{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:25:22Z","timestamp":1789986322391,"version":"4.0.1"},"reference-count":159,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T00:00:00Z","timestamp":1543881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2014-1099"],"award-info":[{"award-number":["2014-1099"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative\/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT\/\u03b2-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGF\u03b2, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis\/Caroli\u2019s disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.<\/jats:p>","DOI":"10.3390\/ijms19123875","type":"journal-article","created":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T11:56:18Z","timestamp":1543924578000},"page":"3875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9883-6882","authenticated-orcid":false,"given":"Stefania","family":"Cannito","sequence":"first","affiliation":[{"name":"Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3614-9320","authenticated-orcid":false,"given":"Chiara","family":"Milani","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0188-2626","authenticated-orcid":false,"given":"Andrea","family":"Cappon","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), Internal Medicine and Hepatology Unit, University of Padova, Via Giustiniani 2, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-5141","authenticated-orcid":false,"given":"Maurizio","family":"Parola","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Strazzabosco","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy"},{"name":"International Center for Digestive Health (ICDH), University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy"},{"name":"Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0899-7613","authenticated-orcid":false,"given":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy"},{"name":"International Center for Digestive Health (ICDH), University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy"},{"name":"Department of Molecular Medicine (DMM), University of Padova, via Gabelli 63, 35121 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mayocp.2015.03.017","article-title":"The cholangiopathies","volume":"90","author":"Lazaridis","year":"2015","journal-title":"Mayo Clin. Proc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1053\/j.gastro.2015.08.045","article-title":"Burden of gastrointestinal, liver, and pancreatic diseases in the united states","volume":"149","author":"Peery","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1053\/j.gastro.2004.08.006","article-title":"The cholangiopathies: Disorders of biliary epithelia","volume":"127","author":"Lazaridis","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"G102","DOI":"10.1152\/ajpgi.00452.2016","article-title":"Emerging concepts in biliary repair and fibrosis","volume":"313","author":"Fabris","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the european network for the study of cholangiocarcinoma (ENS-CCA)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1016\/j.bbadis.2017.08.020","article-title":"Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma","volume":"1864","author":"Chung","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/hep.26979","article-title":"IL-12\/Th1 and IL-23\/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy","volume":"59","author":"Yang","year":"2014","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.immuni.2016.06.009","article-title":"Interleukin-13 activates distinct cellular pathways leading to ductular reaction, steatosis, and fibrosis","volume":"45","author":"Gieseck","year":"2016","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00428-011-1048-3","article-title":"Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered","volume":"458","author":"Desmet","year":"2011","journal-title":"Virchows Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1055\/s-0036-1597816","article-title":"Regression of liver fibrosis","volume":"37","author":"Campana","year":"2017","journal-title":"Semin. Liver Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1172\/JCI66028","article-title":"Evolving therapies for liver fibrosis","volume":"123","author":"Schuppan","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/j.gastro.2013.11.034","article-title":"Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion","volume":"146","author":"Williams","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.bbadis.2017.07.024","article-title":"Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology","volume":"1864","author":"Pinto","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ceb.2018.02.008","article-title":"From a common progenitor to distinct liver epithelial phenotypes","volume":"54","author":"Musch","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/MOG.0b013e3280b079fb","article-title":"Cholangiocyte biology","volume":"23","author":"Bogert","year":"2007","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jhep.2012.10.011","article-title":"The dynamic biliary epithelia: Molecules, pathways, and disease","volume":"58","author":"Tabibian","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.jhep.2011.09.022","article-title":"Development of the bile ducts: Essentials for the clinical hepatologist","volume":"56","author":"Strazzabosco","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_18","first-page":"551","article-title":"Ductular cell reaction in the liver in hepatic injury","volume":"24","author":"Popper","year":"1957","journal-title":"J. Mt. Sinai Hosp. N. Y."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nm.2667","article-title":"Macrophage-derived wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease","volume":"18","author":"Boulter","year":"2012","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/MOG.0b013e32834550b4","article-title":"Hedgehog signaling in cholangiocytes","volume":"27","author":"Omenetti","year":"2011","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00428-011-1050-9","article-title":"Ductal plates in hepatic ductular reactions. Hypothesis and implications. Iii. Implications for liver pathology","volume":"458","author":"Desmet","year":"2011","journal-title":"Virchows Arch."