Candidate genes responsible for human hepatocellular carcinoma identified from differentially expressed genes in hepatocarcinogenesis of the tree shrew (Tupaia belangeri chinesis)

Abstract

Aim: To explore gene expression profiles during hepatocarcinogenesis of the tree shrew, and to find the genes responsible for human hepatocellular carcinoma (HCC). Methods: Tree shrews were used as an animal model for HCC induction employing aflatoxin B1 (AFB1) alone or AFB1 plus hepatitis B virus (HBV) as etiological factors. Gene expression profiles from the tissues of HCC, HCC-surrounding liver tissues (para-HCC) and the corresponding biopsies taken from the same animals before HCC had developed (pre-HCC) were analyzed by cDNA microarray assay to identify differentially expressed genes. Two genes, CuZn-superoxide dismutase (SOD1) and glutathione S-transferase A1 (GSTA1), were further investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical (IHC) assays were done on tree shrew and human HCC samples. Results: Results from the cDNA microarray analysis indicated that the gene expression profiles of HCC between AFB1 and AFB1 + HBV treatment groups were markedly different. A total of 11 genes, including SOD1 and GSTA1, were found changing in expression levels in all detected samples from both groups. Results from RT-PCR and IHC assays indicated that mRNA and protein levels of SOD1 and GSTA1 were markedly downregulated in both tree shrew and human HCC, and downregulation of SOD1 and GSTA1 proteins in human HCC samples was closely correlated with the histopathological grading (P <0.05). Conclusion: The differentially expressed genes found in all HCC cases induced by different etiological factors among different species should be considered as good candidate genes responsible for HCC. Downregulation of SOD1 and GSTA1 might play an important role in hepatocarcinogenesis. © 2007 The Japan Society of Hepatology.