Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC is particularly aggressive and is one of the leading causes of cancer mortality. In recent decades, the epidemiological landscape of HCC has undergone significant changes. While chronic viral hepatitis and excessive alcohol consumption have long been identified as the main risk factors for HCC, non-alcoholic steatohepatitis (NASH), paralleling the worldwide epidemic of obesity and type 2 diabetes, has become a growing cause of HCC in the US and Europe. Here, we review the recent advances in epidemiological, genetic, epigenetic and pathogenic mechanisms as well as experimental mouse models that have improved the understanding of NASH progression toward HCC. We also discuss the clinical management of patients with NASH-related HCC and possible therapeutic approaches.
Author Statement
Research funding: C.D.-M. is supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Contre le Cancer (Comité de Paris, grant RS18/75-85) and Fondation ARC (grant 20171206548). J.-P.C. is supported by INSERM, Ligue Contre le Cancer, Fondation ARC, Fondation pour la Recherche Médicale (FRM), Association Française pour l’Etude du Foie (AFEF) and Plan Cancer (Hétérogénéité tumorale et Ecosystème).
Conflict of interest: None declared.
Informed Consent: Not applicable.
Ethical Approval: Not applicable.
References
[1] Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.10.1002/hep.24199Search in Google Scholar PubMed PubMed Central
[2] Mody K, Abou-Alfa GK. Systemic therapy for advanced hepatocellular carcinoma in an evolving landscape. Curr Treat Options Oncol. 2019;20:3.10.1007/s11864-019-0601-1Search in Google Scholar PubMed
[3] Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156:477–91.e1.10.1053/j.gastro.2018.08.065Search in Google Scholar PubMed PubMed Central
[4] Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease – meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.10.1002/hep.28431Search in Google Scholar PubMed
[5] Pradat P, Virlogeux V, Trepo E. Epidemiology and elimination of HCV-related liver disease. Viruses. 2018;10:545.10.3390/v10100545Search in Google Scholar PubMed PubMed Central
[6] Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20.10.1038/nrgastro.2017.109Search in Google Scholar PubMed
[7] Hannah Jr. WN, Harrison SA. Effect of weight loss, diet, exercise, and bariatric surgery on nonalcoholic fatty liver disease. Clin Liver Dis. 2016;20:339–50.10.1016/j.cld.2015.10.008Search in Google Scholar PubMed
[8] 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;140:124–31.10.1053/j.gastro.2010.09.038Search in Google Scholar PubMed
[9] Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The Global Epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793–801.10.1016/j.jhep.2019.06.021Search in Google Scholar PubMed
[10] Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54:1208–16.10.1002/hep.24491Search in Google Scholar PubMed PubMed Central
[11] Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.10.1002/hep.23527Search in Google Scholar PubMed
[12] 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;10:1342–59.e2.10.1016/j.cgh.2012.10.001Search in Google Scholar PubMed PubMed Central
[13] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22.10.1038/s41591-018-0104-9Search in Google Scholar PubMed PubMed Central
[14] Gupta A, Das A, Majumder K, Arora N, Mayo HG, Singh PP, et al. Obesity is independently associated with increased risk of hepatocellular cancer-related mortality: a systematic review and meta-analysis. Am J Clin Oncol. 2018;41:874–81.10.1097/COC.0000000000000388Search in Google Scholar PubMed PubMed Central
[15] Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin. 2010;26:2183–91.10.1185/03007995.2010.506375Search in Google Scholar PubMed
[16] Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547–55.10.1053/j.gastro.2014.11.039Search in Google Scholar PubMed
[17] Parikh ND, Marrero WJ, Wang J, Steuer J, Tapper EB, Konerman M, et al. Projected increase in obesity and non-alcoholic-steatohepatitis-related liver transplantation waitlist additions in the United States. Hepatology. 2019;70:487–95.10.1002/hep.29473Search in Google Scholar PubMed
[18] Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the prevalence of Hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152:1090–99.e1.10.1053/j.gastro.2017.01.003Search in Google Scholar PubMed PubMed Central