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.4291\/wjgp.v1.i2.30","article-title":"Involvement of cholangiocyte proliferation in biliary fibrosis","volume":"1","author":"Priester","year":"2010","journal-title":"World J. Gastrointest. Pathophysiol."},{"key":"ref_23","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."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1136\/gutjnl-2014-307712","article-title":"Osteopontin: A new player in regulating hepatic ductular reaction and hepatic progenitor cell responses during chronic liver injury","volume":"63","author":"Strazzabosco","year":"2014","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1055\/s-2004-815564","article-title":"Progenitor cells in diseased human liver","volume":"23","author":"Roskams","year":"2003","journal-title":"Semin. Liver Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","article-title":"Wnt\/\u03b2-catenin signaling and disease","volume":"149","author":"Clevers","year":"2012","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1002\/hep.25587","article-title":"Mucin-producing cholangiocarcinoma might derive from biliary tree stem\/progenitor cells located in peribiliary glands","volume":"55","author":"Cardinale","year":"2012","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jhep.2013.02.025","article-title":"Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice","volume":"59","author":"Fiorotto","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1242\/jcs.01169","article-title":"Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors","volume":"117","author":"Tanimizu","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_30","first-page":"65","article-title":"Vascular endothelial growth factors in progenitor cells mediated liver repair","volume":"2","author":"Spirli","year":"2013","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.21037\/hbsn.2016.11.04","article-title":"Pathology of intrahepatic cholangiocarcinoma","volume":"6","author":"Vijgen","year":"2017","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/hep.20650","article-title":"Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis","volume":"41","author":"Clouston","year":"2005","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1002\/hep.22238","article-title":"Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin","volume":"47","author":"Komuta","year":"2008","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nm1377","article-title":"A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells","volume":"12","author":"Lee","year":"2006","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.prp.2005.10.011","article-title":"Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed p63-positive basal\/stem-cell phenotype","volume":"202","author":"Nomoto","year":"2006","journal-title":"Pathol. Res. Pract."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2313850","DOI":"10.1155\/2016\/2313850","article-title":"Members of the cyr61\/ctgf\/nov protein family: Emerging players in hepatic progenitor cell activation and intrahepatic cholangiocarcinoma","volume":"2016","author":"Wu","year":"2016","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fphys.2015.00173","article-title":"Human liver myofibroblasts during development and diseases with a focus on portal (myo)fibroblasts","volume":"6","author":"Lepreux","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1172\/JCI30542","article-title":"Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ","volume":"117","author":"Iredale","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1002\/hep.22701","article-title":"P75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis","volume":"49","author":"Kendall","year":"2009","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1152\/physrev.00013.2007","article-title":"Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.addr.2017.05.007","article-title":"Hepatic stellate cells as key target in liver fibrosis","volume":"121","author":"Higashi","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1055\/s-0035-1550061","article-title":"Origin and function of myofibroblasts in the liver","volume":"35","author":"Wells","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/MOG.0b013e32835264d9","article-title":"Animal models of biliary tract injury","volume":"28","author":"Osterreicher","year":"2012","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.addr.2017.05.017","article-title":"Therapeutic pro-fibrogenic signaling pathways in fibroblasts","volume":"121","author":"Cannito","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1016\/j.ajpath.2015.08.009","article-title":"Myofibroblastic conversion and regeneration of mesothelial cells in peritoneal and liver fibrosis","volume":"185","author":"Lua","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/hep.21792","article-title":"Transforming growth factor-\u03b2 and substrate stiffness regulate portal fibroblast activation in culture","volume":"46","author":"Li","year":"2007","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"d496","DOI":"10.2741\/kinnman","article-title":"Peribiliary myofibroblasts in biliary type liver fibrosis","volume":"7","author":"Kinnman","year":"2002","journal-title":"Front. Biosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"G605","DOI":"10.1152\/ajpgi.00222.2012","article-title":"Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury","volume":"304","author":"Perepelyuk","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jhep.2006.04.014","article-title":"Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis","volume":"45","author":"Kisseleva","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ajpath.2011.03.049","article-title":"Migration of fibrocytes in fibrogenic liver injury","volume":"179","author":"Scholten","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nri2990","article-title":"Fibrocytes: Emerging effector cells in chronic inflammation","volume":"11","author":"Reilkoff","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_54","unstructured":"Tan, M.L., and Webster, D.R. (2018). Histology, kupffer cell. Statpearls, Treasure."