School of Radiation Medicine and Public Health, Soochow University, Suzhou, Jiangsu 215123, China.
J Radiat Res. 2013 Jul 1;54(4):611-9. doi: 10.1093/jrr/rrs136. Epub 2013 Jan 24.
miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy.
miR-34a 是由肿瘤抑制基因 p53 转录诱导的，而 p53 在非小细胞肺癌（NSCLC）中经常下调。为了确定 miR-34a 的下游信号是否足以诱导细胞凋亡并改变细胞放射敏感性，将化学合成的 miR-34a 模拟物递送至 A549 和 H1299 细胞中，无论是否与 γ 射线照射共同处理。结果表明，在这两种 NSCLC 细胞系中，miR-34a 的异位表达以 p53 非依赖性方式诱导了剂量依赖性的细胞生长抑制和细胞凋亡。有趣的是，LyGDI 被发现是 miR-34a 的一个新的靶基因，下调 LyGDI 可促进 Rac1 激活和膜易位，导致细胞凋亡。此外，miR-34a 的恢复可间接降低环氧化酶-2（COX-2）的表达。总之，这些结果表明，恢复 miR-34a 的表达可增强放射诱导的细胞凋亡，部分是通过抑制 LyGDI 信号通路实现的，miR-34a 可能可作为非小细胞肺癌治疗的放射增敏剂。
