters. Conclusions: Loss of P1 activity and reactivation of P3 and P4 are important characteristics in most of Chinese HCC with HBV infection, and increased IGF-II expression from P3 and P4 may play an active role in early proliferation of precancerous liver cells and hepatocarcinogenesis of these cases. Significant increase in fetal transcripts is associated with the p53 mutation and poor prognosis of the HCC patients and might serve as one of identification parameters of poor HCC prognosis.