{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:38:30Z","timestamp":1792611510062,"version":"4.5.0"},"reference-count":186,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T00:00:00Z","timestamp":1548720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2016R1A2B4013891"],"award-info":[{"award-number":["2016R1A2B4013891"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for HCC. A fibrotic liver typically shows persistent hepatocyte death and compensatory regeneration, chronic inflammation, and an increase in reactive oxygen species, which collaboratively create a tumor-promoting microenvironment via inducing genetic alterations and chromosomal instability, and activating various oncogenic molecular signaling pathways. In this article, we review recent advances in fields of liver fibrosis and carcinogenesis, and consider several molecular signaling pathways that promote hepato-carcinogenesis under the microenvironment of liver fibrosis. In particular, we pay attention to emerging roles of the Hippo-YAP\/TAZ signaling pathway in stromal activation, hepatic fibrosis, and liver cancer.<\/jats:p>","DOI":"10.3390\/ijms20030581","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T11:27:52Z","timestamp":1548761272000},"page":"581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP\/TAZ Signaling Pathway"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6252-2571","authenticated-orcid":false,"given":"Hyuk","family":"Moon","sequence":"first","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Brain Korea 21 Project for Medical Science College of Medicine, Yonsei University, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungjoo","family":"Cho","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Brain Korea 21 Project for Medical Science College of Medicine, Yonsei University, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunyeong","family":"Shin","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Brain Korea 21 Project for Medical Science College of Medicine, Yonsei University, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang-Hyub","family":"Han","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon Weonsang","family":"Ro","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,29]]},"reference":[{"key":"ref_1","first-page":"141","article-title":"Update in global trends and aetiology of hepatocellular carcinoma","volume":"22","author":"Rawla","year":"2018","journal-title":"Contemp. Oncol. (Pozn. Pol.)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","author":"Llovet","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Hepatocellular carcinoma","volume":"365","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1053\/j.gastro.2004.09.014","article-title":"Hepatocellular carcinoma in cirrhosis: Incidence and risk factors","volume":"127","author":"Fattovich","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chung, S.I., Moon, H., Kim, D.Y., Cho, K.J., Ju, H.L., Kim, D.Y., Ahn, S.H., Han, K.H., and Ro, S.W. (2016). Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background. BMC Gastroenterol., 16.","DOI":"10.1186\/s12876-016-0423-6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.jhep.2015.10.007","article-title":"Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model","volume":"64","author":"Chung","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_7","first-page":"5","article-title":"Hepatic fibrogenesis: The puzzle of interacting cells, fibrogenic cytokines, regulatory loops, and extracellular matrix molecules","volume":"30","author":"Gressner","year":"1992","journal-title":"Zeitschrift fur Gastroenterologie"},{"key":"ref_8","first-page":"15","article-title":"[Fibrogenesis and fibrolysis in the liver]","volume":"79","author":"Herbst","year":"1995","journal-title":"Verhandlungen der Deutschen Gesellschaft fur Pathologie"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000122594","article-title":"New diagnostic method for liver fibrosis and cirrhosis","volume":"51","author":"Han","year":"2008","journal-title":"Intervirology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s10495-005-1055-4","article-title":"The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis","volume":"10","author":"Elsharkawy","year":"2005","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Baiocchini, A., Montaldo, C., Conigliaro, A., Grimaldi, A., Correani, V., Mura, F., Ciccosanti, F., Rotiroti, N., Brenna, A., and Montalbano, M. (2016). Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151736"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_13","first-page":"75","article-title":"Mechanisms of hepatic fibrosis","volume":"27","author":"Benyon","year":"1998","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/path.1711700203","article-title":"Cellular and molecular aspects of hepatic fibrosis","volume":"170","author":"Burt","year":"1993","journal-title":"J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7260","DOI":"10.3748\/wjg.v20.i23.7260","article-title":"Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update","volume":"20","author":"Elpek","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_16","first-page":"863","article-title":"Lipoproteins and the liver sieve: The role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis","volume":"21","author":"Fraser","year":"1995","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1053\/j.gastro.2011.11.004","article-title":"Lipids in liver disease: Looking beyond steatosis","volume":"142","author":"Schwabe","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s12565-017-0395-9","article-title":"The stellate cell system (vitamin A-storing cell system)","volume":"92","author":"Senoo","year":"2017","journal-title":"Anat. Sci. Int."