A promoter assay and western blotting confirmed that peretinoin promoted the autophagy KU-57788 datasheet related-gene Atg16L1, and electron microscopy revealed increased autophagosome formation due to peretinoin. Atg16L1-transfected HepG2 cells showed suppressed expression of pStat3 and pNFkB. Recombinant IL-6 and palmitic acid induced expression of pSTAT3 and pNFkB in primary hepatocytes in vitro, whereas peretinoin dose-de-pendently suppressed the expression of these genes. Conclusion Peretinoin suppresses the
development of liver steatosis, inflammation, and tumorigenesis by activating Atg16L1-depen-dent autophagy. These results support the clinical efficacy of peretinoin for preventing HCC. Disclosures: Hikari Okada – Employment: Kanazawa University Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, Bayer Japan The following people have nothing to disclose: Masao Honda, SB203580 molecular weight Kai Takegoshi, Naoto Matsuzawa, Taro Yamashita, Yoshio Sakai, Toshinari Takamura, Takuji Tanaka Background and Aims: Cholangiocarcinoma (CCA) is a lethal
neoplasm originating from the biliary epithelium. Risk factors for CCA include liver inflammation and fibrosis. IL-33 has been shown to promote liver inflammation and fibrosis. The AKT cell survival and Hippo cell growth controlling pathways are involved in CCA carcinogenesis and progression. Yes-associated protein (YAP) is a major transcriptional factor of the Hippo pathway. Our aim was to generate a mouse model of CCA incorporating these oncogenic pathways mimicking the human disease. Methods: Ectopic oncogene expression in the biliary tract was accomplished by the Sleeping Beauty transposon transfection system with transduction of constitutively
active AKT and/or YAP. Intrabiliary injection of the transposon-transposase complex was coupled with lobar bile duct ligation in CL57/BL6 wild type or IL-6 −/− mice. After injection, mice were treated with either vehicle or IL-33 i.p. for three consecutive SDHB days. Mice were sacrificed on day 70 and examined for the presence of tumors and tumor burden. Results: Intrabiliary instillation of a sleeping beauty transposon-transposase complex expressing GFP revealed significant transduction of the cholangiocytes, but not hepatocytes, in the bile duct ligated lobe 7 days later; GFP transduction did not require IL-33 administration. Tumor development following intrabiliary instillation of AKT plus YAP, however, was augmented in animals treated with IL-33. Tumors developed in 60% of the animals receiving both oncogenes plus IL-33, but in only 20% of the mice transduced with the oncogenes alone (p<0.05).