SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

JOURNAL OF HEPATOLOGY

卷:67

Article

Merino-Azpitarte, Maite¹  Lozano, Elisa^1,2,3  Perugorria, Maria J.^1,3,4  Esparza-Baquer, Aitor¹  Erice, Oihane¹  Santos-Laso, Alvaro¹  O'Rourke, Colm J.⁵  Andersen, Jesper B.⁵  Jimenez-Aguero, Raul¹  Lacasta, Adelaida¹  D'Amato, Mauro^1,4  Briz, Oscar^2,3  Jalan-Sakrikar, Nidhi⁶  Huebert, Robert C.⁶  Thelen, Kristen M.⁷  Gradilone, Sergio A.⁷  Aransay, Ana M.^3,8  Lavin, Jose L.⁸  Fernandez-Barrena, Maite G.⁹  Matheu, Ander^4,10  Marzioni, Marco¹¹  Gores, Gregory J.⁶  Bujanda, Luis^1,3  Marin, Jose J. G.^2,3  Banales, Jesus M.^1,3,4 

[1] Univ Basque Country UPV EHU, Dept Liver & Gastrointestinal Dis, Biodonostia Res Inst, Donostia Univ Hosp, San Sebastian, Spain

[2] Univ Salamanca, Expt Hepatol & Drug Targeting HEVEFARM, Biomed Res Inst Salamanca IBSAL, Salamanca, Spain

[3] Inst Salud Carlos III, Natl Inst Study Liver & Gastrointestinal Dis, CIBERehd, Madrid, Spain

[4] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[5] Univ Copenhagen, Biotech Res & Innovat Ctr, Dept Hlth & Med Sci, Copenhagen, Denmark

[6] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA

[7] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[8] CIC bioGUNE, Genome Anal Platform, Bizkaia Technol Pk, Derio, Spain

[9] Univ Navarra, CIMA, Hepatol Program, Pamplona, Spain

[10] Donostia Univ Hosp, Biodonostia Res Inst, Neurooncol Grp, San Sebastian, Spain

[11] Univ Politecn Marche, Dept Gastroenterol, Ancona, Italy

关键词: Cholangiocyte differentiation;    Cholangiocarcinoma;    SOX17;    Epigenetics;    Prognosis;   

DOI  :  10.1016/j.jhep.2017.02.017

来源: Elsevier

【 摘 要 】

Background & Aims: 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. Methods: 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. Results: 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 xeno-graft 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/beta-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. Conclusions: 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. Lay summary: 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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