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Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy
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Zeitschriftentitel: | Hepatology |
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Personen und Körperschaften: | , , , , , , , , , , , , , , , , |
In: | Hepatology, 70, 2019, 4, S. 1246-1261 |
Medientyp: | E-Article |
Sprache: | Englisch |
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Ovid Technologies (Wolters Kluwer Health)
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author_facet |
Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. |
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author |
Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. |
spellingShingle |
Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. Hepatology Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy Hepatology |
author_sort |
lozano, elisa |
spelling |
Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. 0270-9139 1527-3350 Ovid Technologies (Wolters Kluwer Health) Hepatology http://dx.doi.org/10.1002/hep.30656 <jats:p>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 <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 = 132) and The Cancer Genome Atlas (TCGA)‐CHOL (n = 36). 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‐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 <jats:italic toggle="yes">hOCT1</jats:italic> 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 <jats:italic toggle="yes">BIRC5</jats:italic> promoter, a gene highly up‐regulated in CCA. <jats:italic toggle="yes">Conclusion</jats:italic>: 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.</jats:p> Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy Hepatology |
doi_str_mv |
10.1002/hep.30656 |
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Online Free |
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Medizin |
format |
ElectronicArticle |
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Ovid Technologies (Wolters Kluwer Health), 2019 |
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Ovid Technologies (Wolters Kluwer Health), 2019 |
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1527-3350 0270-9139 |
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2019 |
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Ovid Technologies (Wolters Kluwer Health) |
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Hepatology |
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49 |
title |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_unstemmed |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_full |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_fullStr |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_full_unstemmed |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_short |
Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_sort |
causes of hoct1‐dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor‐selective gene therapy |
topic |
Hepatology |
url |
http://dx.doi.org/10.1002/hep.30656 |
publishDate |
2019 |
physical |
1246-1261 |
description |
<jats:p>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 <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 = 132) and The Cancer Genome Atlas (TCGA)‐CHOL (n = 36). 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‐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 <jats:italic toggle="yes">hOCT1</jats:italic> 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 <jats:italic toggle="yes">BIRC5</jats:italic> promoter, a gene highly up‐regulated in CCA. <jats:italic toggle="yes">Conclusion</jats:italic>: 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.</jats:p> |
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author | Lozano, Elisa, Macias, Rocio I.R., Monte, Maria J., Asensio, Maitane, del Carmen, Sofia, Sanchez‐Vicente, Laura, Alonso‐Peña, Marta, Al‐Abdulla, Ruba, Munoz‐Garrido, Patricia, Satriano, Letizia, O'Rourke, Colm J., Banales, Jesus M., Avila, Matias A., Martinez‐Chantar, Maria L., Andersen, Jesper B., Briz, Oscar, Marin, Jose J.G. |
author_facet | Lozano, Elisa, Macias, Rocio I.R., Monte, Maria J., Asensio, Maitane, del Carmen, Sofia, Sanchez‐Vicente, Laura, Alonso‐Peña, Marta, Al‐Abdulla, Ruba, Munoz‐Garrido, Patricia, Satriano, Letizia, O'Rourke, Colm J., Banales, Jesus M., Avila, Matias A., Martinez‐Chantar, Maria L., Andersen, Jesper B., Briz, Oscar, Marin, Jose J.G., Lozano, Elisa, Macias, Rocio I.R., Monte, Maria J., Asensio, Maitane, del Carmen, Sofia, Sanchez‐Vicente, Laura, Alonso‐Peña, Marta, Al‐Abdulla, Ruba, Munoz‐Garrido, Patricia, Satriano, Letizia, O'Rourke, Colm J., Banales, Jesus M., Avila, Matias A., Martinez‐Chantar, Maria L., Andersen, Jesper B., Briz, Oscar, Marin, Jose J.G. |
author_sort | lozano, elisa |
container_issue | 4 |
container_start_page | 1246 |
container_title | Hepatology |
container_volume | 70 |
description | <jats:p>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 <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 = 132) and The Cancer Genome Atlas (TCGA)‐CHOL (n = 36). 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‐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 <jats:italic toggle="yes">hOCT1</jats:italic> 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 <jats:italic toggle="yes">BIRC5</jats:italic> promoter, a gene highly up‐regulated in CCA. <jats:italic toggle="yes">Conclusion</jats:italic>: 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.</jats:p> |
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spelling | Lozano, Elisa Macias, Rocio I.R. Monte, Maria J. Asensio, Maitane del Carmen, Sofia Sanchez‐Vicente, Laura Alonso‐Peña, Marta Al‐Abdulla, Ruba Munoz‐Garrido, Patricia Satriano, Letizia O'Rourke, Colm J. Banales, Jesus M. Avila, Matias A. Martinez‐Chantar, Maria L. Andersen, Jesper B. Briz, Oscar Marin, Jose J.G. 0270-9139 1527-3350 Ovid Technologies (Wolters Kluwer Health) Hepatology http://dx.doi.org/10.1002/hep.30656 <jats:p>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 <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 = 132) and The Cancer Genome Atlas (TCGA)‐CHOL (n = 36). 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‐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 <jats:italic toggle="yes">hOCT1</jats:italic> 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 <jats:italic toggle="yes">BIRC5</jats:italic> promoter, a gene highly up‐regulated in CCA. <jats:italic toggle="yes">Conclusion</jats:italic>: 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.</jats:p> Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy Hepatology |
spellingShingle | Lozano, Elisa, Macias, Rocio I.R., Monte, Maria J., Asensio, Maitane, del Carmen, Sofia, Sanchez‐Vicente, Laura, Alonso‐Peña, Marta, Al‐Abdulla, Ruba, Munoz‐Garrido, Patricia, Satriano, Letizia, O'Rourke, Colm J., Banales, Jesus M., Avila, Matias A., Martinez‐Chantar, Maria L., Andersen, Jesper B., Briz, Oscar, Marin, Jose J.G., Hepatology, Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy, Hepatology |
title | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_full | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_fullStr | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_full_unstemmed | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_short | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
title_sort | causes of hoct1‐dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor‐selective gene therapy |
title_unstemmed | Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy |
topic | Hepatology |
url | http://dx.doi.org/10.1002/hep.30656 |