ArticleJournal of hepatology2017
SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma.
Article in Journal of hepatology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 101 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- Secreted chimeric proteins as a strategy to correct SOX17 deficiency and attenuate the malignant phenotype of cholangiocarcinoma cells: a proof-of-concept study.Acta pharmacologica Sinica · 2026Article
- Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma.Frontiers in cell and developmental biology · 2026Article
- Cholangiocarcinoma 2026: status quo, unmet needs and priorities.Nature reviews. Gastroenterology & hepatology · 2026Review
- Molecular mechanisms and genetic features of cholangiocarcinoma: implications for targeted therapeutic strategies.Precision clinical medicine · 2025Review
- Overexpression of KMT9α is associated with poor outcome in cholangiocarcinoma patients.Journal of cancer research and clinical oncology · 2025Article
- Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma.The American journal of pathology · 2025Review
- Positive autoregulation of Sox17 is necessary for gallbladder and extrahepatic bile duct formation.Development (Cambridge, England) · 2025Article
- Wnt/β-Catenin Signaling in Liver Pathobiology.Annual review of pathology · 2025Review
- Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes.Disease models & mechanisms · 2025Article
- Recent research progresses of bioengineered biliary stents.Materials today. Bio · 2024Review
- Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches.Cancers · 2024Review
- Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications.Medical review (2021) · 2024Review
- E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.Hypertension (Dallas, Tex. : 1979) · 2023Article
- Biliatresone: progress in biliary atresia study.World journal of pediatrics : WJP · 2023Review
- Review
- E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension.bioRxiv : the preprint server for biology · 2023Article
- MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells.Journal of hepatology · 2023Article
- Upregulated miR-194-5p suppresses retinal microvascular endothelial cell dysfunction and mitigates the symptoms of hypertensive retinopathy in mice by targeting SOX17 and VEGF signaling.Cell cycle (Georgetown, Tex.) · 2023Article
- DNA methylation in cell plasticity and malignant transformation in liver diseases.Pharmacology & therapeutics · 2023Review
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Authors and funding
25 authors at 12 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsCholangiocarcinoma (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.
methodsSOX17 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.
resultsSOX17 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.
conclusionsSOX17 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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