[19] Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60:110–7.10.1016/j.jhep.2013.08.011Search in Google Scholar PubMed
[20] Pais R, Fartoux L, Goumard C, Scatton O, Wendum D, Rosmorduc O, et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther. 2017;46:856–63.10.1111/apt.14261Search in Google Scholar PubMed
[21] Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–86.10.1002/hep.28785Search in Google Scholar PubMed
[22] Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123–33.10.1002/hep.29466Search in Google Scholar PubMed PubMed Central
[23] Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69:896–904.10.1016/j.jhep.2018.05.036Search in Google Scholar PubMed
[24] Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68:268–79.10.1016/j.jhep.2017.09.003Search in Google Scholar PubMed
[25] Browning MG, Khoraki J, DeAntonio JH, Mazzini G, Mangino MJ, Siddiqui MS, et al. Protective effect of black relative to white race against non-alcoholic fatty liver disease in patients with severe obesity, independent of type 2 diabetes. Int J Obes (Lond). 2018;42:926–29.10.1038/ijo.2017.309Search in Google Scholar PubMed
[26] Pan JJ, Fallon MB. Gender and racial differences in nonalcoholic fatty liver disease. World J Hepatol. 2014;6:274–83.10.4254/wjh.v6.i5.274Search in Google Scholar PubMed PubMed Central
[27] Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19:5219–38.10.2174/13816128113199990381Search in Google Scholar PubMed PubMed Central
[28] Falleti E, Fabris C, Cmet S, Cussigh A, Bitetto D, Fontanini E, et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int. 2011;31:1137–43.10.1111/j.1478-3231.2011.02534.xSearch in Google Scholar PubMed
[29] Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61:75–81.10.1016/j.jhep.2014.02.030Search in Google Scholar PubMed
[30] Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.10.1038/ng.3252Search in Google Scholar PubMed PubMed Central
[31] Ki Kim S, Ueda Y, Hatano E, Kakiuchi N, Takeda H, Goto T, et al. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. Int J Cancer. 2016;139:2512–8.10.1002/ijc.30379Search in Google Scholar PubMed
[32] Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, et al. Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. Carcinogenesis. 2017;38:261–70.10.1093/carcin/bgx005Search in Google Scholar PubMed PubMed Central
[33] de Conti A, Dreval K, Tryndyak V, Orisakwe OE, Ross SA, Beland FA, et al. Inhibition of the cell death pathway in nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is associated with histone H4 lysine 16 deacetylation. Mol Cancer Res. 2017;15:1163–72.10.1158/1541-7786.MCR-17-0109Search in Google Scholar PubMed
[34] Wong CM, Tsang FH, Ng IO. Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol. 2018;15:137–51.10.1038/nrgastro.2017.169Search in Google Scholar PubMed
[35] Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, et al. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology. 2008;48:1810–20.10.1002/hep.22569Search in Google Scholar PubMed PubMed Central
[36] Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest. 2012;122:2871–83.10.1172/JCI63539Search in Google Scholar PubMed PubMed Central
[37] Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122:2884–97.10.1172/JCI63455Search in Google Scholar PubMed PubMed Central
[38] Xu Y, Zalzala M, Xu J, Li Y, Yin L, Zhang Y. A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism. Nat Commun. 2015;6:7466.10.1038/ncomms8466Search in Google Scholar PubMed PubMed Central
[39] Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G, et al. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut. 2016;65:1024–34.10.1136/gutjnl-2014-308969Search in Google Scholar PubMed
[40] Guo Y, Xiong Y, Sheng Q, Zhao S, Wattacheril J, Flynn CR. A micro-RNA expression signature for human NAFLD progression. J Gastroenterol. 2016;51:1022–30.10.1007/s00535-016-1178-0Search in Google Scholar PubMed PubMed Central
[41] Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017;542:450–55.10.1038/nature21365Search in Google Scholar PubMed PubMed Central
[42] Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2019;38:2844–59.10.1038/s41388-018-0619-zSearch in Google Scholar PubMed PubMed Central
[43] Farrell G, Schattenberg JM, Leclercq I, Yeh MM, Goldin R, Teoh N, et al. Mouse models of nonalcoholic steatohepatitis: toward optimization of their relevance to human nonalcoholic steatohepatitis. Hepatology. 2019;69:2241–57.10.1002/hep.30333Search in Google Scholar PubMed
