Atorvastatin prevents pre-neoplastic foci formation through TGF-β 1/TH/pERK axis in vivo and in vitro hepatocarcinogénesis models

RIDRUEJO E; MIRET, N; CALVO C; ALVAREZ L; DEZA Z; ALEJANDRO ESPAÑOL; SAENZ D; ROMERO CALMI G; SALES M; VENOSA G

BOSTON

Congreso; The Liver Meeting; 2019

American Association for the Study of Liver Diseases

Introduction: Hepatocarcinoma (HCC) is the most frequent liver tumor. It is suggested that endocrine dysregulation would be an important initial process for hepatocarcinogenesis. We had previously demonstrated that in a hepatic tumor induction/promotion (I/P) model, cell growth is dysregulated and the proliferation/apoptosis ratio increases. Thyroid hormones (TH) as well as TGF-β1 are involved in these processes. The aim was to analyze the ability of atorvastatin (AT) to prevent hepatocarcinogenesis in different models.Methods: We evaluated the effect of the co-administration of the tumor promoter hexachlorobenzene (HCB) (0.3 and 3mg/kg) with or without (w-wo) AT and inoculated Hep-G2 cells in nude mice on liver histology, PCNA, TGF-β1, and Deiodinase I (DI) levels. We evaluated HCB/w-wo AT effect in Hep-G2 cells and analyzed PCNA, pERK, TGF-β1 and T3 levels. We evaluated the role of pERK and TGF-β1 inhibitors, and T3 administration. We evaluated its effect in angiogenesis trough the release of H2S (vasodilator) in the Hep-G2, neo-angiogenesis in the skin in nude mice, and cell migration (number of cells/area) in the vascular line Ae-hy 296. The role of pERK was evaluated using an inhibitor (PD98059).Results: In nude mice treated with HCB, liver preneoplastic areas were histologically and macroscopically observed (21%, p