Tang Yiting, Cui Yayun, Li Zengpeng, Jiao Zhuqing, Zhang Yong, He Yan, Chen Guangxia, Zhou Qunyan, Wang Wenjie, Zhou Xifa, Luo Judong, Zhang Shuyu
Department of Radiation Oncology, Changzhou Cancer Hospital, Soochow University, Changzhou, 213001, China.
Department of Radiation Oncology, Anhui Provincial Hospital, Hefei, 213001, China.
J Exp Clin Cancer Res. 2016 Jan 12;35:7. doi: 10.1186/s13046-016-0285-3.
Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses.
In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism.
Nine miRNAs, including miR-29b-3p, miR-200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR-208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects.
The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients.
在发达国家和欠发达国家，肺癌长期以来一直是男性中最危险的恶性肿瘤。放射治疗在不可切除的非小细胞肺癌（NSCLC）的治疗管理中起着关键作用，也用于肺癌患者的术后治疗。放射抗性是限制NSCLC患者放射治疗疗效的一个重要因素。越来越多的证据表明，微小RNA（miRNA）在辐射反应中具有多种细胞调节作用。
在本研究中，我们使用miRNA微阵列技术来鉴定肺癌患者放疗前后血清中差异表达的miRNA。我们进一步研究了miR-208a对人肺癌细胞活力、凋亡死亡和细胞周期分布的生物学功能，并探讨了可能的机制。
包括miR-29b-3p、miR-200a-3p和miR-126-3p在内的9种miRNA显著下调，而miR-208a是放疗后患者血清中唯一上调的miRNA（P<0.05）。miR-208a的表达可在肺癌细胞中由X射线照射诱导。miR-208a的强制表达通过靶向p21促进肺癌细胞增殖并诱导放射抗性，同时激活AKT/mTOR途径，而miR-208a的下调则产生相反的效果。此外，miR-208a的下调增加了NSCLC细胞中凋亡细胞的百分比，并抑制了G1期阻滞。此外，肺癌患者血清外泌体部分中的miR-208a可以以时间依赖性方式穿梭到A549细胞中，这可能有助于随后的生物学效应。
本研究提供了证据表明，miR-208a可通过靶向p21影响人肺癌细胞的增殖和放射敏感性，并且可以通过外泌体运输。因此，miR-208a可能作为肺癌患者的潜在治疗靶点。
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