POTENTIAL MOLECULAR MECHANISMS OF STATINS INVOLVED IN THE PREVENTION OF HEPATOCARCINOGENESIS

DEZA, ZAHIRA A; ROMERO-CAÍMI, GISELLE; MIRET NOELIA; ZARATE LORENA; ALVAREZ, LAURA; RIDRUEJO EZEQUIEL

Buenos Aires

Congreso; Reunion Conjunta de Sociedades de Biociencias; 2017

SAIC

Hepatocarcinoma (HCC) accounts for 90% of liver tumors. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), have been used in treatment of tumors. Antitumor activity could involve growth factor-β1 (TGF-β1) and thyroid hormones (TH). Previously we demonstrated that HCB generates proliferation of preneoplastic foci, alteration of HT metabolism,HMGCoAR and TGF-β1 levels,in vivo. The aim of this study was determine the molecular mechanisms of action of statins involved in the prevention of HCC. Hep-G2 cells were used, we analyze dose-dependent effects of atorvastatin (AT) and simvastatin (SM) on HCB (5 μM) treated cells on PCNA (WB) and TGF-β1 (RT-PCR) levels. We assessed whether the effect of pre-treatment with statins on HCB proliferation-induced depends of TGF-β1 as well as HT. Treatment with HCB (5 μM) increased PCNA levels, which were reduced by 71% with 20 μM AT, and 100% with 30 μM AT. Also, with SM 10 μM were reduced by 80% and 100% with SM 20 μM. The increase of TGF-β1 as well as the decrease in DI levels generated by HCB were not observed when cells were preincubatedwith maximum doses of AT and SM. Pre-incubation cells with an inhibitor of TGF-β1 (SB431542, 10 μM) and then treated with HCB showed no increase in PCNA or decrease in ID mRNA levels. However, preincubation with AT 30 together with TGF-β1 exogenous and then treated with HCB increased PCNA and decreased the DImRNA. Also, in Hep-G2 pretreated with different T3doses (T3 10-9, 10-7 T3 10-5 M) for 24 h and subsequent 5 μM HCB, the stimulatory effect of HCB on PCNA levels was not observed. Statins (AT and SM) prevent the proliferative effect of HCB on the Hep-G2 cell line. TGF-β1 as well as T3 may be partly responsible for the protective effect of statins on cell proliferation generated by HCB, and may be molecular targets in the treatment of HCC.