BACKGROUND The mechanisms responsible for cervical cancer radioresistance are still largely unexplored. The present study aimed to identify miRNAs associated with radioresistance of cervical cancer cells. METHODS The radioresistant cervical cancer cell variants were established by repeated selection with irradiation. The miRNA profiles of radioresistant cells and their corresponding controls were analyzed and compared using microarray. Differentially expressed miRNAs were confirmed by quantitative real-time PCR. Cervical cancer cells were transfected with miRNA-specific mimics or inhibitors. Radiosensitivity of cervical cancer cells were determined using colony-forming assay. RESULTS Among the differentially expressed miRNAs, 20 miRNAs showed the similar pattern of alteration (14 miRNAs were overexpressed whilst 6 were suppressed) in all three radioresistant cervical cancer cell variants compared to their controls. A miRNA signature consisting of 4 miRNAs (miR-630, miR-1246, miR-1290 and miR-3138) exhibited more than 5 folds of increase in radioresistant cells. Subsequent analysis revealed that these four miRNAs could be up-regulated in cervical cancer cells by radiation treatment in both time-dependent and dose-dependent manners. Ectopic expression of each of these 4 miRNAs can dramatically increase the survival fraction of irradiated cervical cancer cells. Moreover, inhibition of miR-630, one miRNA of the specific signature, could reverse radioresistance of cervical cancer cells. CONCLUSIONS The present study indicated that miRNA is involved in radioresistance of human cervical cancer cells and that a specific miRNA signature consisting of miR-630, miR-1246, miR-1290 and miR-3138 could promote radioresistance of cervical cancer cells.

中文翻译：

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特定的 miRNA 特征促进人宫颈癌细胞的放射抗性。

背景导致宫颈癌放射抗性的机制在很大程度上仍未被探索。本研究旨在鉴定与宫颈癌细胞放射抗性相关的 miRNA。方法通过辐照重复选择建立抗辐射宫颈癌细胞变异体。使用微阵列分析和比较抗辐射细胞及其相应对照的 miRNA 谱。差异表达的 miRNA 通过定量实时 PCR 得到证实。用 miRNA 特异性模拟物或抑制剂转染宫颈癌细胞。使用集落形成试验测定宫颈癌细胞的放射敏感性。结果 在差异表达的 miRNA 中，与其对照相比，所有三种抗辐射宫颈癌细胞变体中的 20 种 miRNA 显示出相似的改变模式（14 种 miRNA 过表达，而 6 种被抑制）。由 4 个 miRNA（miR-630、miR-1246、miR-1290 和 miR-3138）组成的 miRNA 特征在抗辐射细胞中表现出超过 5 倍的增加。随后的分析表明，这四种 miRNA 在宫颈癌细胞中可以通过放射治疗以时间依赖性和剂量依赖性方式上调。这 4 种 miRNA 中每一种的异位表达都可以显着增加受照射的宫颈癌细胞的存活率。此外，抑制 miR-630（一种具有特定特征的 miRNA）可以逆转宫颈癌细胞的放射抗性。