A STUDY OF REGULATORY MOLECULES INVOLVED IN HEPATOCARCINOGENESIS IN A TRANSGENIC MOUSE MODEL

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Hepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis. Recently, we have reported that Fas ligand (FasL) is critically involved in the induction of chronic immune-mediated liver cell injury that increases HCC incidence (J Exp Med 196 : 1105, 2002) ; however, the molecular mechanisms potentially responsible for carcinogenesis are not well defined. In the current study, we asked the regulatory molecules in liver diseases that displayed different procarcinogenic potentials in a hpatitis B virus (HBV) transgenic mouse model. The results are summarized as follows.1)Transfer of CD8^+-enriched splenocytes caused prolonged disease kinetics and a marked increase in the extent of hepatocyte apoptosis and regeneration. In 12 out of 14 mice the transfer resulted in multiple hepatocellular carcinomas (HCCs) comparable to the manifestations seen in the mice transferred with total splenocytes. In contrast, mice that had received CD4^+-enriched cells demonstrated lower lev … More els of liver disease and developed fewer incidences of HCC (4 of 17). The experiment also revealed that all the groups of mice complicated with HCC developed comparable mean numbers and sizes of tumors. B cell depletion had no effect on disease kinetics in this model. (Cancer Res. 64 : 3326, 2004)2)During more than twelve months of disease progression, 352 (1.7 % of all) genes were expressed differentially between the mice treated with anti-FasL Ab and with PBS (P<0.05), 190 genes of which were assigned to functional groups based on Gene Ontology categories. In the gene groups of enzymes, cell communication, cellular components, signal transduction, and nucleic acid binding, the significant changes due to anti-FasL Ab treatment were observed in 43(1.6% of the gene group), 42(2.0%), 31(1.3%), 28(1.4%), and 22(1.8%) genes, respectively. In the cell communication group, high proportion (4.3%) of cell death control genes was involved in this expression dynamics.3)We identified several genes expressed differentially at the pre-malignant lesions. Among these genes, we focused on Pim-3, which is reported as a member of a proto-oncogene Pim family, but its contribution to hepatocarcinogenesis remains elusive. The mRNA expression was selectively detected in human hepatoma cell lines, but not in normal liver tissues. Pim-3 protein was also expressed in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Moreover, cell proliferation was attenuated in human hepatoma cell lines, HepsB and HuH7, by RNA interference ablation of Pim-3 gene expression. (Int.J.Cancer 114 : 209, 2005)Taken together, these data suggest the molecular mechanisms potentially responsible for hepatocarcinogenesis and the future studies for the development of molecular targets. Less