Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5
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Dexiao Yuan1,*, Jinping Xu1,*, Juan Wang1, Yan Pan1, Jiamei Fu1, Yang Bai1, Jianghong Zhang1, Chunlin Shao1
1Institute of Radiation Medicine, Fudan University, Shanghai 200032, China
*These authors contributed equally to this work
Jianghong Zhang, email: [email protected]
Chunlin Shao, email: [email protected]
Keywords: extracellular mR-1246, exosomes, radioresistance, DR5 gene, bystander effect
Received: February 03, 2016 Accepted: April 09, 2016 Published: April 26, 2016
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.
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