Pathogenesis of Hepatocellular Carcinoma Development in Non-alcoholic Fatty Liver Disease

详细信息    查看全文

• 作者：Kirti Shetty ; Jian Chen ; Ji-hyun Shin ; Wilma Jogunoori…
• 关键词：Hepatocellular carcinoma ; Non ; alcoholic fatty liver disease ; Pathogenesis
• 刊名：Current Hepatitis Reports
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：14
• 期：2
• 页码：119-127
• 全文大小：676 KB
• 参考文献：Papers of particular interest, published recently, have been highlighted as: 鈥?Of importance1.Chalasani NYZ, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592鈥?09.PubMed View Article
  2.Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology. 2014;147:754鈥?4.PubMed View Article
  3.Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274鈥?5.PubMed View Article
  4.Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988鈥?994. Am J Epidemiol. 2013;178:38鈥?5.PubMed Central PubMed View Article
  5.Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124鈥?1.PubMed View Article
  6.Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, et al. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol. 2007;6:161鈥?.PubMed
  7.Farrell GC, Wong VW, Chitturi S. NAFLD in Asia鈥攁s common and important as in the West. Nat Rev Gastroenterol Hepatol. 2013;10:307鈥?8.PubMed View Article
  8.Zhou YJ, Li YY, Nie YQ, Ma JX, Lu LG, Shi SL, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol. 2007;13:6419鈥?4.PubMed Central PubMed View Article
  9.Omagari K, Kadokawa Y, Masuda J, Egawa I, Sawa T, Hazama H, et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol. 2002;17:1098鈥?05.PubMed View Article
  10.鈥?/div>White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342鈥?9. This is a meta-analysis of multiple studies showing epidemiologic evidence for the association between NAFLD and HCC.
  11.Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134鈥?0.PubMed View Article
  12.Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664鈥?.PubMed View Article
  13.Ratziu V, Bonyhay L, Di Martino V, Charlotte F, Cavallaro L, Sayegh-Tainturier MH, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485鈥?3.PubMed View Article
  14.Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36:1349鈥?4.PubMed View Article
  15.Lee SS, Jeong SH, Byoun YS, Chung SM, Seong MH, Sohn HR, et al. Clinical features and outcome of cryptogenic hepatocellular carcinoma compared to those of viral and alcoholic hepatocellular carcinoma. BMC Cancer. 2013;13:335.PubMed Central PubMed View Article
  16.Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461鈥?.PubMed Central PubMed View Article
  17.Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109:325鈥?4.PubMed View Article
  18.World Health Organization. Obesity situation and trends. 2015. www.鈥媤ho.鈥媔nt/鈥媡opics/鈥媜besity/鈥媏n/鈥?/span> . Accessed 12 Feb 2015
  19.Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640鈥?.PubMed View Article
  20.Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol. 2013;24:2449鈥?5.PubMed Central PubMed View Article
  21.Saunders D, Seidel D, Allison M, Lyratzopoulos G. Systematic review: the association between obesity and hepatocellular carcinoma鈥攅pidemiological evidence. Aliment Pharmacol Ther. 2010;31:1051鈥?3.PubMed
  22.Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97:1005鈥?.PubMed Central PubMed
  23.Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569鈥?8.PubMed View Article
  24.Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol. 2010;16:3603鈥?5.PubMed Central PubMed View Article
  25.Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011;54:463鈥?1.PubMed Central PubMed View Article
  26.Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26:2183鈥?1.PubMed View Article
  27.Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428鈥?3.PubMed View Article
  28.Bralet MP, Regimbeau JM, Pineau P, Dubois S, Loas G, Degos F, et al. Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology. 2000;32:200鈥?.PubMed View Article
  29.Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49:851鈥?.PubMed View Article
  30.Aravalli RN, Cressman EN, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol. 2013;87:227鈥?7.PubMed View Article
  31.Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147鈥?3.PubMed View Article
  32.Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH. Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology. 2012;56:1567鈥?4.PubMed Central PubMed View Article
  33.Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461鈥?.PubMed View Article
  34.Liu P, Kimmoun E, Legrand A, Sauvanet A, Degott C, Lardeux B, et al. Activation of NF-kappa B, AP-1 and STAT transcription factors is a frequent and early event in human hepatocellular carcinomas. J Hepatol. 2002;37:63鈥?1.PubMed View Article
  35.Luedde T, Schwabe RF. NF-kappaB in the liver鈥攍inking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8:108鈥?8.PubMed Central PubMed View Article
  36.He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell. 2010;17:286鈥?7.PubMed Central PubMed View Article
  37.He G, Karin M. NF-kappaB and STAT3鈥攌ey players in liver inflammation and cancer. Cell Res. 2011;21:159鈥?8.PubMed Central PubMed View Article
  38.Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694鈥?.PubMed Central PubMed View Article
  39.Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44:1117鈥?1.PubMed View Article
  40.Nakagawa H, Shibata T. Comprehensive genome sequencing of the liver cancer genome. Cancer Lett. 2013;340:234鈥?0.PubMed View Article
  41.Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139:693鈥?06.PubMed Central PubMed View Article
  42.Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197鈥?08.PubMed Central PubMed View Article
  43.Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67:2497鈥?07.PubMed Central PubMed View Article
  44.Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33:547鈥?4.PubMed Central PubMed View Article
  45.Vinciguerra M, Carrozzino F, Peyrou M, Carlone S, Montesano R, Benelli R, et al. Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol. 2009;50:1132鈥?1.PubMed View Article
  46.Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093鈥?01.PubMed View Article
  47.鈥?/div>Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11:886鈥?5. This review highlights recent advances in our understanding between obesity and HCC.
  48.Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol. 2004;68:1003鈥?5.PubMed View Article
  49.Li C, Yang W, Zhang J, Zheng X, Yao Y, Tu K, et al. SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. Int J Mol Sci. 2014;15:7124鈥?8.PubMed Central PubMed View Article
  50.Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19:338鈥?8.PubMed View Article
  51.Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Carteni M, et al. Gut鈥搇iver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutri, Metab, Cardiovasc Dis : NMCD. 2012;22:471鈥?.View Article
  52.Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol. 2012;13:325鈥?2.PubMed Central PubMed View Article
  53.鈥?/div>Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179鈥?5. This important study demonstrates that inflammasome deficiency leads to transmissible dysbiosis in co-housed mice, leading to NASH.
  54.鈥?/div>De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014;59:1738鈥?9. This is a key study showing the link between dysbiosis and fibrogenesis in chronic liver disease.
  55.Ohtani N, Hara E. Roles and mechanisms of cellular senescence in regulation of tissue homeostasis. Cancer Sci. 2013;104:525鈥?0.PubMed View Article
  56.鈥?/div>Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97鈥?01. This is the first evidence of HSC senescence playing a role in liver tumorigenesis.
  57.Zhang Y, Ge X, Heemstra LA, Chen WD, Xu J, Smith JL, et al. Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol. 2012;26:272鈥?0.PubMed Central PubMed View Article
  58.Wolfe A, Thomas A, Edwards G, Jaseja R, Guo GL, Apte U. Increased activation of the Wnt/beta-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther. 2011;338:12鈥?1.PubMed Central PubMed View Article
  59.Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007;67:863鈥?.PubMed View Article
  60.Liangpunsakul S, Chalasani N. Serum vitamin D concentrations and unexplained elevation in ALT among US adults. Dig Dis Sci. 2011;56:2124鈥?.PubMed Central PubMed View Article
  61.Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutri, Metabol, Cardiovasc Dis : NMCD. 2007;17:517鈥?4.View Article
  62.Wang JB, Abnet CC, Chen W, Dawsey SM, Fan JH, Yin LY, et al. Association between serum 25(OH) vitamin D, incident liver cancer and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: a nested case-control study. Br J Cancer. 2013;109:1997鈥?004.PubMed Central PubMed View Article
  63.Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, et al. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology. 2014;60:1222鈥?0.PubMed View Article
  64.Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601鈥?3.PubMed Central PubMed View Article
  65.Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation. Hepatology. 2012;55:1103鈥?1.PubMed View Article
  66.Ghous Z, Akhter J, Pourgholami MH, Morris DL. Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study. Anticancer Res. 2008;28:3757鈥?1.PubMed
  67.Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(574鈥?82):e571.
  68.Neuschwander-Tetri, B.A., Loomba, R., Sanyal, A.J., Lavine, J.E., Van Natta, M.L., Abdelmalek, M.F., Chalasani, N., Dasarathy, S., Diehl, A.M., Hameed, B., et al. (2014). Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet.
  69.鈥?/div>Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504鈥?6. This study demonstrates LPS-activation of HSC leading to fibrogenesis and tumor growth in NAFLD.
  70.Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(913鈥?16), e917.
  
