{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T02:52:41Z","timestamp":1793674361133,"version":"4.5.1"},"reference-count":203,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T00:00:00Z","timestamp":1589932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1R01CA230561-01A1, 1R01CA240004-01 and 1R01CA244993-01"],"award-info":[{"award-number":["1R01CA230561-01A1, 1R01CA240004-01 and 1R01CA244993-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1R01DK107451-01A1"],"award-info":[{"award-number":["1R01DK107451-01A1"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["CA170048"],"award-info":[{"award-number":["CA170048"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-\u03baB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)\/phosphatase and tensin homolog (PTEN)\/Akt, and Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC.<\/jats:p>","DOI":"10.3390\/cancers12051290","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T10:37:38Z","timestamp":1589971058000},"page":"1290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Molecular Mechanisms Regulating Obesity-Associated Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Yetirajam","family":"Rajesh","sequence":"first","affiliation":[{"name":"Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0973-2323","authenticated-orcid":false,"given":"Devanand","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xu, W., and Yu, J. (2017). Obesity and Hepatocellular Carcinoma. Liver Pathophysiology: Therapies and Antioxidants, Academic Press.","DOI":"10.1016\/B978-0-12-804274-8.00020-5"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1001\/jama.2014.732","article-title":"Prevalence of childhood and adult obesity in the United States, 2011\u20132012","volume":"311","author":"Ogden","year":"2014","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.amepre.2011.10.026","article-title":"Obesity and severe obesity forecasts through 2030","volume":"42","author":"Finkelstein","year":"2012","journal-title":"Am. J. Prev. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.3945\/ajcn.2009.28595","article-title":"Increased food energy supply is more than sufficient to explain the US epidemic of obesity","volume":"90","author":"Swinburn","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/ng.274","article-title":"Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity","volume":"41","author":"Thorleifsson","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0140-6736(08)60269-X","article-title":"Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies","volume":"371","author":"Renehan","year":"2008","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.1053\/j.gastro.2004.09.021","article-title":"Obesity and hepatocellular carcinoma","volume":"127","author":"Caldwell","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ebiom.2018.02.022","article-title":"Obesity and Cancer: Existing and New Hypotheses for a Causal Connection","volume":"30","author":"Stone","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"Forner","year":"2018","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1023\/A:1008995217664","article-title":"A prospective study of obesity and cancer risk (Sweden)","volume":"12","author":"Wolk","year":"2001","journal-title":"Cancer Causes Control"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1056\/NEJMoa021423","article-title":"Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults","volume":"348","author":"Calle","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jhep.2013.08.011","article-title":"Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team","volume":"60","author":"Dyson","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/liv.13031","article-title":"The story of HCC in NAFLD: From epidemiology, across pathogenesis, to prevention and treatment","volume":"36","author":"Margini","year":"2016","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/hep.29466","article-title":"Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease","volume":"67","author":"Estes","year":"2018","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","article-title":"From NASH to HCC: Current concepts and future challenges","volume":"16","author":"Anstee","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s00535-012-0739-0","article-title":"Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma","volume":"48","author":"Tanaka","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.ccell.2017.05.006","article-title":"Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS","volume":"31","author":"Yuan","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.ccell.2014.10.002","article-title":"Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage","volume":"26","author":"Tummala","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ccell.2016.05.020","article-title":"Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma","volume":"30","author":"Gomes","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.cell.2008.12.040","article-title":"A role of DNA-PK for the metabolic gene regulation in response to insulin","volume":"136","author":"Wong","year":"2009","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1158\/1078-0432.CCR-14-0842","article-title":"DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival","volume":"21","author":"Cornell","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nrg.2017.72","article-title":"Convergence between biological, behavioural and genetic determinants of obesity","volume":"18","author":"Ghosh","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_29","first-page":"379","article-title":"Genetic And Epigenetic Causes Of Obesity","volume":"28","author":"Thaker","year":"2017","journal-title":"Adolesc. Med. State