MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1
MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1
复制标题
MiR-210-3p 通过靶向 BARD1 保护子宫内膜异位细胞免受氧化应激诱导的细胞周期停滞。
DOI：
10.1038/s41419-019-1395-6
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发表时间：
2019-02-13
影响因子：
9
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
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作者：
Dai, Yongdong;Lin, Xiang;Zhang, Songying
子宫内膜异位症与子宫外环境中良性但不良发展的囊肿有关。氧化不平衡环境诱导DNA损伤并影响子宫内膜基质细胞（ESCs）和子宫内膜上皮细胞的细胞周期进程，但子宫内膜异位细胞如何在氧化应激存在下维持增殖尚不清楚。越来越多的证据表明，异位缺氧微环境和氧化应激可以刺激凋亡细胞的生长，这主要是由于HIF-1α的增加。我们发现，与在位和正常子宫内膜相比，异位病变的间质和腺细胞中主要缺氧相关的miRNA miR-210- 3 p增加，并且与HIF-1α和局部氧化应激诱导的DNA损伤预测因子8-OHdG的表达一致。此外，miR-210- 3 p在低氧条件下在ESC和石川细胞中上调，而在常氧培养中则没有。在低氧条件下，miR-210- 3 p的敲除可诱导ESCs和石川细胞发生G2/M期阻滞，而在常氧条件下则无此效应。BARD 1被鉴定为miR-210- 3 p的靶点。BARD 1在异位组织中的表达低于在位组织和正常组织，并与miR-210- 3 p的表达呈负相关。多因素回归分析显示BARD 1表达下调可作为判断糖尿病严重程度的指标。我们的研究结果表明，miR-210- 3 p通过靶向BARD 1 mRNA的3′非翻译区，使BRCA 1复合物功能失活，从而减弱G2/M细胞周期检查点。子宫内膜异位症小鼠模型实验表明，腹腔注射miR-210- 3 p抑制剂或维生素C抑制了子宫内膜异位症病变的生长。总之，我们的研究结果表明，凋亡细胞通过上调miR-210- 3 p抑制BARD 1/BRCA 1功能，这可能是凋亡细胞在氧化应激下维持生长的潜在机制。此外，抑制miR-210- 3 p和给予维生素C是治疗子宫内膜异位症的有希望的方法。
Endometriosis is associated with benign but adversely developed cysts in the extrauterine environment. The oxidative imbalanced environment induces DNA damage and affects cell cycle progression of endometrial stromal cells (ESCs) and endometrial epithelial cells, but how endometriotic cells maintain proliferation in the presence of oxidative stress is not clear. Growing evidence has indicated that the ectopic hypoxic microenvironment and oxidative stress can stimulate the growth of endometriotic cells, which is mainly due to the increase of HIF-1α. We found that the master hypoxia-associated miRNA miR-210-3p was increased in stromal and glandular cells of ectopic lesions compared with that of eutopic and normal endometria and was consistent with the expression of HIF-1α and the local oxidative stress-induced DNA damage predictor 8-OHdG. Moreover, miR-210-3p was upregulated in ESCs and Ishikawa cells under hypoxic conditions but not in normoxic culture. Knockdown of miR-210-3p induced a G2/M arrest of ESCs and Ishikawa cells under hypoxia, while no effect was found under normoxia. BARD1 was identified as a target of miR-210-3p. BARD1 expression was decreased in endometriotic tissues compared with eutopic and normal endometria and negatively correlated with the expression of miR-210-3p. Multivariate regression analysis showed that BARD1 downregulation could serve as an indicator for endometriotic severity. Our results suggest that miR-210-3p attenuates the G2/M cell cycle checkpoint by inactivating BRCA1 complex function in response to DNA damage under hypoxia via targeting the 3′ untranslated region of BARD1 mRNA. Endometriotic mouse model experiments showed that intraperitoneal injection of the miR-210-3p inhibitor or vitamin C suppressed the growth of endometriotic lesions. Together, our results demonstrate that endometriotic cells inhibit BARD1/BRCA1 function by upregulating miR-210-3p, which might be the underlying mechanism for endometriotic cell maintenance of growth in oxidative stress. Furthermore, inhibition of miR-210-3p and administration of vitamin C are promising approaches for the treatment of endometriosis.