},{"key":"ref_19","first-page":"79","article-title":"Hepatic stellate cells\u2014From the viewpoint of retinoid handling and function of the extracellular matrix","volume":"72","author":"Senoo","year":"1997","journal-title":"Kaibogaku Zasshi J. Anat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"G950","DOI":"10.1152\/ajpgi.00132.2011","article-title":"The extracellular matrix: An active or passive player in fibrosis?","volume":"301","author":"Wight","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1146\/annurev.cb.07.110191.003311","article-title":"Mechanisms and functions of cell death","volume":"7","author":"Ellis","year":"1991","journal-title":"Annu. Rev. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7312","DOI":"10.3748\/wjg.v20.i23.7312","article-title":"Pathogenesis of liver cirrhosis","volume":"20","author":"Zhou","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bbrc.2011.02.009","article-title":"Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation","volume":"407","author":"Fowell","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1016\/j.clinre.2015.06.015","article-title":"Reversibility of liver fibrosis","volume":"39","author":"Sun","year":"2015","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.yexcr.2017.02.038","article-title":"Modulation of hepatic stellate cells and reversibility of hepatic fibrosis","volume":"352","author":"Huang","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2353\/ajpath.2010.090675","article-title":"Liver regeneration after partial hepatectomy: Critical analysis of mechanistic dilemmas","volume":"176","author":"Michalopoulos","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jhep.2018.05.008","article-title":"Liver regeneration requires Yap1-TGFbeta-dependent epithelial-mesenchymal transition in hepatocytes","volume":"69","author":"Oh","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: Mechanisms and clinical relevance","volume":"147","author":"Luedde","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1126\/science.aad7363","article-title":"Understanding the origins of human cancer","volume":"350","author":"Alexandrov","year":"2015","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nm1087","article-title":"Cancer genes and the pathways they control","volume":"10","author":"Vogelstein","year":"2004","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/cbf.891","article-title":"Telomerase activity is repressed during differentiation along the hepatocytic and biliary epithelial lineages: Verification on immortal cell lines from the same origin","volume":"19","author":"Fukutomi","year":"2001","journal-title":"Cell Biochem. Funct."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.tibs.2013.07.001","article-title":"Telomerase: Central regulator of all of the hallmarks of cancer","volume":"38","author":"Low","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1093\/hmg\/10.7.677","article-title":"Telomerase and cancer","volume":"10","author":"Shay","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/hep.20308","article-title":"Telomeres and telomerase: A dual role in hepatocarcinogenesis","volume":"40","author":"Satyanarayana","year":"2004","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5009\/gnl18081","article-title":"Relationship between Telomere Maintenance and Liver Disease","volume":"13","author":"Barnard","year":"2018","journal-title":"Gut Liver"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2253","DOI":"10.1038\/cddis.2016.105","article-title":"ROS homeostasis and metabolism: A dangerous liason in cancer cells","volume":"7","author":"Panieri","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3164\/jcbn.17-90","article-title":"Abundance of DNA adducts of 4-oxo-2-alkenals, lipid peroxidation-derived highly reactive genotoxins","volume":"62","author":"Kawai","year":"2018","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.redox.2016.12.011","article-title":"Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles","volume":"11","author":"Morry","year":"2017","journal-title":"Redox Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.celrep.2016.03.011","article-title":"p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication","volume":"15","author":"Yeo","year":"2016","journal-title":"Cell Rep."},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1002\/hep.23747","article-title":"Conditional beta-catenin loss in mice promotes chemical hepatocarcinogenesis: Role of oxidative stress and platelet-derived growth factor receptor alpha\/phosphoinositide 3-kinase signaling","volume":"52","author":"Zhang","year":"2010","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev-pathol-052016-100322","article-title":"The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer","volume":"12","author":"Affo","year":"2017","journal-title":"Annu. Rev. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrc3803","article-title":"Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles\u2019 heel?","volume":"14","author":"Sabharwal","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/prca.201600028","article-title":"Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine","volume":"10","author":"Schrodl","year":"2016","journal-title":"Proteomics Clin. Appl."