Potential molecular mechanisms of statins involved in the prevention of hepatocarcinogenesis

ALVAREZ L; ROMERO CAIMI G; RIDRUEJO E; DEHEZA Z

Congreso; Sociedad Argentina de Investigación Clínica; 2017

Hepatocarcinoma (HCC) accounts for 90% of liver tumors. Statins, inhibitors of3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), have been usedin treatment of tumors. Antitumor activity could involve growth factor-β1 (TGF-β1)and thyroid hormones (TH). Previously we demonstrated that HCB generatesproliferation of preneoplastic foci, alteration of HT metabolism,HMGCoAR andTGF-β1 levels,in vivo. The aim of this study was determine the molecularmechanisms of action of statins involved in the prevention of HCC. Hep-G2 cellswere used, we analyze dose-dependent effects of atorvastatin (AT) andsimvastatin (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 onHCB 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, and100% with 30 μM AT. Also, with SM 10 μM were reduced by 80% and 100% withSM 20 μM. The increase of TGF-β1 as well as the decrease in DI levels generatedby HCB were not observed when cells were preincubatedwith maximum doses ofAT 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 mRNAlevels. However, preincubation with AT 30 together with TGF-β1 exogenous andthen treated with HCB increased PCNA and decreased the DImRNA. Also, inHep-G2 pretreated with different T3doses (T3 10-9, 10-7 T3 10-5 M) for 24 h andsubsequent 5 μM HCB, the stimulatory effect of HCB on PCNA levels was notobserved. Statins (AT and SM) prevent the proliferative effect of HCB on theHep-G2 cell line. TGF-β1 as well as T3may be partly responsible for the protectiveeffect of statins on cell proliferation generated by HCB, and may be moleculartargets in the treatment of HCC.