ATORVASTATIN PREVENTS PRE-NEOPLASTIC FOCI FORMATION THROUGH TGF-β 1/TH/pERK AXIS IN VIVO AND IN VITRO HEPATOCARCINOGÉNESIS MODELS

RIDUEJO, E; DEZA, Z; ROMERO-CAÍMI, G; MIRET, N; ESPAÑOL, A; SALES, M; CALVO G; SAENZ D; DI VENOSA, G; ALVAREZ L

Boston, Massachusetts

Congreso; The Liver Meeting 2019; 2019

American Association for the Study of liver Diseases (AASLD)

Introduction:Hepatocarcinoma (HCC) is the most frequent liver tumor. It is suggested thatendocrine dysregulation would be an important initial process forhepatocarcinogenesis. We had previously demonstrated that in a hepatic tumorinduction/promotion (I/P) model, cell growth is dysregulated and theproliferation/apoptosis ratio increases. Thyroid hormones (TH) as well as TGF-β1are involved in these processes. The aim was to analyze the ability ofatorvastatin (AT) to prevent hepatocarcinogenesis in different models.Materials and Methods:We evaluated the effect of the co-administration of the tumor promoterhexachlorobenzene (HCB) (0.3 and 3mg/kg) with or without (w-wo) AT and inoculated Hep-G2 cells in nude mice onliver histology, PCNA,  TGF-β1, andDeiodinase I levels.Weevaluated HCB/w-wo AT effect in Hep-G2 cells and analyzed PCNA, pERK, TGF-β1and T3 levels. We evaluated the role of pERK and TGF-β1 inhibitors, and T3administration. We evaluated its effect in angiogenesis trough the release ofH2S (vasodilator) in the Hep-G2, neo-angiogenesis in the skin in nude mice,and  cell migration (number ofcells/area) in the vascular line Ae-hy 296. The role of pERK was evaluatedusing an inhibitor (PD98059).Results: In nude micetreated with HCB, liver preneoplastic areas were histologically andmacroscopically observed (21%, p <0.05). PCNA and TGF-β1 levels increased(38%, 30%, p <0,01 respectively), and DI levels decreased (26%, p <0.01).These alterations were not observed in the group treated with HCB and AT.Inthe Hep-G2 cells, HCB increased PCNA (29%, p <0.01) and H2S (30%, p<0.001); this increase was not observed with HCB and AT. PCNA levels did notvary with AT/TGF-β1 inhibitor. However, when treated with AT/pERK inhibitor,the decrease in PCNA did not reach the basal levels. When Hep-G2 cells weretreated with AT/pERK inhibitor and T3, the decrease in PCNA reached the basallevels.Inthe skin of the mice the vascularization increased (32%, p <0.01) with HCB(0.3 mgkg). This effect was not observed whit HCB/AT.InAe-hy 296 cells, HCB increased PCNA and cell migration (31%, p <0.01, 26%, p<0.05 respectively). Both parameters did not vary with the pERK inhibitor.When treating the cells with HCB, AT and PD98059 no alterations in cellmigration are observed when compared to the control.Conclusion:AT has anti-proliferative and anti-angiogenic effects. TGF-β1, TH and pERKappear to be involved in its mechanism of action.