ANALYSIS OF CELLULAR AND GENETIC ALTERATIONS DURING HEPATOCARCINOGENESIS

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Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa. Recent evidence from this laboratory and others has indicated that allelic losses on chromosome 16 are especially common in HCCs from the Qidong province of China, though not from Beijing. Among the informative Qidong samples, 90% showed loss of heterozygosity (LOH) at the TAT marker locus (chromosome location 16q22) and 58% showed LOH at the DD16S7 locus (16q22-24). Such deletions are often associated with loss of a tumor suppressor gene. We are extending these studies by examining a larger set of samples from Qidong and Beijing, and by concentrating on markers specific to the long (or "q") arm of chromosome 16. To study the involvement of transforming growth factor beta 1 (TGF- beta1) in liver carcinogenesis and the possible escape mechanism(s) of the tumor cells from the growth inhibition of TGF-beta1, TGF-beta1 production in 54 human liver carcinomas and in the surrounding nontumorous liver tissue was analyzed by in situ hybridization and immunohistochemistry. In particular, attempts were undertaken to assess the potential role of insulin-like growth factor II receptor (IGF II R) and TGF-beta type II receptor in the loss of the mitoinhibitory effects in the tumors. The results confirmed and added to the increasing body of data indicating a significant role for TGF-beta1 in the process of hepatic fibrosis/-cirrhosis. However, the hepatocytes were the major source of TGF-beta1 in the tumored and fibrotic livers and this result is different from most of the hepatic fibrosis models. TGF-beta1 transcripts were expressed in 90% of the carcinomas. Immunohistochemical staining for TGF-beta1 generally correlated well with the in situ data, but no protein was detected in seven tumors expressing the transcripts. All the studied hepatocellular carcinomas expressed high levels of type II TGF-beta receptor mRNA. The transcripts for IGF II R were not detected in 56% of the tumors.