[44] Teufel A, Itzel T, Erhart W, Brosch M, Wang XY, Kim YO, et al. Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients. Gastroenterology. 2016;151:513–25.e0.10.1053/j.gastro.2016.05.051Search in Google Scholar PubMed
[45] Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55:435–44.10.1016/j.jhep.2010.10.039Search in Google Scholar PubMed
[46] Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011;301:G825–34.10.1152/ajpgi.00145.2011Search in Google Scholar PubMed PubMed Central
[47] Dowman JK, Hopkins LJ, Reynolds GM, Nikolaou N, Armstrong MJ, Shaw JC, et al. Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle. Am J Pathol. 2014;184:1550–61.10.1016/j.ajpath.2014.01.034Search in Google Scholar PubMed PubMed Central
[48] Hebbard L, George J. Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2011;8:35–44.10.1038/nrgastro.2010.191Search in Google Scholar PubMed
[49] Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549–64.10.1016/j.ccell.2014.09.003Search in Google Scholar PubMed
[50] 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;140:197–208.10.1016/j.cell.2009.12.052Search in Google Scholar PubMed PubMed Central
[51] Kishida N, Matsuda S, Itano O, Shinoda M, Kitago M, Yagi H, et al. Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine. BMC Gastroenterology. 2016;16:61.10.1186/s12876-016-0477-5Search in Google Scholar PubMed PubMed Central
[52] Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69:385–95.10.1016/j.jhep.2018.03.011Search in Google Scholar PubMed PubMed Central
[53] Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 2017;551:340–45.10.1038/nature24302Search in Google Scholar PubMed PubMed Central
[54] Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol. 2016;65:579–88.10.1016/j.jhep.2016.05.005Search in Google Scholar PubMed PubMed Central
[55] Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–92.10.1158/0008-5472.CAN-09-1089Search in Google Scholar PubMed PubMed Central
[56] Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26:331–43.10.1016/j.ccr.2014.07.001Search in Google Scholar PubMed PubMed Central
[57] Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113:1774–83.10.1172/JCI20513Search in Google Scholar PubMed PubMed Central
[58] Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A. 2004;101:2082–7.10.1073/pnas.0308617100Search in Google Scholar PubMed PubMed Central
[59] Fan CY, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem. 1998;273:15639–45.10.1074/jbc.273.25.15639Search in Google Scholar PubMed
[60] Mueller KM, Kornfeld JW, Friedbichler K, Blaas L, Egger G, Esterbauer H, et al. Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology. 2011;54:1398–409.10.1002/hep.24509Search in Google Scholar PubMed PubMed Central
[61] Martinez-Lopez N, Varela-Rey M, Fernandez-Ramos D, Woodhoo A, Vazquez-Chantada M, Embade N, et al. Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis. Hepatology. 2010;52:1621–31.10.1002/hep.23860Search in Google Scholar PubMed PubMed Central
[62] Itoh M, Suganami T, Nakagawa N, Tanaka M, Yamamoto Y, Kamei Y, et al. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol. 2011;179:2454–63.10.1016/j.ajpath.2011.07.014Search in Google Scholar PubMed PubMed Central
[63] Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab. 2013;24:537–45.10.1016/j.tem.2013.05.009Search in Google Scholar PubMed
[64] Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371:2237–8.10.1056/NEJMra1011035Search in Google Scholar PubMed
[65] Bril F, Lomonaco R, Orsak B, Ortiz-Lopez C, Webb A, Tio F, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59:2178–87.10.1002/hep.26988Search in Google Scholar PubMed
[66] Donadon V, Balbi M, Zanette G. Hyperinsulinemia and risk for hepatocellular carcinoma in patients with chronic liver diseases and type 2 diabetes mellitus. Expert Rev Gastroenterol Hepatol. 2009;3:465–7.10.1586/egh.09.41Search in Google Scholar PubMed
[67] Nkontchou G, Bastard JP, Ziol M, Aout M, Cosson E, Ganne-Carrie N, et al. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol. 2010;53:827–33.10.1016/j.jhep.2010.04.035Search in Google Scholar PubMed
[68] Chao LT, Wu CF, Sung FY, Lin CL, Liu CJ, Huang CJ, et al. Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort. Carcinogenesis. 2011;32:876–81.10.1093/carcin/bgr058Search in Google Scholar PubMed PubMed Central