• 作者单位：Kirti Shetty (1)
  Jian Chen (2)
  Ji-hyun Shin (2)
  Wilma Jogunoori (3)
  Lopa Mishra (2)
  
  1. Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
  2. Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard鈥擴nit 1466, Houston, TX, USA
  3. Institute of Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
  
• 刊物主题：Hepatology;
• 出版者：Springer US
• ISSN：1541-0706

文摘

Non-alcoholic fatty liver disease (NAFLD) is being recognized as an increasingly important contributor to the burden of hepatocellular carcinoma (HCC) worldwide. It is often accompanied by obesity and diabetes mellitus and is believed to be the hepatic representation of the metabolic syndrome. HCC development in NAFLD is multifactorial and complex. It is dependent on not only the well-described mechanisms noted in chronic liver injury but also on the molecular derangements associated with obesity and dysmetabolism. These include adipocyte remodeling, adipokine secretion, lipotoxicity, and insulin resistance. Recent advances focus on the importance of the gut-liver axis in accelerating the process of oncogenesis in NAFLD. The Farnesoid X receptor (FXR) has been demonstrated to have important metabolic effects, and its pharmacological activation by obeticholic acid has been recently reported to produce histological improvement in non-alcoholic steatohepatitis (NASH). It is hoped that delineating the mechanisms of hepatic fibrosis and oncogenesis in NASH will lead to enhanced strategies for cancer prevention, surveillance, and therapy in this population.