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Heider, T. ; Mörtl, S. ; Atkinson, M.J.

miR-23a down-regulation suppresses endothelial cell apoptosis by stabilizing XIAP after radiation exposure.

Vortrag: 2015, 06th May 2015, Munich, Germany. (2015)
microRNA miR-23a is down-regulated in human endothelial cells in a dose and time-dependent manner after an acute radiation exposure. We show that down-regulation of miR-23a is required for cell survival after exposure as the reduced miR-23a level allows stabilization of the level of the apoptosis inhibitory protein XIAP.  If miR-23a levels are not allowed to decrease in irradiated cells the levels of the X-linked inhibitor of apoptosis (XIAP) fall and cells enter apoptosis. The high degree of radiation sensitivity of endothelial cells is a limiting factor for the therapeutic dose of radiation in tumour therapy.  We have shown that the non-coding transcriptome, in particular microRNAs (miRNA), is involved in regulating cellular survival after irradiation. These pathways of survival present an attractive therapeutic target to modify sensitivity of both tumour and non-tumour tissues. A detailed expression-kinetic study has verified a dose- and time-dependent regulation of multiple micro RNAs. Amongst these, miR-23a is unusual in that its expression falls in EA.hy926 cells after ionizing radiation. The forced overexpression of miR-23a using both miR-23a mimics and precursor miR-23a forms caused an increased apoptosis after radiation exposure, indicating that this particular miRNA may play an important role in determining the late radiation response of EA.hy926 cells. In silico target identification algorithms identified potential mRNA targets involved in apoptosis, including XIAP. We confirmed that XIAP mRNA is indeed a direct target of miR-23a by luciferase reporter assay. Interestingly, the western blot analysis also showed that XIAP-levels of overexpressed miR-23a endothelial cells were further decreased by ionizing radiation.  The siRNA-mediated down-regulation of XIAP increased apoptosis after irradiation, as did the repression of XIAP translation by overexpression of miR-23a. We conclude therefore that the radiation-induced down-regulation of miR-23a suppresses apoptosis by stabilizing XIAP.
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Publikationstyp Sonstiges: Vortrag
Konferenztitel 2015
Konferzenzdatum 06th May 2015
Konferenzort Munich, Germany
Institut(e) Institute of Radiation Biology (ISB)