Art Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","author":"Romeo","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1194\/jlr.P900013-JLR200","article-title":"A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity","volume":"50","author":"Sookoian","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jhep.2014.02.030","article-title":"Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma","volume":"61","author":"Liu","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/hep.27242","article-title":"Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis","volume":"61","author":"Smagris","year":"2015","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/hep.29273","article-title":"The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation","volume":"66","author":"BasuRay","year":"2017","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9521","DOI":"10.1073\/pnas.1901974116","article-title":"Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis","volume":"116","author":"BasuRay","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1002\/hep.29041","article-title":"The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells","volume":"65","author":"Bruschi","year":"2017","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1002\/hep.23812","article-title":"Patatin-like phospholipase domain-containing 3\/adiponutrin deficiency in mice is not associated with fatty liver disease","volume":"52","author":"Chen","year":"2010","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ng.2901","article-title":"Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease","volume":"46","author":"Kozlitina","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1002\/hep.29021","article-title":"TM6SF2 rs58542926 impacts lipid processing in liver and small intestine","volume":"65","author":"Yang","year":"2017","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11585","DOI":"10.1038\/s41598-019-47737-w","article-title":"The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids","volume":"9","author":"Prill","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8913","DOI":"10.1073\/pnas.1323785111","article-title":"TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content","volume":"111","author":"Mahdessian","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Tang, S., Zhang, J., Mei, T.T., Guo, H.Q., Wei, X.H., Zhang, W.Y., Liu, Y.L., Liang, S., Fan, Z.P., and Ma, L.X. (2019). Association of TM6SF2 rs58542926 T\/C gene polymorphism with hepatocellular carcinoma: A meta-analysis. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6173-4"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease","volume":"378","author":"Cheng","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Luukkonen, P.K., Tukiainen, T., Juuti, A., Sammalkorpi, H., Haridas, P.A.N., Niemela, O., Arola, J., Orho-Melander, M., Hakkarainen, A., and Kovanen, P.T. (2020). Hydroxysteroid 17-beta dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight, 5.","DOI":"10.1172\/jci.insight.132158"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stickel, F., Lutz, P., Buch, S., Nischalke, H.D., Silva, I., Rausch, V., Fischer, J., Weiss, K.H., Gotthardt, D., and Rosendahl, J. (2019). Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology.","DOI":"10.1016\/S0618-8278(19)30195-1"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.hbpd.2018.04.006","article-title":"17-beta-hydroxysteroid dehydrogenase 13 inhibits the progression and recurrence of hepatocellular carcinoma","volume":"17","author":"Chen","year":"2018","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Gellert-Kristensen, H., Richardson, T.G., Davey Smith, G., Nordestgaard, B.G., Tybjaerg-Hansen, A., and Stender, S. (2020). Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population. Hepatology.","DOI":"10.1016\/j.atherosclerosis.2021.06.120"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng1089","article-title":"Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals","volume":"33","author":"Jaenisch","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/bs.pmbts.2016.02.002","article-title":"Epigenetics of Obesity","volume":"140","author":"Lopomo","year":"2016","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1053\/j.gastro.2013.07.047","article-title":"Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease","volume":"145","author":"Murphy","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1152\/physrev.00047.2011","article-title":"S-adenosylmethionine in liver health, injury, and cancer","volume":"92","author":"Lu","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.molmet.2014.04.010","article-title":"Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels","volume":"3","author":"Dahlhoff","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/hep.22990","article-title":"S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model","volume":"50","author":"Lu","year":"2009","journal-title":"Hepatology"},{"key":"ref_54","first-page":"1191","article-title":"Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice","volume":"47","author":"Ariz","year":"2008","journal-title":"Hepatology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1053\/j.gastro.2012.05.050","article-title":"Hepatoma cells from mice deficient in glycine N-methyltransferase have increased RAS signaling and activation of liver kinase B1","volume":"143","author":"Gutierrez","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1096\/fj.02-0078fje","article-title":"Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A","volume":"16","author":"Corrales","year":"2002","journal-title":"FASEB J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1002\/hep.24607","article-title":"Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice","volume":"54","author":"Cano","year":"2011","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0168-8278(00)80122-1","article-title":"Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma","volume":"33","author":"Avila","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1002\/hep.23919","article-title":"Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice","volume":"52","author":"Ko","year":"2010","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"36258","DOI":"10.1074\/jbc.M111.265348","article-title":"Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas","volume":"286","author":"Teng","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3389\/fgene.2019.00486","article-title":"Gene Expression and DNA Methylation Alterations During Non-alcoholic Steatohepatitis-Associated Liver Carcinogenesis","volume":"10","author":"Dreval","year":"2019","journal-title":"Front. