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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/?-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.

SUBMITTER: Merino-Azpitarte M

PROVIDER: S-EPMC5502751 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Merino-Azpitarte Maite M Lozano Elisa E Perugorria María J MJ Esparza-Baquer Aitor A Erice Oihane O Santos-Laso Álvaro Á O'Rourke Colm J CJ Andersen Jesper B JB Jiménez-Agüero Raúl R Lacasta Adelaida A D'Amato Mauro M Briz Óscar Ó Jalan-Sakrikar Nidhi N Huebert Robert C RC Thelen Kristen M KM Gradilone Sergio A SA Aransay Ana M AM Lavín José L JL Fernández-Barrena Maite G MG Matheu Ander A Marzioni Marco M Gores Gregory J GJ Bujanda Luis L Marin José J G JJG Banales Jesús M JM

Journal of hepatology 20170222 1

<h4>Background & aims</h4>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.<h4>Methods</h4>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 i ...[more]

PMID: 28237397

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Project description:Background and aims: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. Incidence is increasing worldwide and these cancers collectively represent the second most common primary liver tumour. CCAs are characterized by genetic and epigenetic alterations that determine their pathogenesis. Hypermethylation of the SOX17 promoter was recently reported in human CCA tumours. SOX17 seems to be a key transcription factor for biliary embryogenesis. Here, we evaluated the role of SOX17 in cholangiocyte differentiation and in cholangiocarcinogenesis. Methods: SOX17 expression and function was evaluated during the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation of normal human cholangiocytes (NHC) and in cholangiocarcinogenesis. Lentiviruses overexpressing or knocking-down SOX17 (Lent-SOX17 and Lent-shRNA-SOX17, respectively) were used. Gene expression arrays were performed. Results: SOX17 expression is highly induced in the later stages of cholangiocyte differentiation from iPSC, and mediates the acquisition of the biliary markers cytokeratin (CK) 7 and 19, as well as fibronectin. In addition, SOX17 becomes progressively downregulated in NHC over serial cell passages in vitro and this event is associated with cellular senescence; however, experimental SOX17 knocking-down in differentiated NHC decreased the expression of both CK7 and 19 without affecting cellular senescence. SOX17 expression is reduced in CCA cells compared to NHC, as well as in human CCA tissue compared to human gallbladder tissue or NHC. In a murine xenograft model, overexpression of SOX17 in CCA cells decreased their tumorigenic capacity related to increased oxidative stress and apoptosis. Interestingly, overexpression of SOX17 in NHC did not affect their survival. Moreover, SOX17 overexpression inhibited the Wnt/β-catenin-dependent proliferation in CCA cells and was associated with upregulation of biliary epithelial markers and restoration of the primary cilium length. Both Wnt3a and TGFβ1 decreased SOX17 expression in NHC in a DNMT1-dependent manner. Inhibition of DNMT1 in CCA cells with siRNAs or pharmacological drugs upregulated SOX17 expression. Conclusion: SOX17 regulates the cholangiocyte phenotype and becomes epigenetically downregulated in CCA. SOX17 acts as a tumour suppressor in CCA, and restoration of its expression may have important therapeutic value.

Project description:UnlabelledBiliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. The goal of this study was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extrahepatic fibrosis. We treated mouse cholangiocytes in three-dimensional (3D) spheroid culture and neonatal extrahepatic duct explants with biliatresone and compounds that regulate glutathione (GSH). We examined the effects of biliatresone on SOX17 levels and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared with untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in GSH, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone.ConclusionBiliatresone decreases GSH and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability; in extrahepatic bile duct explants, it leads to disruption of the extrahepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia. (Hepatology 2016;64:880-893).

Project description:Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.Significance: The histopathogenesis of biliary tract cancer, driven by Tp53 and Kras mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. Cancer Res; 78(16); 4445-51. ©2018 AACR.

Dataset Information

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

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

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