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/cei.12952","article-title":"Production of complement components by cells of the immune system","volume":"188","author":"Lubbers","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/imr.12464","article-title":"Innate immune mediators in cancer: Between defense and resistance","volume":"274","author":"Berraondo","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1146\/annurev.immunol.021908.132629","article-title":"The liver as a lymphoid organ","volume":"27","author":"Crispe","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00281-009-0173-4","article-title":"Microanatomy of the liver immune system","volume":"31","author":"Nemeth","year":"2009","journal-title":"Semin. Immunopathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/S0167-5699(99)01518-2","article-title":"Prometheus through the looking glass: Reflections on the hepatic immune system","volume":"20","author":"Crispe","year":"1999","journal-title":"Immunol. Today"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/cmi.2016.3","article-title":"Liver immunology and its role in inflammation and homeostasis","volume":"13","author":"Robinson","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1016\/j.cell.2018.11.012","article-title":"Inflammatory Cytokine TNFalpha Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture","volume":"175","author":"Peng","year":"2018","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.autrev.2018.06.016","article-title":"Liver-associated immune abnormalities","volume":"18","author":"Grunebaum","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.media.2007.06.010","article-title":"The mechanical response of human liver and its relation to histology: An in vivo study","volume":"11","author":"Mazza","year":"2007","journal-title":"Med. Image Anal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.18632\/oncotarget.12101","article-title":"Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e1751","DOI":"10.1038\/cddis.2015.120","article-title":"Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1\/JNK pathway","volume":"6","author":"Zhao","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.3748\/wjg.v23.i24.4330","article-title":"Implication of the Hedgehog pathway in hepatocellular carcinoma","volume":"23","author":"Viscardi","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"86985","DOI":"10.18632\/oncotarget.13521","article-title":"Hepatocyte specific expression of an oncogenic variant of beta-catenin results in cholestatic liver disease","volume":"7","author":"Lemberger","year":"2016","journal-title":"Oncotarget"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/hep.27332","article-title":"Hepatic inflammation and fibrosis: Functional links and key pathways","volume":"61","author":"Seki","year":"2015","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"187204","DOI":"10.1155\/2013\/187204","article-title":"The inflammatory microenvironment in hepatocellular carcinoma: A pivotal role for tumor-associated macrophages","volume":"2013","author":"Capece","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1053\/j.gastro.2009.06.045","article-title":"c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice","volume":"137","author":"Kodama","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1053\/j.gastro.2010.03.008","article-title":"Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner","volume":"138","author":"Lin","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.20031675","article-title":"SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis","volume":"199","author":"Yoshida","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature04870","article-title":"Nuclear factor-kappaB in cancer development and progression","volume":"441","author":"Karin","year":"2006","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1078\/0171-9335-00182","article-title":"The bcl, NFkappaB and p53\/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells","volume":"80","author":"Saile","year":"2001","journal-title":"Eur. J. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6421","DOI":"10.1074\/jbc.275.9.6421","article-title":"NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis","volume":"275","author":"Kuhnel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6853","DOI":"10.1038\/sj.onc.1203239","article-title":"Activators and target genes of Rel\/NF-kappaB transcription factors","volume":"18","author":"Pahl","year":"1999","journal-title":"Oncogene"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.18.1.621","article-title":"Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity","volume":"18","author":"Karin","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.cellbio.21.122303.115827","article-title":"Recognition and signaling by toll-like receptors","volume":"22","author":"West","year":"2006","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1002\/hep.23795","article-title":"CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice","volume":"52","author":"Aoyama","year":"2010","journal-title":"Hepatology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2174\/157488707781662715","article-title":"Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma","volume":"2","author":"Calvisi","year":"2007","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrgastro.2010.213","article-title":"NF-kappaB in the liver\u2014Linking injury, fibrosis and hepatocellular carcinoma","volume":"8","author":"Luedde","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"G583","DOI":"10.1152\/ajpgi.00422.2005","article-title":"Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: Role of IKK, JNK, and ROS