title: Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis.
abstract: 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.
authors.affiliation: 1] Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands [3] Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Hiddingh
authors.affiliation: Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rajiv S
authors.initials: RS
authors.lastname: Raktoe
authors.affiliation: Department of Pathology, PAMM, Eindhoven, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Jeuken
authors.affiliation: 1] Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands [2] Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
authors.affiliation: 1] Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands [2] Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.affiliation: 1] Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands [2] Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands [3] Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: 1] Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands [2] Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands [3] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012097:Repressor Proteins; D000077204:Temozolomide; D015854:Up-Regulation / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D035683:MicroRNAs; C502542:PHF6 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; D003606:Dacarbazine; D000077204:Temozolomide