title: Gap junctions modulate glioma invasion by direct transfer of microRNA.
abstract: The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity.
authors.affiliation: Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.|Department of Pharmacology & Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey, 07103, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.
authors.forename: Wun Chey
authors.initials: WC
authors.lastname: Sin
authors.affiliation: Department of Pharmacology & Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey, 07103, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
mesh_terms: D001253:Astrocytes / Q000473:pathology*; D001692:Biological Transport / Q000235:genetics; D001932:Brain Neoplasms / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018031:Connexin 43 / Q000235:genetics; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D018031:Connexin 43; C000597931:MIRN-5096 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering
keywords: astrocytes; gap junction; glioma; invasion; microRNA