title: Role of microRNAs Located on Chromosome Arm 10q in Malignant Gliomas.
abstract: Deletions of chromosome arm 10q are found in most glioblastomas and subsets of lower grade gliomas. Mutations in the PTEN gene at 10q23.3 are restricted to less than half of the 10q-deleted gliomas, suggesting additional glioma-associated tumor suppressors on 10q. We investigated 64 astrocytic gliomas of different malignancy grades for aberrant expression of 16 microRNAs (miRNAs) on 10q. Thereby, we identified four miRNAs (miR-107, miR-146b-5p, miR-346, miR-1287-5p) whose expression was frequently down-regulated in anaplastic astrocytomas and/or glioblastomas. DNA methylation analyses revealed 5'-CpG site hypermethylation of miR-346 in more than two-thirds of primary glioblastomas, while aberrant 5'-CpG site methylation of miR-146b-5p was frequent in IDH1-mutant astrocytomas and secondary glioblastomas. Overexpression of either of the four miRNAs in glioma cell lines reduced cell proliferation and/or increased caspase-3/7 activity. Expression analyses of miRNA overexpressing glioma cells and 3'-untranslated region luciferase reporter gene assays revealed evidence that these miRNAs post-transcriptionally regulate expression of glioma-relevant genes, including CDK6 (miR-107), EGFR (miR-146b-5p, miR-1287-5p), TERT and SEMA6A (miR-346), all of which are overexpressed in malignant gliomas in situ. In summary, we show that the 10q-located miRNAs miR-107, miR-146b-5p, miR-346 and miR-1287-5p are frequently down-regulated in malignant gliomas and thereby may support overexpression of important glioma growth-promoting genes.
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Wolter
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werner
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Malzkorn
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.|German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D015536:Down-Regulation; D005910:Glioma / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: astrocytoma; cyclin-dependent kinase 6; epidermal growth factor receptor; microRNA; semaphorin 6a; telomerase reverse transcriptase