P- 28 ATORVASTATIN SHOWS ANTI-PROMOTOR AND ANTI-NEOANGIOGENIC EFFECT IN HEPATOCELLULAR CARCINOMA DEVELOPMENT IN VIVO AND IN VITRO MODEL BY INHIBITING TGF-β1/pERK SIGNALING PATHWAY

Introduction and Objectives

Hepatocellular carcinoma (HCC) represents 90% of liver tumors. Statins may reduce HCC incidence. Its antitumor activities are controversial and may be mediated by disrupting several hepatocarcinogenic pathways. This study aimed to evaluate in vivo and in vitro the anti-proliferative and anti-angiogenic action of atorvastatin (AT) in the development of HCC as well as its mechanisms of action.

Materials and Methods

In vivo model: the pesticide hexachlorobenzene (HCB) was used to promote the development of HCC in Balb/C nude mice inoculated with Hep-G2 cells. Tumor hepatic number, cell proliferation parameters (proliferating cell nuclear antigen, PCNA), cholesterol metabolism (3-hydroxy-3-methylglutaryl-coenzyme-A-reductase, HMGCoAR), angiogenesis and VEGF levels were analyzed. In vitro model: Hep-G2 and Ea-hy926 cells were used to evaluate the effect of AT (2,5; 5 and 5 mg/kg b.w.) on HCB-induced cell proliferation, migration, and vasculogenesis and analyze proliferative parameters.

Results

In vivo: AT 5 mg/kg prevented liver growth and tumor development and inhibited PCNA, TGF-β1 and pERK levels increase. AT 5 mg/kg prevented VEGF levels and skin blood vessel formation. In vitro, AT prevented cell proliferation and migration as well as tubular formation in the endothelial cell line by inhibiting the TGF-β1/p ERK pathway.

Conclusions

We were able to demonstrate the potential AT anti-proliferative and anti-angiogenic effects in an HCC model and the involvement of TGF-β1 and pERK pathways.