Targeting Tgf-Beta Signaling For Obesity/Insulin Resistance-Associated Hepatocellular Carcinoma

Background: Recently, obesity, insulin resistance/type 2 diabetes mellitus and fatty liver disease, i.e., key components of the metabolic syndrome, have been recognized as risk factors for hepatocellular carcinoma (HCC). Obesity and dysmetabolism serve as drivers of oncogenesis in the setting of abnormal hepatic morphology and physiology, and hepatic steatosis may provide the promoting microenvironment for the development of HCC. Dysregulated signaling in the transforming growth factor (TGF)-β pathway plays a central role in immunomodulation, inflammation, and fibrogenesis in the HCC microenvironment. We used a carcinogen Diethylnitrosamine (DEN)-induced HCC mouse model in genetically obese mice [heterozygous Agouti yellow (Ay/a)] and haplo-knock out of Smad3 (a kinase downstream of type II receptor for TGFβ to study the detailed mechanism by which Smad3-dependent TGF-β signaling regulates obesity-associated dysmetabolism in HCC, and to determine whether inhibition of TGF-β signaling could inhibit obesity-associated HCC. Methods:Ay/a mice in C57B/L genetic background were bred with Smad3 knockout mouse (Smad3+/−). Obese and insulin-resistant Ay/a mice were treated with DEN (i.p. 25mg/kg) at 14 days of age to induce HCC. Ay/a mice and DEN-induce HCC mice were treated with TGF-β receptor 2 inhibitor (EW7919, 20 mg/kg orally 3 times/week for 8 weeks). We performed RNA sequencing analysis for 40 mouse liver samples from the groups of mice above. Results: 1. Haplodeficiency of Smad3 significantly decreased obesity Ay/a mouse weight and suppressed fatty liver development. 2. Treatment of TGF-β receptor 2 inhibitor to Ay mice successfully blocked weight gain in Ay/a mice. 3. DEN-induced hepatocarcinogenesis in Ay/a mice occurred significantly earlier than in lean (a/a) C57B/L mice. 4. Inhibition of TGF-β signaling by Smad3 haplodeficiency significantly upregulated lipid catabolic processes and downregulated cytokine-induce leukocyte migration in the fatty livers of Ay/a mice. 5. Inhibition of TGF-β signaling by genetic or pharmacologic inhibitors significantly suppressed HCC development in Ay/a mice. Conclusion: We demonstrated a specific cancer promoting role of TGF-β in metabolic reprogramming in liver cancer cells, highlighting the TGF-β signaling pathway as a potential therapeutic target in obesity/insulin resistance-associated HCC. Citation Format: Jian Chen, Xiaoping Su, Andres Rojas, Robert S Bresalier, John R. Stroehlein, Sai-ching Yeung. Targeting TGF-β signaling for obesity/insulin resistance-associated hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3054.