pathways","volume":"290","author":"Schwabe","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1159\/000343852","article-title":"From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence","volume":"2","author":"Ramakrishna","year":"2013","journal-title":"Liver Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature02924","article-title":"NF-kappaB functions as a tumour promoter in inflammation-associated cancer","volume":"431","author":"Pikarsky","year":"2004","journal-title":"Nature"},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1084\/jem.193.4.417","article-title":"IkappaB kinase alpha is essential for mature B cell development and function","volume":"193","author":"Kaisho","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1002\/1097-0142(20001201)89:11<2274::AID-CNCR16>3.0.CO;2-2","article-title":"Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma","volume":"89","author":"Tai","year":"2000","journal-title":"Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/cr.2010.183","article-title":"NF-kappaB and STAT3\u2014Key players in liver inflammation and cancer","volume":"21","author":"He","year":"2011","journal-title":"Cell Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1126\/science.1083901","article-title":"Hexameric structure and assembly of the interleukin-6\/IL-6 alpha-receptor\/gp130 complex","volume":"300","author":"Boulanger","year":"2003","journal-title":"Science"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"23286","DOI":"10.1016\/S0021-9258(17)31651-4","article-title":"High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130","volume":"269","author":"Ward","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrc1275","article-title":"The STATs of cancer\u2014New molecular targets come of age","volume":"4","author":"Yu","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nri1995","article-title":"Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment","volume":"7","author":"Yu","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1074-7613(00)80011-4","article-title":"Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells","volume":"10","author":"Landowski","year":"1999","journal-title":"Immunity"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2217\/hep.13.7","article-title":"STAT3 in hepatocellular carcinoma: New perspectives","volume":"1","author":"Svinka","year":"2014","journal-title":"Hepatic Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.jhep.2016.02.004","article-title":"IL-6 pathway in the liver: From physiopathology to therapy","volume":"64","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Takahashi, Y. (2017). The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071447"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Adamek, A., and Kasprzak, A. (2018). Insulin-Like Growth Factor (IGF) System in Liver Diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051308"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.bbrc.2012.05.115","article-title":"GH-independent IGF-I action is essential to prevent the development of nonalcoholic steatohepatitis in a GH-deficient rat model","volume":"423","author":"Nishizawa","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"34605","DOI":"10.1038\/srep34605","article-title":"IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner","volume":"6","author":"Nishizawa","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1136\/gut.2003.024505","article-title":"Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury","volume":"54","author":"Sanz","year":"2005","journal-title":"Gut"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"10137","DOI":"10.3748\/wjg.v21.i35.10137","article-title":"IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation","volume":"21","author":"Lei","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.jhep.2017.09.016","article-title":"Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine","volume":"68","author":"Fujiwara","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/jcp.1041580118","article-title":"Actions of platelet-derived growth factor isoforms in mesangial cells","volume":"158","author":"Abboud","year":"1994","journal-title":"J. Cell. Physiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/hep.1840190323","article-title":"Expression of platelet-derived growth factor in a model of acute liver injury","volume":"19","author":"Pinzani","year":"1994","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1172\/JCI117497","article-title":"Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture","volume":"94","author":"Wong","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_97","first-page":"G947","article-title":"Retinol release by activated rat hepatic lipocytes: Regulation by Kupffer cell-conditioned medium and PDGF","volume":"264","author":"Friedman","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7879","DOI":"10.3892\/mmr.2017.7641","article-title":"PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review)","volume":"16","author":"Ying","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1359-6101(02)00090-4","article-title":"Novel PDGF family members: PDGF-C and PDGF-D","volume":"14","author":"Li","year":"2003","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1152\/physrev.1999.79.4.1283","article-title":"Mechanism of action and in vivo role of platelet-derived growth factor","volume":"79","author":"Heldin","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.4065\/81.9.1241","article-title":"Biology of platelet-derived growth factor and its involvement in