title: SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied.
  
  
  
  SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knockdown were used. Gene expression and DNA methylation profiling were performed.
  
  
  
  SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knockdown in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17.
  
  
  
  SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.
  
  
  
  Understanding the molecular mechanisms involved in the pathogenesis of CCA is key in finding new valuable diagnostic and prognostic biomarkers, as well as therapeutic targets. This study provides evidence that SOX17 regulates the differentiation and maintenance of the biliary phenotype, and its downregulation promotes their tumorigenic transformation. SOX17 acts as a tumor suppressor in CCA and its genetic, molecular and/or pharmacological restoration may represent a new promising therapeutic strategy. Moreover, SOX17 expression correlates with the outcome of patients after tumor resection, being a potential prognostic biomarker.
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Merino-Azpitarte
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lozano
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Perugorria
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Aitor
authors.initials: A
authors.lastname: Esparza-Baquer
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Oihane
authors.initials: O
authors.lastname: Erice
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Santos-Laso
authors.affiliation: Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Colm J
authors.initials: CJ
authors.lastname: O'Rourke
authors.affiliation: Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Jiménez-Agüero
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Adelaida
authors.initials: A
authors.lastname: Lacasta
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Briz
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Thelen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Gradilone
authors.affiliation: National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; Genome Analysis Platform, CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: Genome Analysis Platform, CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Lavín
authors.affiliation: Hepatology Program, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernández-Barrena
authors.affiliation: IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Neuro-Oncology Group, Biodonostia Research Institute - Donostia University Hospital, San Sebastian, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.affiliation: Department of Gastroenterology, "Università Politecnica delle Marche", Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain.
authors.forename: José J G
authors.initials: JJG
authors.lastname: Marin
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. Electronic address: jesus.banales@biodonostia.org.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology*; D001652:Bile Ducts / Q000473:pathology*; D002454:Cell Differentiation; D018281:Cholangiocarcinoma / Q000209:etiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D055760:SOXF Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: Cholangiocarcinoma; Cholangiocyte differentiation; Epigenetics; Prognosis; SOX17