{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T23:58:24Z","timestamp":1785887904692,"version":"3.56.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T00:00:00Z","timestamp":1594425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T00:00:00Z","timestamp":1594425600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>A limitation for the treatment of unresectable cholangiocarcinoma (CCA) is its poor response to chemotherapy, which is partly due to reduction of intracellular levels of anticancer drugs through ATP\u2010binding cassette (ABC) pumps. Low expression of SOX17 (SRY\u2010box containing gene 17), a transcription factor that promotes biliary differentiation and phenotype maintenance, has been associated with cholangiocyte malignant transformation. Whether SOX17 is also involved in CCA chemoresistance is investigated in this study.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>SOX17 expression in human CCA cells (EGI\u20101 and TFK\u20101) selectively potentiated cytotoxicity of SN\u201038, 5\u2010fluorouracil and mitoxantrone, but not that of gemcitabine, capecitabine, cisplatin, or oxaliplatin. The analysis of the resistome by TaqMan low\u2010density arrays revealed changes affecting primarily ABC pump expression. Single\u2010gene quantitative real\u2010time PCR, immunoblot, and immunofluorescence analyses confirmed that MRP3 (multidrug resistance associated protein 3), which was highly expressed in CCA human tumors, was down\u2010regulated in SOX17\u2010transduced CCA cells. The substrate specificity of this pump matched that of SOX17\u2010induced <jats:italic toggle=\"yes\">in vitro<\/jats:italic> selective chemosensitization. Functional studies showed lower ability of SOX17\u2010expressing CCA cells to extrude specific MRP3 substrates. Reporter assay of MRP3 promoter (<jats:italic toggle=\"yes\">ABCC3pr<\/jats:italic>) revealed that <jats:italic toggle=\"yes\">ABCC3pr<\/jats:italic> activity was inhibited by SOX17 expression and SOX2\/SOX9 silencing. The latter was highly expressed in CCA. Moreover, SOX2\/9, but not SOX17, induced altered electrophoretic mobility of <jats:italic toggle=\"yes\">ABCC3pr<\/jats:italic>, which was prevented by SOX17. The growth of CCA tumors subcutaneously implanted into immunodeficient mice was inhibited by 5\u2010fluorouracil. This effect was enhanced by co\u2010treatment with adenoviral vectors encoding SOX17.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>SOX9\/2\/17 are involved in MRP3\u2010mediated CCA chemoresistance. Restored SOX17 expression, in addition to its tumor suppression effect, induces selective chemosensitization due to MRP3 down\u2010regulation and subsequent intracellular drug accumulation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31088","type":"journal-article","created":{"date-parts":[[2019,12,21]],"date-time":"2019-12-21T05:19:39Z","timestamp":1576905579000},"page":"949-964","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":25,"title":["MRP3\u2010Mediated Chemoresistance in Cholangiocarcinoma: Target for Chemosensitization Through Restoring SOX17 Expression"],"prefix":"10.1097","volume":"72","author":[{"given":"Elisa","family":"Lozano","sequence":"first","affiliation":[{"name":"Experimental Hepatology and Drug Targeting, IBSAL,University of Salamanca,Salamanca,Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases,Carlos III National Health 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