Abstract 181: Hepatic retinoid signaling in mouse hepatocarcinogenesis models.

Abstract

Abstract Retinoids are known to possess anti-cancer effects and a clinical trial of a synthetic retinoid for hepatocellular carcinoma (HCC) is ongoing recently in Japan. Hepatic retinoid metabolism is usually impaired during development of liver diseases. Loss of retinoid-containing lipid droplets upon hepatic stellate cell (HSC) activation is one of the first events in the development of liver diseases and retinoid stores are progressively lost from HSCs leading to hepatic fibrosis, cirrhosis, and HCC. In the present study, we employed two types of genetically-modified mice for investigating hepatic retinoid metabolism and signaling in diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis models. One is lecithin:retinol acyltransferas (LRAT) knockout (KO) mouse which lacks HSC lipid droplets and has much less hepatic retinoid stores, and the other is a transgenic mouse which expresses dominant negative form of retinoic acid receptor (dnRAR) to block retinoid signaling in the liver. Male 15 day-old mice were given intraperitoneal injections of DEN (25 mg/kg body weight). Eight-month-old DEN-treated Lrat KO mice showed lower liver tumor incidence and dnRAR transgenic mice showed higher incidence than that of respective control mice. In the acute phase after DEN injection, dnRAR transgenic mice exhibited higher hepatic levels of inflammatory cytokines. Two days after DEN injection, lower serum levels of alanine aminotransferase and decreased hepatic levels of cyclin D1 were observed in Lrat KO mice. Lrat KO mice also exhibited increased levels of retinoic acid-responsive genes, including p21, lower levels of cytochrome P450 enzymes required for DEN-bioactivation, and higher levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Our results indicate that Lrat KO mice, instead of almost no hepatic retinoid storage, are less susceptible to DEN-induced hepatocarcinogenesis due to increased hepatic retinoid signaling which is accompanied by higher expression of p21 in the liver. In conclusion, retinoid signaling plays a key role in these hepatocarcinogenesis models. Citation Format: Yohei Shirakami, William S. Blaner, Masahito Shimizu, Hisataka Moriwaki, Mitsuru Seishima. Hepatic retinoid signaling in mouse hepatocarcinogenesis models. [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 181. doi:10.1158/1538-7445.AM2013-181