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/nrm1761","article-title":"The diverse functions of histone lysine methylation","volume":"6","author":"Martin","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/nrm3758","article-title":"Molecular mechanisms of epithelial-mesenchymal transition","volume":"15","author":"Lamouille","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Liu, Y., Lin, H., Jiang, L., Shang, Q., Yin, L., Lin, J.D., Wu, W.S., and Rui, L. (2020). Hepatic Slug epigenetically promotes liver lipogenesis, fatty liver disease, and type 2 diabetes. J. Clin. Investig.","DOI":"10.1172\/JCI128073"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cell.2012.06.013","article-title":"Cancer epigenetics: From mechanism to therapy","volume":"150","author":"Dawson","year":"2012","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1158\/0008-5472.CAN-14-3786","article-title":"Histone Deacetylase HDAC8 Promotes Insulin Resistance and beta-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma","volume":"75","author":"Tian","year":"2015","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/nm.2744","article-title":"Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration","volume":"18","author":"Sun","year":"2012","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1158\/0008-5472.CAN-18-3767","article-title":"HDAC3 Deficiency Promotes Liver Cancer through a Defect in H3K9ac\/H3K9me3 Transition","volume":"79","author":"Ji","year":"2019","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.cmet.2009.02.006","article-title":"Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation","volume":"9","author":"Purushotham","year":"2009","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"9793","DOI":"10.1073\/pnas.0802917105","article-title":"Sirt1 protects against high-fat diet-induced metabolic damage","volume":"105","author":"Pfluger","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/ncomms1001","article-title":"Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer","volume":"1","author":"Herranz","year":"2010","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cmet.2019.06.017","article-title":"Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism","volume":"30","author":"Takeishi","year":"2019","journal-title":"Cell Metab."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Liu, X., Liu, J., Xiao, W., Zeng, Q., Bo, H., Zhu, Y., Gong, L., He, D., Xing, X., and Li, R. (2020). SIRT1 regulates N(6) -methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation. Hepatology.","DOI":"10.1002\/hep.31222"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"852","DOI":"10.7150\/ijbs.19370","article-title":"Emerging roles of SIRT1 in fatty liver diseases","volume":"13","author":"Ding","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cmet.2010.06.009","article-title":"Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis","volume":"12","author":"Kim","year":"2010","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1096\/fj.201700098RR","article-title":"Hepatocyte-specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up-regulation of Bach1, an Nrf2 repressor","volume":"31","author":"Ka","year":"2017","journal-title":"FASEB J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1002\/hep.26413","article-title":"Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients","volume":"58","author":"Marquardt","year":"2013","journal-title":"Hepatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/s41589-018-0150-0","article-title":"Identification of a cellularly active SIRT6 allosteric activator","volume":"14","author":"Huang","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.cell.2019.10.017","article-title":"The Role of Non-coding RNAs in Oncology","volume":"179","author":"Slack","year":"2019","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"88517","DOI":"10.18632\/oncotarget.19774","article-title":"MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis","volume":"8","author":"Ortega","year":"2017","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1158\/0008-5472.CAN-06-4607","article-title":"Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma","volume":"67","author":"Gramantieri","year":"2007","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1172\/JCI63539","article-title":"Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver","volume":"122","author":"Hsu","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1172\/JCI63455","article-title":"MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis","volume":"122","author":"Tsai","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1038\/s41467-018-07786-7","article-title":"miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression","volume":"9","author":"Valdmanis","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.molcel.2017.06.025","article-title":"Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer","volume":"67","author":"Luna","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/mt.2011.265","article-title":"Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells","volume":"20","author":"Fu","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1053\/j.gastro.2007.05.022","article-title":"MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer","volume":"133","author":"Meng","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1136\/gutjnl-2014-308430","article-title":"MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway","volume":"65","author":"Wu","year":"2016","journal-title":"Gut"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1073\/pnas.0907904107","article-title":"miR-221 