[69] Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, et al. Inflammatory and metabolic biomarkers and risk of liver and bilary tract cancer. Hepatology. 2014;60:858–71.10.1002/hep.27016Search in Google Scholar PubMed PubMed Central
[70] Farese Jr. RV, Zechner R, Newgard CB, Walther TC. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab. 2012;15:570–3.10.1016/j.cmet.2012.03.004Search in Google Scholar PubMed PubMed Central
[71] Valenti L, Rametta R, Dongiovanni P, Maggioni M, Fracanzani AL, Zappa M, et al. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes. 2008;57:1355–62.10.2337/db07-0714Search in Google Scholar PubMed
[72] Rametta R, Mozzi E, Dongiovanni P, Motta BM, Milano M, Roviaro G, et al. Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects. Int J Obes (Lond). 2013;37:986–92.10.1038/ijo.2012.181Search in Google Scholar PubMed
[73] Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, et al. Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. Int J Obes (Lond). 2018;42:1544–55.10.1038/s41366-018-0062-9Search in Google Scholar PubMed PubMed Central
[74] Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A. 2010;107:3441–6.10.1073/pnas.0914798107Search in Google Scholar PubMed PubMed Central
[75] Haas JT, Miao J, Chanda D, Wang Y, Zhao E, Haas ME, et al. Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab. 2012;15:873–84.10.1016/j.cmet.2012.05.002Search in Google Scholar PubMed PubMed Central
[76] Nakamura A, Tajima K, Zolzaya K, Sato K, Inoue R, Yoneda M, et al. Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. Diabetologia. 2012;55:3382–91.10.1007/s00125-012-2703-1Search in Google Scholar PubMed
[77] Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35:2203–17.10.1111/liv.12903Search in Google Scholar PubMed
[78] Chettouh H, Fartoux L, Aoudjehane L, Wendum D, Claperon A, Chretien Y, et al. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res. 2013;73:3974–86.10.1158/0008-5472.CAN-12-3824Search in Google Scholar PubMed
[79] Wang H, Lekbaby B, Fares N, Augustin J, Attout T, Schnuriger A, et al. Alteration of splicing factors’ expression during liver disease progression: impact on hepatocellular carcinoma outcome. Hepatol Int. 2019;13:454–67.10.1007/s12072-019-09950-7Search in Google Scholar PubMed
[80] Malaguarnera R, Sacco A, Voci C, Pandini G, Vigneri R, Belfiore A. Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway. Endocrinology. 2012;153:2152–63.10.1210/en.2011-1843Search in Google Scholar PubMed
[81] Martinez-Quetglas I, Pinyol R, Dauch D, Torrecilla S, Tovar V, Moeini A, et al. IGF2 is up-regulated by epigenetic mechanisms in hepatocellular carcinomas and is an actionable oncogene product in experimental models. Gastroenterology. 2016;151:1192–205.10.1053/j.gastro.2016.09.001Search in Google Scholar
[82] Benabou E, Salame Z, Wendum D, Lequoy M, Tahraoui S, Merabtene F, et al. Insulin receptor isoform A favors tumor progression in human hepatocellular carcinoma by increasing stem/progenitor cell features. Cancer Lett. 2019;450:155–68.10.1016/j.canlet.2019.02.037Search in Google Scholar
[83] Tanaka S, Wands JR. Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res. 1996;56:3391–4.Search in Google Scholar
[84] Boissan M, Beurel E, Wendum D, Rey C, Lecluse Y, Housset C, et al. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol. 2005;167:869–77.10.1016/S0002-9440(10)62058-5Search in Google Scholar
[85] Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001;28:29–35.10.1038/ng0501-29Search in Google Scholar PubMed
[86] Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130:1117–28.10.1053/j.gastro.2006.01.006Search in Google Scholar PubMed
[87] Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, et al. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene. 2005;24:6406–17.10.1038/sj.onc.1208788Search in Google Scholar PubMed
[88] Morzyglod L, Cauzac M, Popineau L, Denechaud PD, Fajas L, Ragazzon B, et al. Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma. Hepatology. 2017;65:1352–68.10.1002/hep.28972Search in Google Scholar PubMed
[89] Vinciguerra M, Veyrat-Durebex C, Moukil MA, Rubbia-Brandt L, Rohner-Jeanrenaud F, Foti M. PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology. 2008;134:268–80.10.1053/j.gastro.2007.10.010Search in Google Scholar PubMed
[90] Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927–47.10.1016/j.jhep.2018.06.008Search in Google Scholar PubMed
