SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

M Merino-Azpitarte; E Lozano; M J Perugorria; A Esparza-Baquer; O Erice; A Santos-Laso; Colm O'Rourke; Jesper Bøje Andersen; R Jiménez-Agüero; A Lacasta; M D'Amato; O Briz; N Jalan-Sakrikar; R C Huebert; K M Thelen; S A Gradilone; A M Aransay; J L Lavín; M G Fernández-Barrena; A Matheu; M Marzioni; G J Gores; L Bujanda; J J G Marin; J M Banales

doi:10.1016/j.jhep.2017.02.017

SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

M Merino-Azpitarte, E Lozano, M J Perugorria, A Esparza-Baquer, O Erice, A Santos-Laso, Colm O'Rourke, Jesper Bøje Andersen, R Jiménez-Agüero, A Lacasta, M D'Amato, O Briz, N Jalan-Sakrikar, R C Huebert, K M Thelen, S A Gradilone, A M Aransay, J L Lavín, M G Fernández-Barrena, A MatheuM Marzioni, G J Gores, L Bujanda, J J G Marin, J M Banales

45 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 language	English
Journal	Journal of Hepatology
Volume	67
Issue number	1
Pages (from-to)	72-83
Number of pages	12
ISSN	0168-8278
DOIs	https://doi.org/10.1016/j.jhep.2017.02.017
Publication status	Published - Jul 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jhep.2017.02.017

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Merino-Azpitarte, M., Lozano, E., Perugorria, M. J., Esparza-Baquer, A., Erice, O., Santos-Laso, A., O'Rourke, C., Andersen, J. B., Jiménez-Agüero, R., Lacasta, A., D'Amato, M., Briz, O., Jalan-Sakrikar, N., Huebert, R. C., Thelen, K. M., Gradilone, S. A., Aransay, A. M., Lavín, J. L., Fernández-Barrena, M. G., ... Banales, J. M. (2017). SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma. Journal of Hepatology, 67(1), 72-83. https://doi.org/10.1016/j.jhep.2017.02.017

Merino-Azpitarte, M, Lozano, E, Perugorria, MJ, Esparza-Baquer, A, Erice, O, Santos-Laso, A, O'Rourke, C , Andersen, JB, Jiménez-Agüero, R, Lacasta, A, D'Amato, M, Briz, O, 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 2017, 'SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma', Journal of Hepatology, vol. 67, no. 1, pp. 72-83. https://doi.org/10.1016/j.jhep.2017.02.017

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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.",

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author = "M Merino-Azpitarte and E Lozano and Perugorria, {M J} and A Esparza-Baquer and O Erice and A Santos-Laso and Colm O'Rourke and Andersen, {Jesper B{\o}je} and R Jim{\'e}nez-Ag{\"u}ero and A Lacasta and M D'Amato and O Briz and N Jalan-Sakrikar and Huebert, {R C} and Thelen, {K M} and Gradilone, {S A} and Aransay, {A M} and Lav{\'i}n, {J L} and Fern{\'a}ndez-Barrena, {M G} and A Matheu and M Marzioni and Gores, {G J} and L Bujanda and Marin, {J J G} and Banales, {J M}",

note = "Copyright {\textcopyright} 2017. Published by Elsevier B.V.",

year = "2017",

month = jul,

doi = "10.1016/j.jhep.2017.02.017",

language = "English",

volume = "67",

pages = "72--83",

journal = "Journal of Hepatology",

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TY - JOUR

T1 - SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

AU - Merino-Azpitarte, M

AU - Lozano, E

AU - Perugorria, M J

AU - Esparza-Baquer, A

AU - Erice, O

AU - Santos-Laso, A

AU - O'Rourke, Colm

AU - Andersen, Jesper Bøje

AU - Jiménez-Agüero, R

AU - Lacasta, A

AU - D'Amato, M

AU - Briz, O

AU - Jalan-Sakrikar, N

AU - Huebert, R C

AU - Thelen, K M

AU - Gradilone, S A

AU - Aransay, A M

AU - Lavín, J L

AU - Fernández-Barrena, M G

AU - Matheu, A

AU - Marzioni, M

AU - Gores, G J

AU - Bujanda, L

AU - Marin, J J G

AU - Banales, J M

PY - 2017/7

Y1 - 2017/7

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 - Journal Article

U2 - 10.1016/j.jhep.2017.02.017

DO - 10.1016/j.jhep.2017.02.017

M3 - Journal article

C2 - 28237397

SN - 0168-8278

VL - 67

SP - 72

EP - 83

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 1

ER -

SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

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