Abstract 5245: Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic mice

Abstract

Abstract Hepatocellular carcinoma (HCC) develops with progressive accumulation of multiple genetic changes. An acyclic retinoid peretinoin is reported to suppress the development of HCC, but the molecular mechanism in detail remains to be obscure. Here we evaluated the effect of peretinoin on preneoplastic nodules and HCC developed in platelet derived growth factor-c (PDGF-C) transgenic mice liver by gadolinium ethoxybenzyl diethylenetriamide pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and whole exome sequence analysis. We confirmed the progressive accumulation of somatic mutations in hypervascular liver cancer tissues compared with hypovascular precancerous tissues and non-cancerous background liver tissues in PDGF-C transgenic mice. Surprisingly, peretinoin treatment in HCC as well as preneoplastic nodules resulted in the accumulation of less gene mutations compared with vehicle. Gd-EOB-DTPA uptake capacity and its transporter OATP1 was confirmed to be re-activated in peretinoin treated nodules in mice. Gene and protein expression analysis indicated the inactivation of cell cycle with low Ki-67 labeling indexes in peretinoin treated nodules. The reversion of Gd-EOB-DTPA uptake capacity was confirmed in preneoplastic nodules and a subset of classical hypervascular HCCs. Notably, peretinoin supplementation induced the expression of OATP1B3 in mature hepatocyte-like HCC cell lines in vitro, whereas supplementation of tretinoin (all-trans retinoic acid) had no such effects and rather suppressed OATP1B3. Taken together, our data suggested the utility of peretinoin to revert the malignant transformation processes of hepatocytes by preventing accumulation of gene mutations especially in early stages of hepatocarcinogenesis. Peretinoin but not tretinoin can induce the expression of a mature hepatocyte marker OATP1B3, suggesting that peretinoin may exert its anti-tumor effect with hepatocytic differentiation capacity independently of the activation of retinoic acid signaling. Note: This abstract was not presented at the meeting. Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Peretinoin prevents the accumulation of somatic gene mutations and reverts neoplastic lesions to normal liver-like in platelet-derived growth factor-c transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5245. doi:10.1158/1538-7445.AM2017-5245