overexpression contributes to liver tumorigenesis","volume":"107","author":"Pineau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ebiom.2018.09.051","article-title":"Targeting hepatic miR-221\/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice","volume":"37","author":"Jiang","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1158\/0008-5472.CAN-11-1144","article-title":"miR-221 silencing blocks hepatocellular carcinoma and promotes survival","volume":"71","author":"Park","year":"2011","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1158\/1078-0432.CCR-09-0092","article-title":"MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality","volume":"15","author":"Gramantieri","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5651","DOI":"10.1038\/onc.2008.178","article-title":"MiR-221 controls CDKN1C\/p57 and CDKN1B\/p27 expression in human hepatocellular carcinoma","volume":"27","author":"Fornari","year":"2008","journal-title":"Oncogene"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.jhep.2015.03.019","article-title":"MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer","volume":"63","author":"Bae","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_95","first-page":"36","article-title":"Non-Coding RNAs in Primary Liver Cancer","volume":"2","author":"Ghidini","year":"2015","journal-title":"Front. Med. (Lausanne)"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrgastro.2017.169","article-title":"Non-coding RNAs in hepatocellular carcinoma: Molecular functions and pathological implications","volume":"15","author":"Wong","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12967-020-02225-y","article-title":"Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2\/AKT pathway","volume":"18","author":"Chi","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1002\/iub.2137","article-title":"Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization","volume":"71","author":"Wang","year":"2019","journal-title":"IUBMB Life"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12943-018-0838-5","article-title":"Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation","volume":"17","author":"Liu","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1158\/0008-5472.CAN-14-1192","article-title":"Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway","volume":"75","author":"Cui","year":"2015","journal-title":"Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1053\/j.gastro.2006.08.026","article-title":"Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA","volume":"132","author":"Panzitt","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/hep4.1184","article-title":"Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune-mediated liver damage","volume":"2","author":"Sookoian","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1158\/0008-5472.CAN-16-1508","article-title":"Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation","volume":"77","author":"Malakar","year":"2017","journal-title":"Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"22640","DOI":"10.1038\/srep22640","article-title":"Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability","volume":"6","author":"Yan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1002\/hep.20920","article-title":"Insulin resistance: A metabolic pathway to chronic liver disease","volume":"42","author":"Bugianesi","year":"2005","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1053\/j.gastro.2007.03.059","article-title":"Obesity, inflammation, and insulin resistance","volume":"132","author":"Shoelson","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.molmet.2019.12.014","article-title":"Mechanisms of insulin resistance related to white, beige, and brown adipocytes","volume":"34","author":"Czech","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1172\/JCI29069","article-title":"Inflammation and insulin resistance","volume":"116","author":"Shoelson","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9047","DOI":"10.1074\/jbc.275.12.9047","article-title":"The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)","volume":"275","author":"Aguirre","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1126\/science.1227568","article-title":"JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation","volume":"339","author":"Han","year":"2013","journal-title":"Science"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/nrc3610","article-title":"The microbiome and cancer","volume":"13","author":"Schwabe","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jhep.2019.08.016","article-title":"Gut microbiome in HCC\u2014Mechanisms, diagnosis and therapy","volume":"72","author":"Schwabe","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1097\/MOG.0000000000000349","article-title":"Intestinal microbiota and nonalcoholic