MiR-495 functions as an adjuvant to radiation therapy by reducing the radiation-induced bystander effect
MiR-495 functions as an adjuvant to radiation therapy by reducing the radiation-induced bystander effect
复制标题
MiR-495 通过减少辐射引起的旁观者效应，充当放射治疗的佐剂。
DOI：
10.1093/abbs/gmw098
复制
发表时间：
2016-11-01
影响因子：
3.7
通讯作者：
Song, Haifeng
中科院分区：
文献类型：
--
作者：
Fu, Jie;Jiang, Mengmeng;Song, Haifeng
放射诱导的旁观者效应（里贝）是肿瘤放射治疗中的一个重要因素，它可增加放疗后正常细胞损伤的概率和继发癌的可能性。在这里，我们确定了miR-495在减轻放射治疗期间的RIBE中的作用。荧光素酶报告基因分析结果证实miR-495通过靶向Sp1 3 '非翻译区调控内皮型一氧化氮合酶（eNOS）。因此，放射后，肿瘤细胞表达的eNOS和Sp1比对照组少。基于流式细胞术和酶联免疫吸附试验的体外细胞辐射数据证实，一氧化氮（NO）及其下游产物转化生长因子β1（TGF-β1）是促进RIBE的关键信号因子。当用miR-495过表达的HepG 2和ZR 75 -1肿瘤细胞的培养基处理时，观察到更少的正常LO 2肝细胞损伤和更少的微核。相应地，用miR-495 Escheromir处理导致更高的NO和TGF-β1水平和更多的损伤的LO 2细胞。体内实验表明，与对照组相比，局部照射过表达miR-495的肿瘤在未照射的肝组织中产生较少的坏死灶。与癌旁组织相比，临床癌组织中miR-495表达上调，放射线照射可显著降低癌细胞系中miR-495的表达水平。总之，miR-495可能有希望作为肿瘤放射治疗的佐剂，以减少涉及Sp1/eNOS通路的RIBE。
The radiation-induced bystander effect (RIBE) is an important factor in tumor radiation therapy because it may increase the probability of normal cellular injury and the likelihood of secondary cancers after radiotherapy. Here, we identified the role of miR-495 in alleviating RIBEs during radiotherapy. Luciferase reporter assay results confirmed that miR-495 regulated endothelial nitric oxide synthase (eNOS) by targeting the Sp1 3'-untranslated region. Consequently, after radiation, tumor cells expressed less eNOS and Sp1 than controls. In vitro cell irradiation data based on flow-cytometric analysis and enzymed linked immunosorbent assay confirmed that nitric oxide (NO) and its downstream product transforming growth factor β1 (TGF-β1) were critical signaling factors contributing to RIBEs. Fewer normal LO2 liver cells were injured and fewer micronuclei were observed when treated with the medium of the miR-495 overexpressing HepG2 and ZR75-1 tumor cells. Accordingly, treatment with the miR-495 antagomir led to higher NO and TGF-β1 levels and more injured LO2 cells. In vivo experiments indicated that local irradiation of tumors overexpressing miR-495 produced fewer necrotic foci in non-irradiated liver tissue compared with controls. miR-495 was upregulated in clinical cancer tissues compared with adjacent non-cancerous tissues, and radiation significantly reduced the expression level of miR-495 in carcinoma cell lines. In summary, miR-495 may have promise as an adjuvant for tumor radiation therapy to decrease RIBEs involving the Sp1/eNOS pathway.