MicroRNA-138 Regulates DNA Damage Response in Small Cell Lung Cancer Cells by Directly Targeting H2AX
MicroRNA-138 Regulates DNA Damage Response in Small Cell Lung Cancer Cells by Directly Targeting H2AX
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DOI：
10.3109/07357907.2015.1006329
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发表时间：
2015-04
影响因子：
2.4
通讯作者：
Huan Yang;Jinwen Luo;Zhiguang Liu;R. Zhou;Hong-lin Luo
中科院分区：
文献类型：
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作者：
Huan Yang;Jinwen Luo;Zhiguang Liu;R. Zhou;Hong-lin Luo
肺癌是世界范围内癌症死亡的主要原因，小细胞肺癌（SCLC）占所有肺癌病例的很大比例。即便如此，控制SCLC发展的潜在机制仍然知之甚少，尽管几十年的深入研究，SCLC相关的癌症死亡率仍然很高。我们注意到miR-138和H2AX都与各种恶性肿瘤的发展有关。此外，最近有报道显示miR-138通过靶向H2AX介导DNA损伤反应。根据这些数据，我们试图通过调节H2AX表达来表征miR-138在SCLC细胞生长和细胞周期进程中的作用。结果显示，miR-138在SCLC肿瘤组织以及三种SCLC细胞系中均显著下调。在一种SCLC细胞系NCI-H2081中成功设计miR-138过表达后，我们观察到细胞生长显著减少，细胞周期进展明显受到抑制。此外，我们能够证明miR-138能够有效抑制H2AX的表达，这表明H2AX可能是miR-138的下游执行子。与这一假设一致，我们发现在SCLC生长和细胞周期调节方面，工程H2AX敲低达到了与miR-138过表达相似的效果。我们还发现H2AX过表达在很大程度上消除了miR-138介导的SCLC癌细胞生长和细胞周期进展抑制，这强烈表明，至少在体外，miR-138通过靶向H2AX有效调节SCLC的发展。此外，我们发现较低的miR-138表达赋予SCLC细胞更大的DNA损伤修复能力。最后，我们能够证明miR-138过表达抑制SCLC细胞的DNA损伤修复，而miR-138敲低进一步促进IR后这些细胞的DNA损伤修复。迄今为止，还没有研究表明miR-138/H2AX机制在SCLC发展中的作用。我们的研究结果可能有助于开发新的SCLC诊断和治疗方法。
Lung cancer is the leading cause of cancer death worldwide and small cell lung cancer (SCLC) accounts for a significant proportion of all lung cancer cases. Even so, the underlying mechanism governing SCLC development remains poorly understood and SCLC related cancer death stands high despite decades of intensive investigation. We noted that both miR-138 and H2AX have been implicated in development of various malignancies. Also, there is a recent report showing the role of miR-138 in mediating DNA damage response by targeting H2AX. In light of these data, we sought to characterize the role of miR-138 for SCLC cell growth and cell-cycle progression by regulating H2AX expression. Results showed that miR-138 is significantly down-regulated in SCLC tumor tissues as well as in three SCLC cell lines. After successfully engineering miR-138 overexpression in one of the SCLC cell lines, NCI-H2081, we observed a remarkable reduction of cell growth and a significant inhibition on cell-cycle progression. Moreover, we were able to show that miR-138 potently inhibits H2AX expression, which suggests that H2AX may serve as a downstream executor for miR-138. Consistent with this hypothesis, we found that engineered H2AX knockdown achieves a similar effect as observed for miR-138 overexpression in terms of SCLC growth and cell cycle regulation. We also showed that H2AX overexpression largely abolished miR-138-mediated SCLC cancer cell growth and cell-cycle progression inhibition, which strongly suggests, at least in vitro, that miR-138 potently regulates SCLC development by targeting H2AX. In addition, we found lower miR-138 expression confers SCLC cells with greater DNA damage repair capacity. Finally, we were able to show miR-138 overexpression inhibits DNA damage repair in SCLC cells while miR-138 knockdown further facilitates DNA damage repair in these cells after IR. To date, there has been no study showing the role of miR-138/H2AX machinery in SCLC development. Our results may shed a light to development of new lines of SCLC diagnosis and treatment approaches.