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1055\/s-0035-1550057","article-title":"Resolution of liver fibrosis: Basic mechanisms and clinical relevance","volume":"35","author":"Ramachandran","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Atri, C., Guerfali, F.Z., and Laouini, D. (2018). Role of human macrophage polarization in inflammation during infectious diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061801"},{"key":"ref_57","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_58","doi-asserted-by":"crossref","first-page":"44544","DOI":"10.1038\/srep44544","article-title":"Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-\u03b2-dependent emperipolesis in HBV cirrhotic patients","volume":"7","author":"Shi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jhep.2009.12.022","article-title":"Foxa1 and foxa2 regulate bile duct development in mice","volume":"52","author":"Strazzabosco","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1034\/j.1600-0676.2001.021002105.x","article-title":"Expression of isoforms and splice variants of the latent transforming growth factor \u03b2 binding protein (LTBP) in cultured human liver myofibroblasts","volume":"21","author":"Gartung","year":"2001","journal-title":"Liver"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/S0014-5793(01)02656-4","article-title":"Transforming growth factor \u03b2 signal transduction in hepatic stellate cells via SMAD2\/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts. TGF\u03b2 signal transduction during transdifferentiation of hepatic stellate cells","volume":"502","author":"Dooley","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"207","DOI":"10.4254\/wjh.v6.i4.207","article-title":"Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition","volume":"6","author":"Lee","year":"2014","journal-title":"World J. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/hep.28274","article-title":"Integrin \u03b1v\u03b26 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis","volume":"63","author":"Peng","year":"2016","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/hep.28382","article-title":"Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis","volume":"63","author":"Locatelli","year":"2016","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0092-8674(00)80545-0","article-title":"The integrin \u03b1v\u03b26 binds and activates latent TGF \u03b21: A mechanism for regulating pulmonary inflammation and fibrosis","volume":"96","author":"Munger","year":"1999","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1002\/hep.21143","article-title":"Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases","volume":"43","author":"Fabris","year":"2006","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/hep.22015","article-title":"Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development","volume":"47","author":"Fabris","year":"2008","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"691","DOI":"10.3892\/mmr.2014.2689","article-title":"Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A","volume":"11","author":"Lu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1091\/mbc.3.2.211","article-title":"Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors","volume":"3","author":"Berse","year":"1992","journal-title":"Mol. Biol. Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1002\/hep.23511","article-title":"Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice","volume":"51","author":"Spirli","year":"2010","journal-title":"Hepatology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"360.e7","DOI":"10.1053\/j.gastro.2009.09.005","article-title":"ERK1\/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice","volume":"138","author":"Spirli","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_72","first-page":"68","article-title":"Expression of vascular endothelial growth factors and their receptors by hepatic progenitor cells in human liver diseases","volume":"2","author":"Franchitto","year":"2013","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S1386-6346(03)00112-8","article-title":"ERK\/MAPK-dependent pi3k\/AKT phosphorylation through VEGFR-1 after VEGF stimulation in activated hepatic stellate cells","volume":"26","author":"Takahashi","year":"2003","journal-title":"Hepatol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cytogfr.2015.10.002","article-title":"The PDGF system and its antagonists in liver fibrosis","volume":"28","author":"Weiskirchen","year":"2016","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_75","first-page":"714","article-title":"Role of PDGFR-\u03b2\/pi3k\/AKT signaling pathway in PDGF-BB induced myocardial fibrosis in rats","volume":"6","author":"Fan","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1002\/hep.26384","article-title":"Platelet-derived growth factor-D and rho gtpases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma","volume":"58","author":"Cadamuro","year":"2013","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"30708","DOI":"10.1074\/jbc.M113.478685","article-title":"Transforming growth factor-\u03b2 (TGF-\u03b2)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires STAT3 signaling activation","volume":"288","author":"Liu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.jhep.2003.11.012","article-title":"Connective tissue growth factor induces c-fos gene activation and cell proliferation through p44\/42 map kinase in primary rat hepatic stellate cells","volume":"40","author":"Gao","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/01.LAB.0000017365.18894.D3","article-title":"Effects and regulation of connective tissue growth factor on hepatic stellate cells","volume":"82","author":"Paradis","year":"2002","journal-title":"Lab Investig."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.jpedsurg.2004.10.017","article-title":"Optimum prednisolone usage in patients with biliary atresia postportoenterostomy","volume":"40","author":"Kobayashi","year":"2005","journal-title":"J. Pediatr. Surg."