[91] Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568–76.10.1053/j.gastro.2007.10.039Search in Google Scholar PubMed
[92] Lake AD, Novak P, Hardwick RN, Flores-Keown B, Zhao F, Klimecki WT, et al. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci. 2014;137:26–35.10.1093/toxsci/kft230Search in Google Scholar
[93] Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY. Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Oncotarget. 2017;8:63370–81.10.18632/oncotarget.18812Search in Google Scholar
[94] Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell. 2018;175:133–45.e15.10.1016/j.cell.2018.08.020Search in Google Scholar
[95] Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J, Garcia-Ruiz C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol. 2009;50:789–96.10.1016/j.jhep.2008.12.016Search in Google Scholar
[96] Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol. 2003;38:605–14.10.1016/S0168-8278(03)00029-1Search in Google Scholar
[97] Toriguchi K, Hatano E, Tanabe K, Takemoto K, Nakamura K, Koyama Y, et al. Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency. J Gastroenterol Hepatol. 2014;29:1109–18.10.1111/jgh.12481Search in Google Scholar PubMed
[98] Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatol Int. 2015;9:93–104.10.1007/s12072-014-9582-0Search in Google Scholar PubMed PubMed Central
[99] Spiotto MT, Banh A, Papandreou I, Cao H, Galvez MG, Gurtner GC, et al. Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth. Cancer Res. 2010;70:78–88.10.1158/0008-5472.CAN-09-2747Search in Google Scholar PubMed PubMed Central
[100] D’Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status. Clin Chim Acta. 2015;451:97–102.10.1016/j.cca.2015.01.003Search in Google Scholar PubMed
[101] Boursier J, Diehl AM. Nonalcoholic fatty liver disease and the gut microbiome. Clin Liver Dis. 2016;20:263–75.10.1016/j.cld.2015.10.012Search in Google Scholar PubMed
[102] Brandi G, De Lorenzo S, Candela M, Pantaleo MA, Bellentani S, Tovoli F, et al. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis. 2017;38:231–40.10.1093/carcin/bgx007Search in Google Scholar PubMed
[103] Mathur R, Barlow GM. Obesity and the microbiome. Expert Rev Gastroenterol Hepatol. 2015;9:1087–99.10.1586/17474124.2015.1051029Search in Google Scholar PubMed
[104] Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013;58:120–7.10.1002/hep.26319Search in Google Scholar PubMed
[105] Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–9.10.1002/hep.26093Search in Google Scholar PubMed
[106] Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104:979–84.10.1073/pnas.0605374104Search in Google Scholar PubMed PubMed Central
[107] Rabot S, Membrez M, Bruneau A, Gerard P, Harach T, Moser M, et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010;24:4948–59.10.1096/fj.10.164921Search in Google Scholar
[108] 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;482:179–85.10.1038/nature10809Search in Google Scholar PubMed PubMed Central
[109] Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151:733–46.e12.10.1053/j.gastro.2016.06.022Search in Google Scholar PubMed PubMed Central
[110] Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14:527–39.10.1038/nrgastro.2017.72Search in Google Scholar PubMed PubMed Central
[111] Chu H, Williams B, Schnabl B. Gut microbiota, fatty liver disease, and hepatocellular carcinoma. Liver Res. 2018;2:43–51.10.1016/j.livres.2017.11.005Search in Google Scholar PubMed PubMed Central
[112] Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–11.10.1136/gut.48.2.206Search in Google Scholar PubMed PubMed Central
[113] Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–87.10.1002/hep.22848Search in Google Scholar PubMed
[114] Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 2010;52:1322–33.10.1002/hep.23845Search in Google Scholar PubMed
[115] 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;21:504–16.10.1016/j.ccr.2012.02.007Search in Google Scholar PubMed PubMed Central
[116] Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47:571–9.10.1016/j.jhep.2007.04.019Search in Google Scholar PubMed PubMed Central
[117] Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323–34.e7.10.1053/j.gastro.2010.03.052Search in Google Scholar PubMed PubMed Central
[118] Jia W, Xie G. Probiotics, bile acids and gastrointestinal carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15:205.10.1038/nrgastro.2018.24Search in Google Scholar PubMed PubMed Central
