中科院近代物理研究所空間輻射生物研究室科研人員利用microRNA增加細(xì)胞輻射敏感性研究取得新進(jìn)展,，首次報(bào)道了miR-185通過(guò)靶向調(diào)控關(guān)鍵的DNA損傷傳感因子ATR增強(qiáng)電離輻射誘導(dǎo)的細(xì)胞凋亡及增殖抑制等效應(yīng),。
microRNA(miRNA)是一類內(nèi)源性非編碼小RNA分子，能夠在轉(zhuǎn)錄后水平通過(guò)與靶基因mRNA的3’非編碼區(qū)（3’-UTR）相結(jié)合而調(diào)控靶基因的表達(dá),。miRNA參與多種生命進(jìn)程,，如細(xì)胞生長(zhǎng)與分化、凋亡,、發(fā)育,、癌癥發(fā)生等。現(xiàn)已證實(shí),，miRNA在細(xì)胞輻射應(yīng)激響應(yīng)過(guò)程中發(fā)揮重要作用,，能夠參與調(diào)節(jié)H2AX、ATM等DNA損傷感受因子,。
科研人員研究發(fā)現(xiàn),，電離輻射能夠引起腎癌細(xì)胞miR-185表達(dá)下調(diào)，而過(guò)表達(dá)miR-185能夠增加細(xì)胞的輻射敏感性（圖1）,。生物信息學(xué)分析表明,，DNA損傷應(yīng)答因子ATR是miR-185潛在的靶基因，熒光素酶報(bào)告載體實(shí)驗(yàn)和突變實(shí)驗(yàn)證明了miR-185能夠通過(guò)與ATRmRNA的3’-UTR區(qū)結(jié)合直接靶向調(diào)節(jié)ATR,，過(guò)表達(dá)miR-185能夠在mRNA和蛋白水平抑制ATR,。實(shí)驗(yàn)表明，miR-185通過(guò)抑制ATR信號(hào)通路增強(qiáng)了輻射誘導(dǎo)的細(xì)胞凋亡（圖2）及增殖抑制（圖3）,。
此項(xiàng)研究揭示了miRNA參與細(xì)胞輻射敏感性的新機(jī)制,，對(duì)利用miRNA調(diào)控腫瘤輻射敏感性的研究具有重要意義。
研究成果在Cell Death&Disease發(fā)表,。（生物谷 Bioon.com）
生物谷推薦的英文摘要
Cell Death and Disease doi:10.1038/cddis.2013.227
Repression of ATR pathway by miR-185 enhances radiation-induced apoptosis and proliferation inhibition
J Wang, J He, F Su, N Ding, W Hu, B Yao, W Wang and G Zhou
Cellular responses to DNA damage induced by intrinsic and extrinsic genotoxic stresses are highly regulated by complex signaling pathways, such as activation of the phosphoinositide-3-kinase-like protein kinase family and their downstream genes. Disruption of these signaling pathways leads to genome instability and cell death, and thus may provide potential novel strategies for cancer therapy. Here, we find that the expression of a human microRNA (miRNA), hsa-miR-185, is downregulated in response to ionizing radiation. Elevation of miR-185 sensitizes renal cell carcinoma cells to X-rays both in vitro and in vivo. Bioinformatic analysis shows that the ATM- and Rad3-related (ATR) kinase, a master conductor of cellular responses to DNA damage and DNA replication stresses, is a target of miR-185. This prediction was validated by luciferase reporter and mutation assays. We also demonstrated that miR-185 negatively regulates ATR expression at post-transcriptional level. miR-185 enhances radiation-induced apoptosis and inhibition of proliferation by repressing ATR pathway. In conclusion, our findings indicate a previously unreported regulatory mechanism for ATR expression mediated by miR-185 and shed light on the potential application of miRNAs both as direct cancer therapeutics and as tools to sensitize tumor cells to radiotherapy.