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1016\/j.jpedsurg.2005.07.056","article-title":"Connective tissue growth factor expression is increased in biliary epithelial cells in biliary atresia","volume":"40","author":"Narkewicz","year":"2005","journal-title":"J. Pediatr. Surg."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"35593","DOI":"10.1074\/jbc.R600027200","article-title":"Re-solving the cadherin-catenin-actin conundrum","volume":"281","author":"Weis","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1002\/hep.29652","article-title":"\u03b2-catenin and interleukin-1\u03b2-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis","volume":"67","author":"Kaffe","year":"2018","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/hep.28774","article-title":"Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice","volume":"64","author":"Okabe","year":"2016","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1136\/gut.2009.188367","article-title":"Characterisation of the liver progenitor cell niche in liver diseases: Potential involvement of wnt and notch signalling","volume":"59","author":"Spee","year":"2010","journal-title":"Gut"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"G39","DOI":"10.1152\/ajpgi.00263.2007","article-title":"Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis","volume":"294","author":"Cheng","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1002\/hep.28138","article-title":"Posttranslational regulation of polycystin-2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage","volume":"62","author":"Spirli","year":"2015","journal-title":"Hepatology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Just, P.A., Poncy, A., Charawi, S., Dahmani, R., Traore, M., Dumontet, T., Drouet, V., Dumont, F., Gilgenkrantz, H., and Colnot, S. (2015). LKB1 and notch pathways interact and control biliary morphogenesis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145400"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/01.pas.0000161325.36348.25","article-title":"Peripheral bile duct paucity and cholestasis in the liver of a patient with alagille syndrome: Further evidence supporting a lack of postnatal bile duct branching and elongation","volume":"29","author":"Libbrecht","year":"2005","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"641","DOI":"10.2353\/ajpath.2007.070073","article-title":"Analysis of liver repair mechanisms in alagille syndrome and biliary atresia reveals a role for notch signaling","volume":"171","author":"Fabris","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Morell, C.M., Fiorotto, R., Meroni, M., Raizner, A., Torsello, B., Cadamuro, M., Spagnuolo, G., Kaffe, E., Sutti, S., and Albano, E. (2017). Notch signaling and progenitor\/ductular reaction in steatohepatitis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187384"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/ni.2304","article-title":"Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization","volume":"13","author":"Xu","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1016\/j.yexcr.2009.06.018","article-title":"Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells","volume":"315","author":"Hirose","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/hep.28768","article-title":"Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators yap and taz","volume":"64","author":"Yi","year":"2016","journal-title":"Hepatology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/hep.21660","article-title":"Bile ductules and stromal cells express hedgehog ligands and\/or hedgehog target genes in primary biliary cirrhosis","volume":"45","author":"Jung","year":"2007","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jhep.2007.07.032","article-title":"Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells","volume":"48","author":"Yang","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Kagan, P., Sultan, M., Tachlytski, I., Safran, M., and Ben-Ari, Z. (2017). Both mapk and stat3 signal transduction pathways are necessary for IL-6-dependent hepatic stellate cells activation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176173"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1172\/JCI73742","article-title":"Biliary repair and carcinogenesis are mediated by il-33-dependent cholangiocyte proliferation","volume":"124","author":"Li","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1089\/jir.2008.0027","article-title":"Monocyte chemoattractant protein-1 (mcp-1): An overview","volume":"29","author":"Deshmane","year":"2009","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Zimmermann, H.W., Seidler, S., Nattermann, J., Gassler, N., Hellerbrand, C., Zernecke, A., Tischendorf, J.J., Luedde, T., Weiskirchen, R., and Trautwein, C. (2010). Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011049"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"G765","DOI":"10.1152\/ajpgi.00308.2005","article-title":"Secretion of MCP-1\/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts","volume":"290","author":"Kruglov","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00281-009-0167-2","article-title":"Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis","volume":"31","author":"Borchers","year":"2009","journal-title":"Semin. Immunopathol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1002\/hep.22890","article-title":"Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1\u03b1-mediated stellate cell activation","volume":"49","author":"Hong","year":"2009","journal-title":"Hepatology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/hep4.1178","article-title":"Neutrophils alleviate fibrosis in the CCL4-induced mouse chronic liver injury model","volume":"2","author":"Saijou","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Shi, W.P., Ju, D., Li, H., Yuan, L., Cui, J., Luo, D., Chen, Z.N., and Bian, H. (2018). CD147 promotes CXCL1 expression and modulates liver