[119] Jung IH, Choi JH, Chung YY, Lim GL, Park YN, Park SW. Predominant activation of JAK/STAT3 pathway by interleukin-6 is implicated in hepatocarcinogenesis. Neoplasia. 2015;17:586–97.10.1016/j.neo.2015.07.005Search in Google Scholar PubMed PubMed Central
[120] Bernstein H, Bernstein C, Payne CM, Dvorak K. Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol. 2009;15:3329–40.10.3748/wjg.15.3329Search in Google Scholar PubMed PubMed Central
[121] 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;499:97–101.10.1038/nature12347Search in Google Scholar PubMed
[122] Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer – mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10:455–65.10.1038/nrendo.2014.94Search in Google Scholar PubMed PubMed Central
[123] Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–72.10.1053/j.gastro.2012.09.008Search in Google Scholar PubMed
[124] Feldstein AE. Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Semin Liver Dis. 2010;30:391–401.10.1055/s-0030-1267539Search in Google Scholar PubMed
[125] Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15:8591–638.10.3390/ijms15058591Search in Google Scholar PubMed PubMed Central
[126] Lanthier N. Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: why and how? World J Hepatol. 2015;7:2184–8.10.4254/wjh.v7.i19.2184Search in Google Scholar PubMed PubMed Central
[127] Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS One. 2016;11:e0159524.10.1371/journal.pone.0159524Search in Google Scholar PubMed PubMed Central
[128] Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. 2012;72:3977–86.10.1158/0008-5472.CAN-12-0938Search in Google Scholar PubMed PubMed Central
[129] Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol. 2016;13:316–27.10.1038/cmi.2015.104Search in Google Scholar PubMed PubMed Central
[130] Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, et al. Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med. 2019;25:641–55.10.1038/s41591-019-0379-5Search in Google Scholar PubMed
[131] Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell. 2010;18:485–98.10.1016/j.ccr.2010.10.002Search in Google Scholar PubMed PubMed Central
[132] Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479:547–51.10.1038/nature10599Search in Google Scholar PubMed
[133] Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.10.1038/nature16969Search in Google Scholar
[134] Gomes AL, Teijeiro A, Buren S, Tummala KS, Yilmaz M, Waisman A, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30:161–75.10.1016/j.ccell.2016.05.020Search in Google Scholar
[135] McPherson S, Henderson E, Burt AD, Day CP, Anstee QM. Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60:1055–62.10.1016/j.jhep.2014.01.010Search in Google Scholar
[136] Hegde P, Weiss E, Paradis V, Wan J, Mabire M, Sukriti S, et al. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver. Nat Commun. 2018;9:2146.10.1038/s41467-018-04450-ySearch in Google Scholar
[137] European Association for the Study of the Liver. Electronic address eee, European Association for the study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.10.1016/j.jhep.2018.03.019Search in Google Scholar
[138] Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019;16:411–28.10.1038/s41575-019-0145-7Search in Google Scholar
[139] Hester CA, Rich NE, Singal AG, Yopp AC. Comparative analysis of nonalcoholic steatohepatitis- versus viral hepatitis- and alcohol-related liver disease-related hepatocellular carcinoma. J Natl Compr Canc Netw. 2019;17:322–29.10.6004/jnccn.2018.7105Search in Google Scholar
[140] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Raoul J, Zeuzem S, et al. Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2007;25:LBA1.10.1200/jco.2007.25.18_suppl.lba1Search in Google Scholar
[141] Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.10.1016/S1470-2045(08)70285-7Search in Google Scholar
[142] Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.10.1016/S0140-6736(18)30207-1Search in Google Scholar
[143] Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.10.1016/S0140-6736(16)32453-9Search in Google Scholar
[144] Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.10.1056/NEJMoa1717002Search in Google Scholar PubMed PubMed Central
