{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:00:06Z","timestamp":1774008006855,"version":"3.50.1"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"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":[[2019,10]]},"abstract":"<jats:p>Although the multi\u2010tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene <jats:italic toggle=\"yes\">SLC22A1<\/jats:italic>) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of <jats:italic toggle=\"yes\">SLC22A1<\/jats:italic> were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n\u00a0=\u00a0132) and The Cancer Genome Atlas (TCGA)\u2010CHOL (n\u00a0=\u00a036). Decreased <jats:italic toggle=\"yes\">hOCT1<\/jats:italic> mRNA correlated with hypermethylation status of the <jats:italic toggle=\"yes\">SLC22A1<\/jats:italic> promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce <jats:italic toggle=\"yes\">hOCT1<\/jats:italic> mRNA decay were analyzed in paired samples of TCGA\u2010CHOL (n\u00a0=\u00a09) and Copenhagen (n\u00a0=\u00a057) cohorts. Consistent up\u2010regulation in tumor tissue was found for miR\u2010141 and miR\u2010330. High proportion of aberrant <jats:italic toggle=\"yes\">hOCT1<\/jats:italic> mRNA splicing in CCA was also seen. Lentiviral\u2010mediated transduction of eCCA (EGI\u20101 and TFK\u20101) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the <jats:italic toggle=\"yes\">BIRC5<\/jats:italic> promoter, a gene highly up\u2010regulated in CCA. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The reason for impaired hOCT1\u2010mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib.<\/jats:p>","DOI":"10.1002\/hep.30656","type":"journal-article","created":{"date-parts":[[2019,4,11]],"date-time":"2019-04-11T23:00:11Z","timestamp":1555023611000},"page":"1246-1261","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":50,"title":["Causes of hOCT1\u2010Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor\u2010Selective Gene Therapy"],"prefix":"10.1097","volume":"70","author":[{"given":"Elisa","family":"Lozano","sequence":"first","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL,University of Salamanca,Salamanca,Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health 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Institute,Madrid,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria L.","family":"Martinez\u2010Chantar","sequence":"additional","affiliation":[{"name":"Liver Disease Laboratory,CIC bioGUNE, Technology Park of Vizcaya,Vizcaya,Spain"},{"name":"National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute,Madrid,Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1760-5244","authenticated-orcid":false,"given":"Jesper B.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Biotech Research and Innovation Centre, Department of Health and Medical Sciences,University of Copenhagen,Copenhagen,Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar","family":"Briz","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL,University of 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