steatohepatitis","volume":"33","author":"Brandl","year":"2017","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10809","article-title":"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/hep.28356","article-title":"The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota","volume":"63","author":"Boursier","year":"2016","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/hep.26093","article-title":"Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH","volume":"57","author":"Zhu","year":"2013","journal-title":"Hepatology"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/hep.30036","article-title":"Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease","volume":"69","author":"Ponziani","year":"2019","journal-title":"Hepatology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nature12347","article-title":"Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome","volume":"499","author":"Yoshimoto","year":"2013","journal-title":"Nature"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1158\/2159-8290.CD-16-0932","article-title":"Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity","volume":"7","author":"Loo","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.ccr.2012.02.007","article-title":"Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4","volume":"21","author":"Dapito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1002\/hep.23845","article-title":"Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents","volume":"52","author":"Yu","year":"2010","journal-title":"Hepatology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/CCO.0000000000000042","article-title":"Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer","volume":"26","author":"Lade","year":"2014","journal-title":"Curr. Opin. Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1158\/0008-5472.CAN-06-1078","article-title":"Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor","volume":"67","author":"Yang","year":"2007","journal-title":"Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/S0092-8674(00)00062-3","article-title":"Targeted disruption of the nuclear receptor FXR\/BAR impairs bile acid and lipid homeostasis","volume":"102","author":"Sinal","year":"2000","journal-title":"Cell"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1136\/gutjnl-2015-310283","article-title":"Microbiota-induced obesity requires farnesoid X receptor","volume":"66","author":"Parseus","year":"2017","journal-title":"Gut"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/gutjnl-2012-303150","article-title":"Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice","volume":"63","author":"Lu","year":"2014","journal-title":"Gut"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S0140-6736(14)61933-4","article-title":"Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial","volume":"385","author":"Loomba","year":"2015","journal-title":"Lancet"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cell.2009.12.052","article-title":"Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression","volume":"140","author":"Park","year":"2010","journal-title":"Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2010.12.008","article-title":"NF-kappaB, inflammation, and metabolic disease","volume":"13","author":"Baker","year":"2011","journal-title":"Cell Metab."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.cell.2005.04.014","article-title":"IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis","volume":"121","author":"Maeda","year":"2005","journal-title":"Cell"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.ccr.2006.12.016","article-title":"Deletion of NEMO\/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma","volume":"11","author":"Luedde","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/hep.24341","article-title":"Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells","volume":"54","author":"Csak","year":"2011","journal-title":"Hepatology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"15324","DOI":"10.1073\/pnas.1100255108","article-title":"Inflammasome is a central player in the induction of obesity and insulin resistance","volume":"108","author":"Stienstra","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.jhep.2017.01.022","article-title":"NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice","volume":"66","author":"Mridha","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.ccell.2014.09.003","article-title":"Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes","volume":"26","author":"Wolf","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1126\/science.1137221","article-title":"Lymphotoxin beta receptor-dependent control of lipid homeostasis","volume":"316","author":"Lo","year":"2007","journal-title":"Science"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nature24302","article-title":"Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity","volume":"551","author":"Shalapour","year":"2017","journal-title":"Nature"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nature16969","article-title":"NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis","volume":"531","author":"Ma","year":"2016","journal-title":"Nature"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.jhep.2016.05.005","article-title":"A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer","volume":"65","author":"Asgharpour","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.tranon.2019.04.021","article-title":"The role of natural killer cells in hepatocellular carcinoma development and treatment: A narrative review","volume":"12","author":"Juengpanich","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.3389\/fimmu.2019.01255","article-title":"Retained NK Cell Phenotype and Functionality in Non-alcoholic Fatty Liver Disease","volume":"10","author":"Stiglund","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1002\/cncr.11266","article-title":"Expression and prognostic role of tumor suppressor gene PTEN\/MMAC1\/TEP1 in hepatocellular carcinoma","volume":"97","author":"Hu","year":"2003","journal-title":"Cancer"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1172\/JCI20513","article-title":"Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas","volume":"113","author":"Horie","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1002\/hep.22737","article-title":"Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes","volume":"49","author":"Vinciguerra","year":"2009","journal-title":"Hepatology"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1053\/j.gastro.2007.10.010","article-title":"PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65\/mTOR-dependent mechanism","volume":"134","author":"Vinciguerra","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cmet.2009.10.004","article-title":"Akt2 is required for hepatic lipid accumulation in models of insulin resistance","volume":"10","author":"Leavens","year":"2009","journal-title":"Cell Metab."