fibrogenesis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041145"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1002\/hep.28817","article-title":"The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating src tyrosine kinase activity","volume":"64","author":"Fiorotto","year":"2016","journal-title":"Hepatology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1007\/s00109-015-1319-6","article-title":"Interleukin-27 and IFN\u03b3 regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis","volume":"93","author":"Basset","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"577.e1","DOI":"10.1053\/j.gastro.2014.06.043","article-title":"Roles for chemokines in liver disease","volume":"147","author":"Marra","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/hep.26069","article-title":"Proapoptotic effects of the chemokine, cxcl 10 are mediated by the noncognate receptor tlr4 in hepatocytes","volume":"57","author":"Sahin","year":"2013","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.idc.2010.07.006","article-title":"Cholangiocarcinoma: New insights into disease pathogenesis and biology","volume":"24","author":"Braconi","year":"2010","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.freeradbiomed.2013.07.034","article-title":"Inflammation-related DNA damage and expression of CD133 and Oct3\/4 in cholangiocarcinoma patients with poor prognosis","volume":"65","author":"Thanan","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1159\/000360502","article-title":"Molecular pathogenesis of cholangiocarcinoma","volume":"32","author":"Rizvi","year":"2014","journal-title":"Dig. Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.3390\/jcm4121958","article-title":"Epithelial-to-mesenchymal transition and cancer invasiveness: What can we learn from cholangiocarcinoma?","volume":"4","author":"Brivio","year":"2015","journal-title":"J. Clin. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1016\/j.freeradbiomed.2012.01.018","article-title":"Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma","volume":"52","author":"Thanan","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s41021-016-0055-7","article-title":"Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells","volume":"38","author":"Kawanishi","year":"2016","journal-title":"Genes Environ."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s12199-018-0740-1","article-title":"Inflammation and cancer","volume":"23","author":"Murata","year":"2018","journal-title":"Environ. Health Prev. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1158\/1055-9965.EPI-07-2717","article-title":"Urinary 8-oxo-7,8-dihydro-2\u2032-deoxyguanosine in patients with parasite infection and effect of antiparasitic drug in relation to cholangiocarcinogenesis","volume":"17","author":"Thanan","year":"2008","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_118","first-page":"6388","article-title":"Human ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide","volume":"61","author":"Jaiswal","year":"2001","journal-title":"Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.jhep.2004.07.016","article-title":"Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells","volume":"41","author":"Yoon","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"G88","DOI":"10.1152\/ajpgi.00539.2003","article-title":"Inducible nitric oxide synthase upregulates cyclooxygenase-2 in mouse cholangiocytes promoting cell growth","volume":"287","author":"Ishimura","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1158\/1535-7163.299.3.3","article-title":"The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of akt and induces apoptosis in human cholangiocarcinoma cells","volume":"3","author":"Wu","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1002\/hep.20143","article-title":"Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by akt inactivation and bax translocation","volume":"39","author":"Zhang","year":"2004","journal-title":"Hepatology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1053\/gast.2001.20875","article-title":"Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes","volume":"120","author":"Jaiswal","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1172\/JCI76452","article-title":"Wnt signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited","volume":"125","author":"Boulter","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1158\/1541-7786.MCR-13-0503","article-title":"Cocarcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development","volume":"12","author":"Lozano","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.ccr.2013.04.019","article-title":"A critical role for notch signaling in the formation of cholangiocellular carcinomas","volume":"23","author":"Zender","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1053\/j.gastro.2005.01.055","article-title":"Inducible nitric oxide synthase up-regulates notch-1 in mouse cholangiocytes: Implications for carcinogenesis","volume":"128","author":"Ishimura","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.clinre.2011.10.007","article-title":"PSC, AIH and overlap syndrome in inflammatory bowel disease","volume":"36","author":"Trivedi","year":"2012","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.clinre.2012.02.003","article-title":"Genetics in primary sclerosing cholangitis","volume":"36","author":"Naess","year":"2012","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1751-2980.2012.00605.x","article-title":"Recent insights in primary sclerosing cholangitis","volume":"13","author":"Ponsioen","year":"2012","journal-title":"J. Dig. Dis."