Journal
HEPATOLOGY
Volume 70, Issue 4, Pages 1246-1261Publisher
WILEY
DOI: 10.1002/hep.30656
Keywords
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Categories
Funding
- Carlos III Institute of Health, Spain [PI18/01075, PI16/00598, PI15/00179] Funding Source: Medline
- Consejería de Educación, Junta de Castilla y León [SA063P17, SA015U13] Funding Source: Medline
- Danish Cancer Society [R98-A6446] Funding Source: Medline
- Instituto de Salud Carlos III [PI15/00179, PI16/00598] Funding Source: Medline
- Junta de Castilla y León, Spain [SA063P17, SA015U13] Funding Source: Medline
- Ministry of Education, Culture and Sports, Spain [BOE-A-2015-9456] Funding Source: Medline
- Ministry of Science and Innovation, Spain [SAF2016-75197-R, SAF2013-40620-R] Funding Source: Medline
- Novo Nordisk Foundation [14040] Funding Source: Medline
- Secretaría de Estado de Investigación, Desarrollo e Innovación [SAF2016-75197-R, SAF2013-40620-R, SAF2017-87301-R] Funding Source: Medline
- Fundación Samuel Solórzano Barruso, Spain [FS/10-2014, FS/13-2017, FS/08-2017] Funding Source: Medline
- Ekonomiaren Garapen eta Lehiakortasun Saila, Eusko Jaurlaritza [2013111114] Funding Source: Medline
- Gobierno Vasco-Departamento de Salud, Spain [2013111114] Funding Source: Medline
- Junta de Castilla y León, Fondo Social Europeo [EDU/828/2014] Funding Source: Medline
- Fundación Samuel Solórzano Barruso, Spain [FS/08-2017, FS/10-2014, FS/13-2017] Funding Source: Medline
- Fundación Mutua Madrileña [Call 2015] Funding Source: Medline
- Asociación Española Contra el Cancer, Spain [AECC-2017] Funding Source: Medline
- P.M.G.: European Association for the Study of the Liver (EASL) individual Sheila Sherlock Postdoc Fellowship, Marie Sklodowska-Curie Fellowships (MirChol and Epi-Target) Funding Source: Medline
- Fundación Vasca de Innovación e Investigación Sanitarias, Spain [Bioef BIO15/CA/011] Funding Source: Medline
- Fundación Científica Asociación Española Contra el Cáncer [AECC-2017] Funding Source: Medline
- Ministerio de Economía, Industria y Competitividad, Spain [SAF2017-87301-R] Funding Source: Medline
- Fundación Mutua Madrileña, Spain [Call 2015] Funding Source: Medline
- University of Salamanca, Spain [2018] Funding Source: Medline
- Basque Foundation for Innovation and Health Research: EiTB Maratoia, Spain [BIO15/CA/016/BD] Funding Source: Medline
- Kraeftens Bekaempelse [R98-A6446] Funding Source: Medline
- MSCA postdoc fellowship Funding Source: Medline
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Although the multi-tyrosine 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 SLC22A1) 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 SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 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 hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent up-regulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) 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 BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated 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.
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