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Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis

Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes an...

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Autores principales: Hiddingh, Lotte, Raktoe, Rajiv S., Jeuken, Judith, Hulleman, Esther, Noske, David P., Kaspers, Gertjan J. L., Vandertop, W. Peter, Wesseling, Pieter, Wurdinger, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052714/
https://www.ncbi.nlm.nih.gov/pubmed/24919120
http://dx.doi.org/10.1038/srep05260
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author Hiddingh, Lotte
Raktoe, Rajiv S.
Jeuken, Judith
Hulleman, Esther
Noske, David P.
Kaspers, Gertjan J. L.
Vandertop, W. Peter
Wesseling, Pieter
Wurdinger, Thomas
author_facet Hiddingh, Lotte
Raktoe, Rajiv S.
Jeuken, Judith
Hulleman, Esther
Noske, David P.
Kaspers, Gertjan J. L.
Vandertop, W. Peter
Wesseling, Pieter
Wurdinger, Thomas
author_sort Hiddingh, Lotte
collection PubMed
description Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma.
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spelling pubmed-40527142014-06-12 Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis Hiddingh, Lotte Raktoe, Rajiv S. Jeuken, Judith Hulleman, Esther Noske, David P. Kaspers, Gertjan J. L. Vandertop, W. Peter Wesseling, Pieter Wurdinger, Thomas Sci Rep Article Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma. Nature Publishing Group 2014-06-11 /pmc/articles/PMC4052714/ /pubmed/24919120 http://dx.doi.org/10.1038/srep05260 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Hiddingh, Lotte
Raktoe, Rajiv S.
Jeuken, Judith
Hulleman, Esther
Noske, David P.
Kaspers, Gertjan J. L.
Vandertop, W. Peter
Wesseling, Pieter
Wurdinger, Thomas
Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title_full Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title_fullStr Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title_full_unstemmed Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title_short Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis
title_sort identification of temozolomide resistance factors in glioblastoma via integrative mirna/mrna regulatory network analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052714/
https://www.ncbi.nlm.nih.gov/pubmed/24919120
http://dx.doi.org/10.1038/srep05260
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