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s12016-014-8442-y","article-title":"Animal models in primary biliary cirrhosis and primary sclerosing cholangitis","volume":"48","author":"Pollheimer","year":"2015","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.bbadis.2017.06.027","article-title":"Animal models of biliary injury and altered bile acid metabolism","volume":"1864","author":"Mariotti","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ajpath.2014.10.013","article-title":"A new MDR2\u2212\/\u2212 mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer","volume":"185","author":"Ikenaga","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Fiorotto, R., Amenduni, M., Mariotti, V., Cadamuro, M., Fabris, L., Spirli, C., and Strazzabosco, M. (2018). Animal models for cystic fibrosis liver disease (CFLD). Biochim. Biophys. Acta Mol. Basis Dis.","DOI":"10.1016\/j.bbadis.2018.07.026"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.24351","article-title":"Risk factors for cholangiocarcinoma","volume":"54","author":"Tyson","year":"2011","journal-title":"Hepatology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1572-0241.2004.04067.x","article-title":"Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis","volume":"99","author":"Burak","year":"2004","journal-title":"Am. J. Gastroenterol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0168-8278(01)00288-4","article-title":"Hepatic and extrahepatic malignancies in primary sclerosing cholangitis","volume":"36","author":"Bergquist","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cgh.2012.09.009","article-title":"Classification, diagnosis, and management of cholangiocarcinoma","volume":"11","author":"Razumilava","year":"2013","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"419","DOI":"10.4254\/wjh.v2.i12.419","article-title":"Pathological classification of intrahepatic cholangiocarcinoma based on a new concept","volume":"2","author":"Nakanuma","year":"2010","journal-title":"World J. Hepatol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1440-1827.2011.02665.x","article-title":"Pathological spectrum of intrahepatic cholangiocarcinoma arising in non-biliary chronic advanced liver diseases","volume":"61","author":"Nakanuma","year":"2011","journal-title":"Pathol. Int."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1136\/gut.38.2.265","article-title":"P53 protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis","volume":"38","author":"Rizzi","year":"1996","journal-title":"Gut"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1136\/gut.48.3.403","article-title":"K-ras mutations in the bile of patients with primary sclerosing cholangitis","volume":"48","author":"Kubicka","year":"2001","journal-title":"Gut"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1053\/gast.2002.36021","article-title":"P16ink4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and psc-associated cholangiocarcinoma","volume":"123","author":"Taniai","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1093\/hmg\/ddg274","article-title":"Cellular and subcellular localization of the arpkd protein; fibrocystin is expressed on primary cilia","volume":"12","author":"Ward","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/ng833","article-title":"The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein","volume":"30","author":"Ward","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1053\/j.gastro.2011.04.030","article-title":"Polycystic liver diseases: Congenital disorders of cholangiocyte signaling","volume":"140","author":"Strazzabosco","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"F890","DOI":"10.1152\/ajprenal.00341.2007","article-title":"Mechanoregulation of intracellular Ca2+ in human autosomal recessive polycystic kidney disease cyst-lining renal epithelial cells","volume":"294","author":"Rohatgi","year":"2008","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/hep.22636","article-title":"The camp effectors epac and protein kinase a (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD)","volume":"49","author":"Banales","year":"2009","journal-title":"Hepatology"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1093\/ndt\/gfn744","article-title":"Activation of the Akt\/mtor pathway in autosomal recessive polycystic kidney disease (ARPKD)","volume":"24","author":"Fischer","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1002\/hep.26554","article-title":"Protein kinase a-dependent pser(675)-\u03b2-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis","volume":"58","author":"Spirli","year":"2013","journal-title":"Hepatology"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"9063","DOI":"10.1128\/MCB.25.20.9063-9072.2005","article-title":"Phosphorylation of \u03b2-catenin by cyclic AMP-dependent protein kinase stabilizes \u03b2-catenin through inhibition of its ubiquitination","volume":"25","author":"Hino","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2353\/ajpath.2008.070381","article-title":"Biliary and pancreatic dysgenesis in mice harboring a mutation in PKHD1","volume":"172","author":"Gallagher","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/sj.ki.5002294","article-title":"A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation","volume":"72","author":"Woollard","year":"2007","journal-title":"Kidney Int."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1538\/expanim.49.51","article-title":"Characterization of a novel polycystic kidney rat model with accompanying polycystic liver","volume":"49","author":"Katsuyama","year":"2000","journal-title":"Exp. Anim."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1111\/j.1572-0241.2008.01796.x","article-title":"Hepatitis B virus infection and intrahepatic cholangiocarcinoma in korea: A case-control study","volume":"103","author":"Lee","year":"2008","journal-title":"Am. J. Gastroenterol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.canlet.2006.09.011","article-title":"Molecular pathology of biliary tract cancers","volume":"250","author":"Fava","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"630543","DOI":"10.1155\/2012\/630543","article-title":"Molecular pathogenesis of cholangiocarcinoma","volume":"2012","author":"Fava","year":"2012","journal-title":"Int. J. Hepatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3875\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:31:09Z","timestamp":1760196669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/3875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,4]]},"references-count":159,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["ijms19123875"],"URL":"https:\/\/doi.org\/10.3390\/ijms19123875","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,4]]}}}