title: Interaction between transcription factors PAX6/PAX6-5a and specific members of miR-183-96-182 cluster, may contribute to glioma progression in glioblastoma cell lines.
abstract: A misbalance between proliferation and differentiation of neural stem cells in niches for adult brain neurogenesis is a key mechanism in glioma pathogenesis. In the adult brain, the expression of Pax6 marks stem cells in the forebrain neurogenic niche. We analyzed the expression profile of the two active in vertebrates Pax6 isoforms, Pax6 and Pax6-5a, along with the expression of microRNA cluster miR-183-96-182 in a large set of glioma patient specimens and glioma cell lines which showed opposite expression level, low and high, respectively, with the progression of tumor malignancy. Our results from biochemical and in vitro studies in glioma cell lines disclosed a specific regulation of the PAX6-5a isoform by miR-183. Mechanistically, we show that the downregulation of the lipid kinase SPHK1 by both PAX6 isoforms and the simultaneous induction of CTNDD2 expression, specifically by PAX6-5a, results in reduced glioma cell survival, decreased migration and invasion and increased cell death, in glioma cell lines. Taken together, our findings point towards the important role of PAX6 and define PAX6-5a as a new essential player in glioma development. Finally, we propose that the expression level of TFs PAX6/PAX6-5a and miR-183-96-182 may potentially serve as prognostic markers for the progression of glioma tumors from low- to high-grade with a potential to identify new therapeutic approaches.
authors.affiliation: Research Group Molecular Developmental Neurobiology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pavlakis
authors.affiliation: Research Group Molecular Developmental Neurobiology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Anton B
authors.initials: AB
authors.lastname: Tonchev
authors.affiliation: Department of Neurology, Medical University of Varna, 9002 Varna, Bulgaria.
authors.forename: Ara
authors.initials: A
authors.lastname: Kaprelyan
authors.affiliation: Neurosurgery Clinic, University Hospital of the Medical University of Varna, 9002 Varna, Bulgaria.
authors.forename: Yavor
authors.initials: Y
authors.lastname: Enchev
authors.affiliation: Research Group Molecular Developmental Neurobiology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Stoykova
mesh_terms: D000328:Adult; D000465:Algorithms; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000071841:PAX6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C533449:MIRN183 microRNA, human; D035683:MicroRNAs; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger