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首页> 外文期刊>Thoracic cancer. >Rad51 in regulating the radiosensitivity of non‐small cell lung cancer with different epidermal growth factor receptor mutation status
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Rad51 in regulating the radiosensitivity of non‐small cell lung cancer with different epidermal growth factor receptor mutation status

机译：Rad51调节具有不同表皮生长因子受体突变状态的非小细胞肺癌的放射敏感性

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AbstractBackgroundNon-small cell lung cancer (NSCLC) harboring kinase-domain mutations in epidermal growth factor receptors (EGFR) has been observed to be sensitive to ionizing radiation (IR). We explore Rad51-dependent homologous recombination (HR) DNA repair in regulating radiosensitivity in two NSCLC cell lines with different EGFR mutation status.MethodsNSCLC cell lines, wild-type EGFR A549 and mutant EGFR H820 with an in-frame deletion in exon 19 of EGFR (ΔE746–E750), were cultured. Radiosensitivity was estimated by colony forming assay. Rad51 expression was evaluated by quantitative real time-polymerase chain reaction and Western-blot. Lentiviral small hairpin ribonucleic acid-Rad51 and ΔE746–E750 deletion mutant EGFR were constructed and transfected into cells. Flowcytometry assay was used to analyze DNA double strand breaks, cell cycle alterations, and apoptosis.ResultsA549 had a higher survival factor (SF)2 (0.66 vs. 0.44) and lower α/β value (4.07 vs. 9.01). Compared with the A549 cell, the H820 cell exhibited defective arrest in the S-phase, a higher rate of G2/M accumulation, early apoptosis, and residual γ-H2AX. Downregulated Rad51 expression decreased SF2 (0.42 vs. 0.31) and increased the α/β ratio (7.51 vs. 10.5), G2/M accumulation, early apoptosis, and γ-H2AX in two cell lines. H820 had a low IR-induced Rad51 expression and nuclear translocation. Exogenous expression of the ΔE746–E750 deletion mutant EGFR caused the A549 cell to become more radiosensitive.ConclusionsAn EGFR mutated NSCLC cell line is sensitive to IR, which is correlated with reduced IR-induced Rad51 expression and nuclear translocation. The signaling pathway of EGFR maintaining Rad51 protein levels maybe a novel lung cancer therapeutic target to overcome radioresistance.
机译：摘要背景已观察到在表皮生长因子受体（EGFR）中具有激酶结构域突变的非小细胞肺癌（NSCLC）对电离辐射（IR）敏感。我们探讨了Rad51依赖的同源重组（HR）DNA修复在调节具有不同EGFR突变状态的两种NSCLC细胞系中的放射敏感性中的方法。 （ΔE746–E750）被培养。通过菌落形成测定法估计放射敏感性。 Rad51表达通过实时定量聚合酶链反应和Western印迹进行评估。构建了慢病毒小发夹状核糖核酸-Rad51和ΔE746-E750缺失突变型EGFR，并将其转染到细胞中。流式细胞仪检测DNA双链断裂，细胞周期改变和凋亡。结果A549的生存因子（SF）2较高（0.66 vs. 0.44），α/β值较低（4.07 vs 9.01）。与A549细胞相比，H820细胞在S期停滞缺陷，G2 / M积累率更高，早期凋亡和残留的γ-H2AX更高。下调的Rad51表达降低了两个细胞系中的SF2（0.42对0.31）并增加了α/β比（7.51对10.5），G2 / M积累，早期凋亡和γ-H2AX。 H820具有低IR诱导的Rad51表达和核易位。 ΔE746–E750缺失突变体EGFR的外源表达导致A549细胞变得放射敏感性更高。结论EGFR突变的NSCLC细胞系对IR敏感，这与IR诱导的Rad51表达减少和核易位相关。 EGFR维持Rad51蛋白水平的信号传导途径可能是克服放射抗性的新型肺癌治疗靶点。

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