Hepatocarcinoma (HCC) is a sixth most common cancer becoming a global problem since its incidence is increasing. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), have been used in treatment of diferents tumors. Its precise anti-tumoral mechanism of action has not been established. The
same could involve growth factor-β1 (TGF-β1) and thyroid hormones (TH). Previously we demonstrated that hexachlorobenzene (HCB), dioxin-like toxic, 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 generated by HCB. 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 deiodinase type 1(DI) levels generated by HCB were not observed when cells were preincubated with 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 DI mRNA levels. However, preincubation with AT 30 together with TGF- β1 exogenous and then treated with HCB increased PCNA and decreased the DI mRNA. Also, in Hep-G2 pretreated with different T3 doses (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. Keywords: HCC, Statins, Thyroid hormones, TGF- β1