Zhang Peijing, Wang Li, Rodriguez-Aguayo Cristian, Yuan Yuan, Debeb Bisrat G, Chen Dahu, Sun Yutong, You M James, Liu Yongqing, Dean Douglas C, Woodward Wendy A, Liang Han, Yang Xianbin, Lopez-Berestein Gabriel, Sood Anil K, Hu Ye, Ang K Kian, Chen Junjie, Ma Li
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nat Commun. 2014 Dec 5;5:5671. doi: 10.1038/ncomms6671.
Tumour cells associated with therapy resistance (radioresistance and drug resistance) are likely to give rise to local recurrence and distant metastatic relapse. Recent studies revealed microRNA (miRNA)-mediated regulation of metastasis and epithelial-mesenchymal transition; however, whether specific miRNAs regulate tumour radioresistance and can be exploited as radiosensitizing agents remains unclear. Here we find that miR-205 promotes radiosensitivity and is downregulated in radioresistant subpopulations of breast cancer cells, and that loss of miR-205 is highly associated with poor distant relapse-free survival in breast cancer patients. Notably, therapeutic delivery of miR-205 mimics via nanoliposomes can sensitize the tumour to radiation in a xenograft model. Mechanistically, radiation suppresses miR-205 expression through ataxia telangiectasia mutated (ATM) and zinc finger E-box binding homeobox 1 (ZEB1). Moreover, miR-205 inhibits DNA damage repair by targeting ZEB1 and the ubiquitin-conjugating enzyme Ubc13. These findings identify miR-205 as a radiosensitizing miRNA and reveal a new therapeutic strategy for radioresistant tumours.
与治疗抗性（放射抗性和药物抗性）相关的肿瘤细胞很可能导致局部复发和远处转移复发。最近的研究揭示了微小RNA（miRNA）介导的转移和上皮-间质转化调控；然而，特定的miRNA是否调节肿瘤放射抗性以及能否被用作放射增敏剂仍不清楚。在此，我们发现miR-205可促进放射敏感性，且在乳腺癌细胞的放射抗性亚群中表达下调，并且miR-205的缺失与乳腺癌患者远处无复发生存率低高度相关。值得注意的是，通过纳米脂质体进行miR-205模拟物的治疗性递送可使异种移植模型中的肿瘤对辐射敏感。从机制上讲，辐射通过共济失调毛细血管扩张症突变基因（ATM）和锌指E盒结合同源框1（ZEB1）抑制miR-205的表达。此外，miR-205通过靶向ZEB1和泛素结合酶Ubc13抑制DNA损伤修复。这些发现确定miR-205为一种放射增敏性miRNA，并揭示了一种针对放射抗性肿瘤的新治疗策略。
