他汀类药物对肝细胞癌的作用及机制研究进展

doi:10.3969/j.issn.1672-5069.2015.02.033

摘要/Abstract

摘要： 他汀类药物（3-羟基-3-甲基戊二酰辅酶A还原酶抑制）常用于降低胆固醇水平,且发现其能降低发生肝细胞癌（Hepatocellular carcinoma,HCC）的风险。他汀类药物在抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡及分化、抗血管形成、降低肿瘤细胞侵袭性、影响细胞周期、阻滞小G蛋白异戊二烯化、影响信号转导等方面均有作用,但其作用的确切分子机制尚不完全清楚,主要包括以下两条途径：依赖与不依赖HMG-CoA还原酶途径。本文将对他汀类药物抗肿瘤作用及可能机制做一介绍,以期为肝细胞癌的治疗提供新的思路。

关键词: 肝细胞癌, 他汀类, 机制

Abstract: Statins（3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors） are widely prescribed to reduce serum cholesterol levels,which is associated with a reduced risk of hepatocellular carcinoma（HCC）. Statins have effects in inhibiting tumor cell proliferation,inducing tumor cell apoptosis and differentiation,resistance to blood vessel formation,reducing the invasive tumor cells,affecting the cell cycle,blocking small G protein isoprene,signal transduction and so on. However,the underlying mechanism remains unclear,it mainly includes the following two ways:rely on and do not rely on HMG CoA reductase pathway. In this article,the anti-cancer effect and the mechanism of statins will be reviewed.

Key words: Hepatocellular carcinoma, Statins, Mechanism

张宁, 赵彩彦. 他汀类药物对肝细胞癌的作用及机制研究进展[J]. 实用肝脏病杂志, 2015, 18(3): 329-332.

Zhang Ning, Zhao Caiyan. Mechanism of statins in inhibiting hepatocellular carcinoma occurrence[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2015, 18(3): 329-332.

