title: Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5.
abstract: MiRNAs in the circulation have been demonstrated to be a type of signaling molecule involved in intercellular communication but little is known about their role in regulating radiosensitivity. This study aims to investigate the effects of extracellular miRNAs induced by ionizing radiation (IR) on cell proliferation and radiosensitivity. The miRNAs in the conditioned medium (CM) from irradiated and non-irradiated A549 lung cancer cells were compared using a microarray assay and the profiles of 21 miRNAs up and down-regulated by radiation were confirmed by qRT-PCR. One of these miRNAs, miR-1246, was especially abundant outside the cells and had a much higher level compared with that inside of cells. The expressions of miR-1246 in both A549 and H446 cells increased along with irradiation dose and the time post-irradiation. By labeling exosomes and miR-1246 with different fluorescence dyes, it was found that the extracellular miR-1246 could shuttle from its donor cells to other recipient cells by a non-exosome associated pathway. Moreover, the treatments of cells with miR-1246 mimic or its antisense inhibitor showed that the extracellular miR-1246 could enhance the proliferation and radioresistance of lung cancer cells. A luciferase reporter-gene transfer experiment demonstrated that the death receptor 5 (DR5) was the direct target of miR-1246, and the kinetics of DR5 expression was opposite to that of miR-1246 in the irradiated cells. Our results show that the oncogene-like extracellular miR-1246 could act as a signaling messenger between irradiated and non-irradiated cells, more importantly, it contributes to cell radioresistance by directly suppressing the DR5 gene.
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Dexiao
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Fu
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Shao
mesh_terms: D000072283:A549 Cells; D024201:Bystander Effect; D049109:Cell Proliferation / Q000528:radiation effects*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D055354:Exosomes / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011836:Radiation Tolerance; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D014162:Transfection
chemical_list: D017077:Culture Media, Conditioned; C577700:MIRN1246 microRNA, human; D035683:MicroRNAs; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human
keywords: DR5 gene; bystander effect; exosomes; extracellular mR-1246; radioresistance