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10.1016/j.jhep.2017.02.017

http://scihub22266oqcxt.onion/10.1016/j.jhep.2017.02.017
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C5502751!5502751!28237397
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suck abstract from ncbi


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pmid28237397      J+Hepatol 2017 ; 67 (1): 72-83
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  • SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma #MMPMID28237397
  • Merino-Azpitarte M; Lozano E; Perugorria M; Esparza-Baquer A; Erice O; Santos-Laso A; O'Rourke C; Andersen J; Jiménez-Agüero R; Lacasta A; D'Amato M; Briz O; Jalan-Sakrikar N; Huebert R; Thelen K; Gradilone S; Aransay A; Lavín J; Fernández-Barrena M; Matheu A; Marzioni M; Gores G; Bujanda L; Marin J; Banales J
  • J Hepatol 2017[Jul]; 67 (1): 72-83 PMID28237397show ga
  • 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 knock-down 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 knock-down 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. 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.
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