Abstract 844: Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice

Abstract

Abstract Background and aims: Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR)-α due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRα, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese and diabetic mice. Methods: Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. Results: In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared to basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK, RXRα, and Stat3 proteins in the livers of experimental mice. It also increased the expression of RARβ and p21CIP1 mRNA, while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin were decreased by ACR treatment, whereas the QUICKI values were increased, indicating improved insulin sensitivity. The serum levels of TNF-α and the expression levels of TNF-α, IL-6, and IL-1β mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. Conclusion: ACR may be, therefore, useful in the chemoprevention of obesity-related HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 844. doi:10.1158/1538-7445.AM2011-844