Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, France.
Cell Death Dis. 2013 Mar 14;4(3):e544. doi: 10.1038/cddis.2013.71.
The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization.
缺氧细胞对放疗和化疗的抵抗力是癌症治疗中的一个主要问题。最近，出现了一种缺氧诱导因子 (HIF) 依赖性转录调控的附加模式，涉及到一组特定的 microRNAs (miRNAs) 的调节，包括 miR-210。我们最近表明，HIF-1 诱导的 miR-210 也通过正反馈环稳定 HIF-1。因此，我们假设通过在常氧条件下稳定 HIF-1，miR-210 可以保护癌细胞免受辐射。我们开发了一种非小细胞肺癌 (NSCLC) 衍生的细胞系 (A549)，该细胞系稳定表达 miR-210 (pmiR-210) 或对照 miRNA (pmiR-Ctl)。表达 miR-210 的细胞表现出与线粒体缺陷和糖酵解表型相关的 HIF-1 显著稳定。细胞在常氧和缺氧条件下接受 0 至 10 Gy 的辐射水平。在常氧条件下表达 miR-210 的细胞与缺氧条件下的对照细胞具有相同的放射抗性。在缺氧条件下，由于凋亡减少，pmiR-210 细胞的死亡率较低，即使在 10 Gy 时也能生长。这种 miR-210 表型在另一种 NSCLC 细胞系 (H1975) 和 HeLa 细胞中得到了重现。我们已经确定放射抗性与 p53 和细胞周期状态无关。此外，我们还表明，基因组双链断裂 (DSB) 焦点在 pmiR-210 细胞中比在 pmiR-Ctl 细胞中消失得更快，这表明 miR-210 表达促进了更有效的 DSB 修复。最后，在 pmiR-210 细胞中无效化 HIF-1 消除了放射抗性表型，表明这种机制依赖于 HIF-1。总之，miR-210 似乎是缺氧癌细胞放射抗性的一个组成部分。鉴于大多数 miRNAs 的高稳定性，肿瘤细胞可以在再氧合发生的情况下利用这一优势，并表明靶向 miR-210 的策略可以增强肿瘤的放射增敏作用。
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