disease","volume":"81","author":"Alvarez","year":"2006","journal-title":"Mayo Clin. Proc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1073\/pnas.0409722102","article-title":"Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma","volume":"102","author":"Campbell","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/ijc.25469","article-title":"Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis","volume":"128","author":"Maass","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1053\/j.gastro.2006.09.014","article-title":"A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis","volume":"131","author":"Llovet","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1158\/1535-7163.MCT-06-0720","article-title":"Platelet-derived growth factor receptor-alpha: A novel therapeutic target in human hepatocellular cancer","volume":"6","author":"Stock","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.devcel.2008.11.010","article-title":"Hedgehog signaling in development and cancer","volume":"15","author":"Jiang","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nrm1622","article-title":"Communicating with Hedgehogs","volume":"6","author":"Hooper","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jhep.2010.10.003","article-title":"Hedgehog signaling in the liver","volume":"54","author":"Omenetti","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/hep.25559","article-title":"Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease","volume":"55","author":"Guy","year":"2012","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/labinvest.3700537","article-title":"Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation","volume":"87","author":"Omenetti","year":"2007","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/hep.23998","article-title":"Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis","volume":"53","author":"Syn","year":"2011","journal-title":"Hepatology"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Philips, G.M., Chan, I.S., Swiderska, M., Schroder, V.T., Guy, C., Karaca, G.F., Moylan, C., Venkatraman, T., Feuerlein, S., and Syn, W.K. (2011). Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023943"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1053\/j.gastro.2012.07.115","article-title":"Hedgehog controls hepatic stellate cell fate by regulating metabolism","volume":"143","author":"Chen","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.biocel.2010.10.015","article-title":"The role of Hedgehog signaling in fibrogenic liver repair","volume":"43","author":"Choi","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1093\/carcin\/bgi292","article-title":"Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis","volume":"27","author":"Sicklick","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/hep.22649","article-title":"Blocking the hedgehog pathway inhibits hepatoblastoma growth","volume":"49","author":"Eichenmuller","year":"2009","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4161\/cbt.5.1.2379","article-title":"Hedgehog signaling in human hepatocellular carcinoma","volume":"5","author":"Patil","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/nrc1229","article-title":"Hedgehog signalling in cancer formation and maintenance","volume":"3","author":"Hebrok","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00441-001-0479-6","article-title":"Mechanisms of TGF-beta-mediated apoptosis","volume":"307","author":"Schuster","year":"2002","journal-title":"Cell Tissue Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0168-8278(99)80010-5","article-title":"The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo","volume":"30","author":"Hellerbrand","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1074\/jbc.275.4.2247","article-title":"Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury","volume":"275","author":"Friedman","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-beta: The master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/resp.13415","article-title":"TGF-beta: Master regulator of inflammation and fibrosis","volume":"23","author":"Stewart","year":"2018","journal-title":"Respirology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nrc1926","article-title":"Tumour microenvironment: TGFbeta: The molecular Jekyll and Hyde of cancer","volume":"6","author":"Bierie","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm3434","article-title":"TGFbeta signalling in context","volume":"13","author":"Massague","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.24653","article-title":"Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss","volume":"55","author":"Morris","year":"2012","journal-title":"Hepatology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"E71","DOI":"10.1073\/pnas.1517188113","article-title":"Dysregulated YAP1\/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a\/1b-deficient mice","volume":"113","author":"Nishio","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1053\/j.gastro.2013.01.056","article-title":"Transforming growth factor-beta signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1","volume":"144","author":"Yang","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1073\/pnas.1322731111","article-title":"Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis","volume":"111","author":"Nakagawa","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1053\/j.gastro.2017.07.014","article-title":"Transforming Growth Factor-beta Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail","volume":"153","author":"Moon","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1002\/hep.29606","article-title":"Barrier to autointegration factor 1, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3, and splicing factor 3b subunit 4 as early-stage cancer decision markers and drivers of hepatocellular carcinoma","volume":"67","author":"Shen","year":"2018","journal-title":"Hepatology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0083-6729(07)00009-X","article-title":"Vitamin K-dependent actions of Gas6","volume":"78","year":"2008","journal-title":"Vitam. Horm."