中科院近代物理研究所空间辐射生物研究室科研人员利用microRNA增加细胞辐射敏感性研究取得新进展，首次报道了miR-185通过靶向调控关键的DNA损伤传感因子ATR增强电离辐射诱导的细胞凋亡及增殖抑制等效应。
microRNA(miRNA)是一类内源性非编码小RNA分子，能够在转录后水平通过与靶基因mRNA的3’非编码区（3’-UTR）相结合而调控靶基因的表达。miRNA参与多种生命进程，如细胞生长与分化、凋亡、发育、癌症发生等。现已证实，miRNA在细胞辐射应激响应过程中发挥重要作用，能够参与调节H2AX、ATM等DNA损伤感受因子。
科研人员研究发现，电离辐射能够引起肾癌细胞miR-185表达下调，而过表达miR-185能够增加细胞的辐射敏感性（图1）。生物信息学分析表明，DNA损伤应答因子ATR是miR-185潜在的靶基因，荧光素酶报告载体实验和突变实验证明了miR-185能够通过与ATRmRNA的3’-UTR区结合直接靶向调节ATR，过表达miR-185能够在mRNA和蛋白水平抑制ATR。实验表明，miR-185通过抑制ATR信号通路增强了辐射诱导的细胞凋亡（图2）及增殖抑制（图3）。
此项研究揭示了miRNA参与细胞辐射敏感性的新机制，对利用miRNA调控肿瘤辐射敏感性的研究具有重要意义。
研究成果在Cell Death&Disease发表。（生物谷 Bioon.com）
生物谷推荐的英文摘要
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.