[145] Hassan I, Gane E. Improving survival in patients with hepatocellular carcinoma related to chronic hepatitis C and B but not in those related to non-alcoholic steatohepatitis or alcoholic liver disease: a 20-year experience from a national programme. Intern Med J. 2019;49:1405–11.10.1111/imj.14304Search in Google Scholar PubMed
[146] Bengtsson B, Stal P, Wahlin S, Bjorkstrom NK, Hagstrom H. Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis. Liver Int. 2019;39:1098–108.10.1111/liv.14087Search in Google Scholar PubMed
[147] Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97:2347–53.10.1210/jc.2012-1267Search in Google Scholar PubMed
[148] de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019;70:710–21.10.1016/j.jhep.2018.11.034Search in Google Scholar PubMed PubMed Central
[149] Lebeaupin C, Vallee D, Rousseau D, Patouraux S, Bonnafous S, Adam G, et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology. 2018;68:515–32.10.1002/hep.29847Search in Google Scholar PubMed
[150] 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;67:863–7.10.1158/0008-5472.CAN-06-1078Search in Google Scholar PubMed
[151] Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis. 2007;28:940–6.10.1093/carcin/bgl249Search in Google Scholar PubMed PubMed Central
[152] Su H, Ma C, Liu J, Li N, Gao M, Huang A, et al. Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol. 2012;303:G1245–53.10.1152/ajpgi.00439.2011Search in Google Scholar PubMed PubMed Central
[153] Deuschle U, Schuler J, Schulz A, Schluter T, Kinzel O, Abel U, et al. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One. 2012;7:e43044.10.1371/journal.pone.0043044Search in Google Scholar PubMed PubMed Central
[154] Attia YM, Tawfiq RA, Ali AA, Elmazar MM. The FXR agonist, obeticholic acid, suppresses HCC proliferation & metastasis: role of IL-6/STAT3 signalling pathway. Sci Rep. 2017;7:12502.10.1038/s41598-017-12629-4Search in Google Scholar PubMed PubMed Central
[155] Kainuma M, Takada I, Makishima M, Sano K. Farnesoid X receptor activation enhances transforming growth factor beta-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells. Int J Mol Sci. 2018;19:pii. E1898.10.3390/ijms19071898Search in Google Scholar PubMed PubMed Central
[156] Sepe V, Distrutti E, Fiorucci S, Zampella A. Farnesoid X receptor modulators 2014-present: a patent review. Expert Opin Ther Pat. 2018;28:351–64.10.1080/13543776.2018.1459569Search in Google Scholar PubMed
[157] Inoue M, Itoh H, Tanaka T, Chun TH, Doi K, Fukunaga Y, et al. Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-gamma. Arterioscler Thromb Vasc Biol. 2001;21:560–6.10.1161/01.ATV.21.4.560Search in Google Scholar PubMed
[158] Miura K, Ohnishi H, Morimoto N, Minami S, Ishioka M, Watanabe S, et al. Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet. Cancer Sci. 2019;110:771–83.10.1111/cas.13902Search in Google Scholar PubMed PubMed Central
[159] Yamashita T, Honda M, Takatori H, Nishino R, Minato H, Takamura H, et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol. 2009;50:100–10.10.1016/j.jhep.2008.07.036Search in Google Scholar PubMed
[160] Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–83.10.1053/j.gastro.2010.12.006Search in Google Scholar PubMed PubMed Central
[161] 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;15:7124–38.10.3390/ijms15057124Search in Google Scholar PubMed PubMed Central
[162] Evert M, Calvisi DF, Evert K, De Murtas V, Gasparetti G, Mattu S, et al. V-AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin activation induces a module of metabolic changes contributing to growth in insulin-induced hepatocarcinogenesis. Hepatology. 2012;55:1473–84.10.1002/hep.25600Search in Google Scholar PubMed
[163] Lally JSV, Ghoshal S, DePeralta DK, Moaven O, Wei L, Masia R, et al. Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 2019;29:174–82.e5.10.1016/j.cmet.2018.08.020Search in Google Scholar
[164] Piccinin E, Villani G, Moschetta A. Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators. Nat Rev Gastroenterol Hepatol. 2019;16:160–74.10.1038/s41575-018-0089-3Search in Google Scholar
[165] Piccinin E, Peres C, Bellafante E, Ducheix S, Pinto C, Villani G, et al. Hepatic peroxisome proliferator-activated receptor gamma coactivator 1beta drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice. Hepatology. 2018;67:884–98.10.1002/hep.29484Search in Google Scholar