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Holstein, E., Binder, M., and Mikulits, W. (2018). Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19124111"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"G899","DOI":"10.1152\/ajpgi.00382.2015","article-title":"TAM receptor tyrosine kinase function and the immunopathology of liver disease","volume":"310","author":"Mukherjee","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Qi, N., Liu, P., Zhang, Y., Wu, H., Chen, Y., and Han, D. (2013). Development of a spontaneous liver disease resembling autoimmune hepatitis in mice lacking tyro3, axl and mer receptor tyrosine kinases. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066604"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/hep.21237","article-title":"Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells","volume":"44","author":"Lafdil","year":"2006","journal-title":"Hepatology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.2217\/bmm-2016-0210","article-title":"Gas6 as a putative noninvasive biomarker of hepatic fibrosis","volume":"10","author":"Bellan","year":"2016","journal-title":"Biomark. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.jhep.2015.04.013","article-title":"Gas6\/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation","volume":"63","author":"Barcena","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e2700","DOI":"10.1038\/cddis.2017.113","article-title":"Molecular insights of Gas6\/TAM in cancer development and therapy","volume":"8","author":"Wu","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12943-018-0769-1","article-title":"Targeting Gas6\/TAM in cancer cells and tumor microenvironment","volume":"17","author":"Wu","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.devcel.2010.09.011","article-title":"The hippo signaling pathway in development and cancer","volume":"19","author":"Pan","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.devcel.2010.11.012","article-title":"The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway","volume":"19","author":"Varelas","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.devcel.2009.12.012","article-title":"Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded","volume":"18","author":"Yu","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.devcel.2010.06.015","article-title":"The Merlin\/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals","volume":"19","author":"Zhang","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrm.2017.87","article-title":"Mechanobiology of YAP and TAZ in physiology and disease","volume":"18","author":"Panciera","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nrd4161","article-title":"The two faces of Hippo: Targeting the Hippo pathway for regenerative medicine and cancer treatment","volume":"13","author":"Johnson","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.274027.115","article-title":"Mechanisms of Hippo pathway regulation","volume":"30","author":"Meng","year":"2016","journal-title":"Genes Dev."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.cub.2008.02.034","article-title":"SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila","volume":"18","author":"Goulev","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1101\/gad.1602907","article-title":"Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control","volume":"21","author":"Zhao","year":"2007","journal-title":"Genes Dev."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1101\/gad.197582.112","article-title":"Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs)","volume":"26","author":"Mo","year":"2012","journal-title":"Genes Dev."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"46","DOI":"10.15252\/emmm.201506089","article-title":"Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2","volume":"9","author":"Loforese","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"352ra108","DOI":"10.1126\/scitranslmed.aaf2304","article-title":"Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration","volume":"8","author":"Fan","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"G471","DOI":"10.1152\/ajpgi.00153.2017","article-title":"Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury","volume":"314","author":"Konishi","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"16017","DOI":"10.1038\/ncomms16017","article-title":"YAP determines the cell fate of injured mouse hepatocytes in vivo","volume":"8","author":"Miyamura","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.jhep.2015.04.011","article-title":"The Hippo pathway effector YAP controls mouse hepatic stellate cell activation","volume":"63","author":"Mannaerts","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"21387","DOI":"10.1038\/srep21387","article-title":"Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation","volume":"6","author":"Caliari","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1172\/JCI93557","article-title":"Extracellular matrix as a driver of progressive fibrosis","volume":"128","author":"Herrera","year":"2018","journal-title":"J. Clin. Investing."