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

Maite Merino-Azpitarte, Elisa Lozano, María J. Perugorria, Aitor Esparza-Baquer, Oihane Erice, Álvaro Santos-Laso, Colm J. O'Rourke, Jesper B. Andersen, Raúl Jiménez-Agüero, Adelaida Lacasta, Mauro D'Amato, Óscar Briz, Nidhi Jalan-Sakrikar, Robert C Huebert, Kristen M. Thelen, Sergio A. Gradilone, Ana M. Aransay, José L. Lavín, Maite G. Fernández-Barrena, Ander Matheu & 5 others Marco Marzioni, Gregory James Gores, Luis Bujanda, José J G Marin, Jesús M. Banales

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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 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. 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.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Aug 28 2016

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Cholangiocarcinoma
Neoplasms
Induced Pluripotent Stem Cells
Down-Regulation
Biomarkers
Neoplastic Cell Transformation
Maintenance
Phenotype
Catenins
Lentivirus
Survival
DNA Fingerprinting
Cilia
DNA Methylation
Heterografts
Epigenomics
Methylation
Molecular Biology
Oxidative Stress
Therapeutics

Keywords

  • Cholangiocarcinoma
  • Cholangiocyte differentiation
  • Epigenetics
  • Prognosis
  • SOX17

ASJC Scopus subject areas

  • Hepatology

Cite this

Merino-Azpitarte, M., Lozano, E., Perugorria, M. J., Esparza-Baquer, A., Erice, O., Santos-Laso, Á., ... Banales, J. M. (Accepted/In press). SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2017.02.017

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. / Merino-Azpitarte, Maite; Lozano, Elisa; Perugorria, María J.; Esparza-Baquer, Aitor; Erice, Oihane; Santos-Laso, Álvaro; O'Rourke, Colm J.; Andersen, Jesper B.; Jiménez-Agüero, Raúl; Lacasta, Adelaida; D'Amato, Mauro; Briz, Óscar; Jalan-Sakrikar, Nidhi; Huebert, Robert C; Thelen, Kristen M.; Gradilone, Sergio A.; Aransay, Ana M.; Lavín, José L.; Fernández-Barrena, Maite G.; Matheu, Ander; Marzioni, Marco; Gores, Gregory James; Bujanda, Luis; Marin, José J G; Banales, Jesús M.

In: Journal of Hepatology, 28.08.2016.

Research output: Contribution to journalArticle

Merino-Azpitarte, M, Lozano, E, Perugorria, MJ, Esparza-Baquer, A, Erice, O, Santos-Laso, Á, O'Rourke, CJ, Andersen, JB, Jiménez-Agüero, R, Lacasta, A, D'Amato, M, Briz, Ó, Jalan-Sakrikar, N, Huebert, RC, Thelen, KM, Gradilone, SA, Aransay, AM, Lavín, JL, Fernández-Barrena, MG, Matheu, A, Marzioni, M, Gores, GJ, Bujanda, L, Marin, JJG & Banales, JM 2016, 'SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2017.02.017
Merino-Azpitarte M, Lozano E, Perugorria MJ, Esparza-Baquer A, Erice O, Santos-Laso Á et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. Journal of Hepatology. 2016 Aug 28. https://doi.org/10.1016/j.jhep.2017.02.017
Merino-Azpitarte, Maite ; Lozano, Elisa ; Perugorria, María J. ; Esparza-Baquer, Aitor ; Erice, Oihane ; Santos-Laso, Álvaro ; O'Rourke, Colm J. ; Andersen, Jesper B. ; Jiménez-Agüero, Raúl ; Lacasta, Adelaida ; D'Amato, Mauro ; Briz, Óscar ; Jalan-Sakrikar, Nidhi ; Huebert, Robert C ; Thelen, Kristen M. ; Gradilone, Sergio A. ; Aransay, Ana M. ; Lavín, José L. ; Fernández-Barrena, Maite G. ; Matheu, Ander ; Marzioni, Marco ; Gores, Gregory James ; Bujanda, Luis ; Marin, José J G ; Banales, Jesús M. / SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. In: Journal of Hepatology. 2016.
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abstract = "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 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. 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.",
keywords = "Cholangiocarcinoma, Cholangiocyte differentiation, Epigenetics, Prognosis, SOX17",
author = "Maite Merino-Azpitarte and Elisa Lozano and Perugorria, {Mar{\'i}a J.} and Aitor Esparza-Baquer and Oihane Erice and {\'A}lvaro Santos-Laso and O'Rourke, {Colm J.} and Andersen, {Jesper B.} and Ra{\'u}l Jim{\'e}nez-Ag{\"u}ero and Adelaida Lacasta and Mauro D'Amato and {\'O}scar Briz and Nidhi Jalan-Sakrikar and Huebert, {Robert C} and Thelen, {Kristen M.} and Gradilone, {Sergio A.} and Aransay, {Ana M.} and Lav{\'i}n, {Jos{\'e} L.} and Fern{\'a}ndez-Barrena, {Maite G.} and Ander Matheu and Marco Marzioni and Gores, {Gregory James} and Luis Bujanda and Marin, {Jos{\'e} J G} and Banales, {Jes{\'u}s M.}",
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TY - JOUR

T1 - SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

AU - Merino-Azpitarte, Maite

AU - Lozano, Elisa

AU - Perugorria, María J.

AU - Esparza-Baquer, Aitor

AU - Erice, Oihane

AU - Santos-Laso, Álvaro

AU - O'Rourke, Colm J.

AU - Andersen, Jesper B.

AU - Jiménez-Agüero, Raúl

AU - Lacasta, Adelaida

AU - D'Amato, Mauro

AU - Briz, Óscar

AU - Jalan-Sakrikar, Nidhi

AU - Huebert, Robert C

AU - Thelen, Kristen M.

AU - Gradilone, Sergio A.

AU - Aransay, Ana M.

AU - Lavín, José L.

AU - Fernández-Barrena, Maite G.

AU - Matheu, Ander

AU - Marzioni, Marco

AU - Gores, Gregory James

AU - Bujanda, Luis

AU - Marin, José J G

AU - Banales, Jesús M.

PY - 2016/8/28

Y1 - 2016/8/28

N2 - 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 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. 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.

AB - 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 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. 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.

KW - Cholangiocarcinoma

KW - Cholangiocyte differentiation

KW - Epigenetics

KW - Prognosis

KW - SOX17

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