title: MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM.
abstract: Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype. Altered sensitivity to apoptosis played only a minor role in this resistance mechanism. Instead, we identified the induction of autophagy to be regulated downstream of the miR-138/BIM axis and to promote cell survival following TMZ exposure. Our data thus define miR-138 as a glioblastoma cell survival-promoting miRNA associated with resistance to TMZ therapy in vitro and with tumor progression in vivo.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Stojcheva
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Gennadi
authors.initials: G
authors.lastname: Schechtmann
authors.affiliation: Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Sass
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Florea
authors.affiliation: Molecular Proteomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Stefanski
authors.affiliation: Molecular Proteomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Stühler
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Wolter
authors.affiliation: Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Müller
authors.affiliation: Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Mathematics, Technische Universität München, Garching, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, partner site Essen/Düsseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Happold
mesh_terms: D000072224:Bcl-2-Like Protein 11 / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D000072224:Bcl-2-Like Protein 11; C546110:MIRN138 microRNA, human; D035683:MicroRNAs
keywords: BIM; chemoresistance; glioblastoma; miR-138; temozolomide