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"30029","DOI":"10.1038\/srep30029","article-title":"omega-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP\/TAZ degradation","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2016.09.016","article-title":"Hepatocyte TAZ\/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis","volume":"24","author":"Wang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.ccell.2016.05.005","article-title":"YAP\/TAZ at the Roots of Cancer","volume":"29","author":"Zanconato","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nrc3458","article-title":"The Hippo pathway and human cancer","volume":"13","author":"Harvey","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Moya, I.M., and Halder, G. (2018). Hippo-YAP\/TAZ signalling in organ regeneration and regenerative medicine. Nat. Rev. Mol. Cell Biol.","DOI":"10.1038\/s41580-018-0086-y"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/978-1-4939-8910-2_26","article-title":"The Hippo Signaling Pathway in Regenerative Medicine","volume":"1893","author":"Hong","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1002\/hep.24587","article-title":"Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor\/yes-associated protein-mediated activation","volume":"54","author":"Urtasun","year":"2011","journal-title":"Hepatology"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1128\/MCB.00064-09","article-title":"Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo","volume":"29","author":"Juric","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"840","DOI":"10.3892\/or.2012.2176","article-title":"Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma","volume":"29","author":"Huo","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"540","DOI":"10.5483\/BMBRep.2014.47.10.177","article-title":"Cross-talk between Wnt\/beta-catenin and Hippo signaling pathways: A brief review","volume":"47","author":"Kim","year":"2014","journal-title":"BMB Rep."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cell.2014.06.013","article-title":"YAP\/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response","volume":"158","author":"Azzolin","year":"2014","journal-title":"Cell"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/ncb2884","article-title":"A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway","volume":"16","author":"Mohseni","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"ra42","DOI":"10.1126\/scisignal.2005049","article-title":"Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma","volume":"7","author":"Zhang","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1038\/onc.2010.504","article-title":"AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma","volume":"30","author":"Xu","year":"2011","journal-title":"Oncogene"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.1038\/s41467-018-07394-5","article-title":"NUAK2 is a critical YAP target in liver cancer","volume":"9","author":"Yuan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1158\/0008-5472.CAN-12-3793","article-title":"YAP\/TEAD-mediated transcription controls cellular senescence","volume":"73","author":"Xie","year":"2013","journal-title":"Cancer Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"261365","DOI":"10.1155\/2014\/261365","article-title":"Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma","volume":"2014","author":"Han","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Kim, G.J., Kim, H., and Park, Y.N. (2013). Increased expression of Yes-associated protein 1 in hepatocellular carcinoma with stemness and combined hepatocellular-cholangiocarcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075449"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/cas.12587","article-title":"TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma","volume":"106","author":"Xiao","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1073\/pnas.0911427107","article-title":"Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver","volume":"107","author":"Lu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1073\/pnas.0911409107","article-title":"Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression","volume":"107","author":"Song","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.cell.2007.07.019","article-title":"Elucidation of a universal size-control mechanism in Drosophila and mammals","volume":"130","author":"Dong","year":"2007","journal-title":"Cell"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1002\/cncr.24495","article-title":"Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma","volume":"115","author":"Xu","year":"2009","journal-title":"Cancer"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/ncb2756","article-title":"Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts","volume":"15","author":"Calvo","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/s11684-013-0256-4","article-title":"Inflammation and liver tumorigenesis","volume":"7","author":"Sun","year":"2013","journal-title":"Front. Med."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1136\/gutjnl-2017-314061","article-title":"Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma","volume":"67","author":"Kim","year":"2018","journal-title":"Gut"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"eaaj1757","DOI":"10.1126\/scisignal.aaj1757","article-title":"The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors","volume":"11","author":"Hagenbeek","year":"2018","journal-title":"Sci. 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