Abstract 100A: Prognostic significance of the expression levels of target genes of retinoic acid in hepatocellular carcinoma.

Abstract

Abstract Hepatocellular carcinoma (HCC), a common and fatal malignancy, is increasing in incidence in developed countries. HCC generally arises in cirrhotic livers and has a poor prognosis because of the high incidence of disease recurrence after curative treatment. To improve patient prognosis, identification of new targets for early detection, chemoprevention, and treatment is urgently required. In the pathogenesis of chronic liver disease, activation of hepatic stellate cells accompanied by decreasing vitamin A storage has been observed, leading to development of the hypothesis that the loss of retinoid content is closely associated with the progression of chronic liver diseases including HCC. In a previous study, we observed steatohepatitis and HCC development in transgenic mice that express a dominant-negative form of RAR in a liver-specific manner. These findings indicate that identifying genes regulated by retinoid signaling is important for understanding the molecular mechanisms of liver disease leading to hepatocarcinogenesis. To identify novel retinoic acid (RA)-responsive genes facilitating the antitumor activity of RA in hepatocellular carcinoma (HCC), we performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs), chromatin immunoprecipitation analysis of the retinoic acid receptor (RAR), and gene expression analysis. We identified 201 candidate genes with promoter regions containing consensus RAREs using in silico analysis. We identified 126 candidate genes with functional RAREs which are occupied by RAR and finally selected 26 RA-responsive genes in 2 human HCC and 1 human breast cancer cell lines. Among these genes, we identified OTU domain-containing 7B (OTUD7B) and frizzled family receptor 4 (FZD4) as potential inducers of RA-mediated antitumor activity. OTUD7B and FZD4 were involved in the regulation of nuclear factor κB and Wnt/β-catenin signaling, respectively, and affected the viability of HCC cell lines. To evaluate the clinical significance of RA-responsive genes in HCC, gene expression analysis was performed using tumor and nontumor tissues from 171 patients. In univariate and multivariate analyses, low OTUD7B mRNA expression in tumor tissue was associated with a poor prognosis forHCC patients. Conclusion: We identified RA-responsive genes that exhibit antitumor activity against HCC cells. These findings provide useful information to understand the molecular mechanisms underlying the chemopreventive effects of RA against liver diseases, including HCC. Citation Format: Goshi Shiota, Keita Kanki. Prognostic significance of the expression levels of target genes of retinoic acid in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 100A. doi:10.1158/1538-7445.AM2013-100A