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.jhep.2011.03.025","article-title":"Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway","volume":"55","author":"Kudo","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/ijo.2008.116","article-title":"AMPK: A key regulator of energy balance in the single cell and the whole organism","volume":"32","author":"Hardie","year":"2008","journal-title":"Int. J. Obes. (Lond.)"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1016\/j.celrep.2017.03.011","article-title":"Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet","volume":"18","author":"Woods","year":"2017","journal-title":"Cell Rep."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"25226","DOI":"10.1074\/jbc.M202489200","article-title":"The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways","volume":"277","author":"Fryer","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nature07976","article-title":"Autophagy regulates lipid metabolism","volume":"458","author":"Singh","year":"2009","journal-title":"Nature"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1101\/gad.2016211","article-title":"Autophagy-deficient mice develop multiple liver tumors","volume":"25","author":"Takamura","year":"2011","journal-title":"Genes Dev."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.molcel.2013.08.003","article-title":"Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy","volume":"51","author":"Ichimura","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1365-2443.2010.01473.x","article-title":"Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution","volume":"16","author":"Taguchi","year":"2011","journal-title":"Genes Cells"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/ng.2256","article-title":"Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma","volume":"44","author":"Guichard","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/hep.26616","article-title":"MicroRNA\/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC)","volume":"59","author":"Petrelli","year":"2014","journal-title":"Hepatology"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2015.5370","article-title":"Nonalcoholic fatty liver disease: A systematic review","volume":"313","author":"Rinella","year":"2015","journal-title":"JAMA"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1002\/hep.25762","article-title":"The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association","volume":"55","author":"Chalasani","year":"2012","journal-title":"Hepatology"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrgastro.2013.183","article-title":"NAFLD, NASH and liver cancer","volume":"10","author":"Michelotti","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/hep.27545","article-title":"Liver cancer biopsy\u2014Back to the future?","volume":"61","author":"Torbenson","year":"2015","journal-title":"Hepatology"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1053\/j.gastro.2005.03.084","article-title":"Sampling variability of liver biopsy in nonalcoholic fatty liver disease","volume":"128","author":"Ratziu","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/gast.2002.35354","article-title":"The utility of radiological imaging in nonalcoholic fatty liver disease","volume":"123","author":"Saadeh","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.cgh.2014.11.027","article-title":"Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique","volume":"13","author":"Lin","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.cld.2012.05.001","article-title":"Can NASH be diagnosed, graded, and staged noninvasively?","volume":"16","author":"Grandison","year":"2012","journal-title":"Clin. Liver Dis."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease","volume":"7","author":"Shah","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/hep.21984","article-title":"Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers","volume":"47","author":"Guha","year":"2008","journal-title":"Hepatology"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jhep.2016.04.014","article-title":"Imagestream detection and characterisation of circulating tumour cells\u2014A liquid biopsy for hepatocellular carcinoma?","volume":"65","author":"Ogle","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1002\/hep.26151","article-title":"Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection","volume":"57","author":"Sun","year":"2013","journal-title":"Hepatology"},{"key":"ref_171","doi-asserted-by":"crossref","unstructured":"Li, J., Chen, L., Zhang, X., Zhang, Y., Liu, H., Sun, B., Zhao, L., Ge, N., Qian, H., and Yang, Y. (2014). Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096185"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1158\/1078-0432.CCR-17-1063","article-title":"Circulating Tumor Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma","volume":"24","author":"Sun","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.18632\/oncotarget.6104","article-title":"pERK\/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1053\/j.gastro.2017.01.015","article-title":"Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis","volume":"152","author":"Alonso","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1194\/jlr.P056002","article-title":"Biomarkers of NAFLD progression: A lipidomics approach to an epidemic","volume":"56","author":"Gorden","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_176","first-page":"751","article-title":"Overview of the Updated AASLD Guidelines for the Management of HCC","volume":"13","author":"Heimbach","year":"2017","journal-title":"Gastroenterol. Hepatol. (N. Y.)"