Therapeutic Delivery of miR-200c Enhances Radiosensitivity in Lung Cancer
Therapeutic Delivery of miR-200c Enhances Radiosensitivity in Lung Cancer
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DOI：
10.1038/mt.2014.79
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发表时间：
2014-08-01
影响因子：
12.4
通讯作者：
Welsh, James W.
中科院分区：
文献类型：
--
作者：
Cortez, Maria Angelica;Valdecanas, David;Welsh, James W.
microRNA (miR)-200s及其负调节因子ZEB1在上皮间质转化的背景下被广泛研究。miR-200s的缺失已被证明可以增强癌症的侵袭性和转移，而mir - 200mirna的替代已被证明可以抑制包括肺癌在内的几种类型肿瘤的细胞生长。在这里，我们揭示了miR-200c （miR-200家族的一员）在调节细胞内活性氧信号中的新功能，并探索了其与已知的增加氧化应激的疗法（如辐射）联合使用的潜在应用。我们发现，miR-200c过表达通过直接调控氧化应激反应基因PRDX2、GAPB/Nrf2和SESN1来增加细胞放射敏感性，从而抑制DNA双链断裂修复，增加活性氧水平，上调p21。我们使用肺癌异种移植模型来进一步证明全身递送miR-200c增强肺癌放射敏感性的治疗潜力。我们的研究结果表明，miR-200c的抗肿瘤作用部分源于其对氧化应激反应的调节；他们进一步提出，miR-200c联合放疗可能代表未来的一种治疗策略。
The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative, stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.