参考文献

[1] Jemal A,Bray F,Center MM,et al. Global cancer statistics. CA Cancer J Clin,2011,61（2）:69-90.
[2] Borena W,Strohmaier S,Lukanova A,et al. Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer,2012,131（1）:193-200.
[3] Chiu HF,Ho SC,Chen CC,et al. Statin use and the risk of liver cancer:a population-based case-control study. Am J Gastroenterol,2011,106（5）:894-898.
[4] Tsan YT,Lee CH,Wang JD,et al. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol,2012,30（6）:623-630.
[5] El-Serag HB,Johnson ML,Hachem C,et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology,2009,136（5）:1601-1608.
[6] Silva MA,Swanson AC,Gandhi PJ,et al. Statin-related adverse events:a meta-analysis. Clin Ther,2006,28（1）:26-35.
[7] Lai SW,Liao KF,Lai HC,et al. Statin use and risk of hepatocellular carcinoma. Eur J Epidemiol,2013,28（6）:485-492.
[8] Gopal K,Johnson TC,Gopal S,et al. Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment. Hepatology,2006,44（2）:335-340.
[9] Targher G,Bertolini L,Padovani R,et al. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol, 2007,46（6）:1126-1132.
[10] Ikeda M,Abe K,Yamada M,et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology,2006,44（1）:117-125.
[11] Ye J,Wang C,Sumpter R Jr,et al. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. Proc Natl Acad Sci U S A,2003,100（26）:15865-15870.
[12] Rombouts K,Kisanga E,Hellemans K,et al. Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol,2003,38（5）:564-572.
[13] Harrison SA,Rossaro L,Hu KQ,et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology,2010,52（3）:864-874.
[14] Rao GA,Pandya PK. Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C. Gastroenterology,2011,140（1）:144-152.
[15] Kawata S,Yamasaki E,Nagase T,et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma:A randomized controlled trial. Br J Cancer,2001,84（7）:886-891.
[16] Friedman GD,Flick ED,Udaltsova N,et al. Screening statins for possible carcinogenic risk:up to 9 years of follow-up of 361,859 recipients. Pharmacoepidemiol Drug Saf,2008,17（1）:27-36. [17] Weis M,Heeschen C,Glassford AJ,et al. Statins have biphasic effects on angiogenesis. Circulation,2002,105（6）:739-745.
[18] Tatsuta M,Iishi H,Baba M,et al. Suppression by pravastatin, an inhibitor of p21ras isoprenylation of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Br J Cancer,1998,77（4）:581-587.
[19] MacDonald JS,Gerson RJ,Kornbrust DJ,et al. Preclinical evaluation of lovastatin. Am J Cardiol,1988,62（15）:16J-27J.
[20] Hamelin BA,Turgeon J. Hydrophilicity/lipophilicity:relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci,1998,19（1）:26-37.
[21] Browning DR,Martin RM. Statins and risk of cancer:a systematic review and meta analysis. Int J Cancer,2007,120（4）:833-843.
[22] Dale KM,Coleman CI,Henyan NN,et al. Statins and cancer risk:a meta-analysis. JAMA,2006,295（1）:74-80.
[23] Barrington RE,Subler MA,Rands E,et al. A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol Cell Biol,1998,18（1）:85-92.
[24] Magee T,Marshall C. New sights into the interaction of Ras with the plasma embrane. Cell,1999,98（1）:9-12.
[25] Shirouzu M,Morinaka K,Koyama S,et al. Interactions of the aminoacid residue at position 31 of the c-Ha-Ras protein with Raf-1 and RalGDS. J Biol Chem,1998,273（13）:7737-7742.
[26] Denoyelle C,Vasse M,Korner M,et al. Cerivastatin,an inhibitor of HMG-CoA reductase,inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines:an in vitro study. Carcinogenesis,2001,22（8）:1139-1148.
[27] Relja B,Meder F,Wang M,et al. Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK. Int J Oncol,2011,38（3）:879-885.
[28] Kops GJ,De Ruiter ND,De Vries-Smits AM,et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature,1999,398（6782）:630-634.
[29] Hutchinson J,Jin J,Cardiff RD,et al. Activation of Akt （Protein Kinase B） in mammary eoithelium provides a critical cell survival signal required for tumor progression. Mol cell Biol,2001,21（6）:2203-2212.
[30] Denoyelle C,Albanese P,Uzan G,et al. Molecular mechanism of the anti-cancer activity of cerivastatin,an inhibitor of HMG-CoA reductase,on aggressive human breast cancer cells. Cell Signal,2003,15（3）:327-338.
[31] Asslan R,Pradines A,Favre G,et al. Tyrosine kinase-dependent modulation of 3-hydroxy-3-methylglutaryl-CoA reductase in human breast adenocarcinoma SKBR-3 cells. J Biochem,1998,330（Pt1）:241-246.
[32] Vermeulen K,Van Bockstaele DR,Berneman ZN. The cell cycle: a review of regulation,deregulation and therapeutic targets in cancer. Cell Prolif,2003,36（3）:131-149.
[33] Coqueret O,Gascan H. Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem,2000,275（25）:18794-18800.
[34] Bienvenu F,Gascan H,Coqueret O. Cyclin D1 represses STAT3 activation through a Cdk4-independent mechanism. J Biol Chem,2001,276（20）:16840-16847.
[35] Aggarwal BB,Kunnumakkara AB,Harikumar KB,et al. Signal transducer and activator of transcription-3,inflammation,and cancer:how intimate is the relationship. Ann N Y Acad Sci,2009,1171:59-76.
[36] Calliot F. Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence. World J Gastroenterol,2009,15（3）:300-309.
[37] Liu Y,Fuchs J,Li C,et al. IL-6,a risk factor for hepatocellular carcinoma:FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells. Cell Cycle,2010,9（17）:3423-3427.
[38] Arnaud C,Burger F,Steffens S,et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes:new evidence for direct anti-inflammatory effects of statins. Arterioscler Thromb Vasc Biol,2005,25（6）:1231-1236.
[39] Loppnow H,Zhang L,Buerke M,et al. Statins potently reduce the cytokine-mediated IL-6 release in SMC/MNC cocultures. J Cell Mol Med,2011,15（4）:994-1004.
[40] Jougasaki M,Ichiki T,Takenoshita Y,et al. Statins suppress interleukin-6-induced monocyte chemo-attractant protein-1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells. Br J Pharmacol, 2010,159（6）:1294-1303.
[41] Katz MS. Therapy Insight:Potential of statins for cancer chemoprevention and therapy. Nat Clin Pract Oncol,2005,2（2）:82-89.