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1056\/NEJMoa1717002","article-title":"Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma","volume":"379","author":"Meyer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/S1470-2045(18)30146-3","article-title":"Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): A final analysis of a phase 3, randomised, placebo-controlled study","volume":"19","author":"Rimassa","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/S1470-2045(18)30937-9","article-title":"Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Zhu","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s11605-018-4004-6","article-title":"Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis","volume":"23","author":"Li","year":"2019","journal-title":"J. Gastrointest. Surg."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"E987","DOI":"10.1152\/ajpendo.00133.2013","article-title":"Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl\/6 mice","volume":"305","author":"Tajima","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1111\/liv.14048","article-title":"Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma","volume":"39","author":"Schulte","year":"2019","journal-title":"Liver Int."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/apt.12352","article-title":"Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis","volume":"38","author":"Hoofnagle","year":"2013","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1053\/j.gastro.2012.10.005","article-title":"Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis","volume":"144","author":"Singh","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.metabol.2017.02.014","article-title":"The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease\/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement","volume":"71","author":"Athyros","year":"2017","journal-title":"Metabolism"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.3748\/wjg.v25.i24.2977","article-title":"Immunotherapy for hepatocellular carcinoma: Current and future","volume":"25","author":"Johnston","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1\/2 dose escalation and expansion trial","volume":"389","author":"Sangro","year":"2017","journal-title":"Lancet"},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Li, D., Li, N., Zhang, Y.F., Fu, H., Feng, M., Schneider, D., Su, L., Wu, X., Zhou, J., and Mackay, S. (2020). Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice. Gastroenterology.","DOI":"10.1053\/j.gastro.2020.02.011"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1136\/gutjnl-2011-301708","article-title":"Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: Population-based and in vitro studies","volume":"62","author":"Chen","year":"2013","journal-title":"Gut"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1158\/1940-6207.CAPR-11-0228","article-title":"Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis","volume":"5","author":"Bhalla","year":"2012","journal-title":"Cancer Prev. Res. (Phila)"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jhep.2015.08.028","article-title":"Hepatocellular carcinoma and lifestyles","volume":"64","author":"Saran","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1053\/j.gastro.2015.04.005","article-title":"Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis","volume":"149","author":"Friedman","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jhep.2013.02.012","article-title":"The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease","volume":"59","author":"Ryan","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.jhep.2008.09.011","article-title":"Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis","volume":"50","author":"Sorrentino","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/hep.27774","article-title":"Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis","volume":"62","author":"Hoki","year":"2015","journal-title":"Hepatology"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1136\/gut.2008.151977","article-title":"High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease","volume":"58","author":"Kantartzis","year":"2009","journal-title":"Gut"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/nrc.2017.78","article-title":"Exercise-dependent regulation of the tumour microenvironment","volume":"17","author":"Koelwyn","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.jhep.2015.01.017","article-title":"Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis","volume":"62","author":"Piguet","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/hep.29230","article-title":"A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)","volume":"66","author":"Srivastava","year":"2017","journal-title":"Hepatology"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1021\/acs.bioconjchem.5b00254","article-title":"Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)","volume":"26","author":"Rajasekaran","year":"2015","journal-title":"Bioconjug. Chem."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/5\/1290\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:30:36Z","timestamp":1760175036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/5\/1290"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,20]]},"references-count":203,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["cancers12051290"],"URL":"https:\/\/doi.org\/10.3390\/cancers12051290","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,20]]}}}