[166] Sharabi K, Lin H, Tavares CD, Dominy JE, Camporez JP, Perry RJ, et al. Selective chemical inhibition of PGC-1alpha gluconeogenic activity ameliorates Type 2 diabetes. Cell. 2017;169:148–60.e15.10.1016/j.cell.2017.03.001Search in Google Scholar
[167] Sun H, Yang W, Tian Y, Zeng X, Zhou J, Mok MT, et al. An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma. Nat Commun. 2018;9:5214.10.1038/s41467-018-07402-8Search in Google Scholar
[168] Celikbilek M, Gursoy S, Deniz K, Karaman A, Zararsiz G, Yurci A. Mean platelet volume in biopsy-proven non-alcoholic fatty liver disease. Platelets. 2013;24:194–9.10.3109/09537104.2012.688898Search in Google Scholar
[169] Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152:745–61.10.1053/j.gastro.2016.11.048Search in Google Scholar
[170] El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.10.1016/S0140-6736(17)31046-2Search in Google Scholar
[171] Gustafson MP, DiCostanzo AC, Wheatley CM, Kim CH, Bornschlegl S, Gastineau DA, et al. A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood. J Immunother Cancer. 2017;5:30.10.1186/s40425-017-0231-8Search in Google Scholar PubMed PubMed Central
[172] Koelwyn GJ, Quail DF, Zhang X, White RM, Jones LW. Exercise-dependent regulation of the tumour microenvironment. Nat Rev Cancer. 2017;17:620–32.10.1038/nrc.2017.78Search in Google Scholar PubMed
© 2020 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Special Issue: ‘Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights’ / Editors: Gérard S. Chetrite and Bruno Féve
- Editorial Preface
- Preface to special issue on “Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights”
- Original Article
- Aromatase in normal and diseased liver
- Review Articles
- Hepatocellular carcinoma in the context of non-alcoholic steatohepatitis (NASH): recent advances in the pathogenic mechanisms
- Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models
- Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis
- Hypothyroidism and nonalcoholic fatty liver disease – a chance association?
- Mini-Review Article
- The impact of steatosis on liver regeneration
- Regular Issue
- Original Articles
- Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats
- 3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line
- Machine learning as new promising technique for selection of significant features in obese women with type 2 diabetes
- Implementation of a novel self-induced promoter for the expression of pharmaceutical peptides in Escherichia coli: YY(3-36) peptide
- Comparison of the effect of 12- and 24-session cardiac rehabilitation on physical, psychosocial and biomedical factors in ischemic heart disease patients
- The stimulation protocol in poor responder IVF; a minimal or high-dose stimulation? – A meta-analysis
- Review Articles
- Cell free DNA: revolution in molecular diagnostics – the journey so far
- Genitourinary syndrome of menopause (GSM) and laser VEL: a review
Articles in the same Issue
- Special Issue: ‘Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights’ / Editors: Gérard S. Chetrite and Bruno Féve
- Editorial Preface
- Preface to special issue on “Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights”
- Original Article
- Aromatase in normal and diseased liver
- Review Articles
- Hepatocellular carcinoma in the context of non-alcoholic steatohepatitis (NASH): recent advances in the pathogenic mechanisms
- Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models
- Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis
- Hypothyroidism and nonalcoholic fatty liver disease – a chance association?
- Mini-Review Article
- The impact of steatosis on liver regeneration
- Regular Issue
- Original Articles
- Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats
- 3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line
- Machine learning as new promising technique for selection of significant features in obese women with type 2 diabetes
- Implementation of a novel self-induced promoter for the expression of pharmaceutical peptides in Escherichia coli: YY(3-36) peptide
- Comparison of the effect of 12- and 24-session cardiac rehabilitation on physical, psychosocial and biomedical factors in ischemic heart disease patients
- The stimulation protocol in poor responder IVF; a minimal or high-dose stimulation? – A meta-analysis
- Review Articles
- Cell free DNA: revolution in molecular diagnostics – the journey so far
- Genitourinary syndrome of menopause (GSM) and laser VEL: a review