miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-κB in high-grade serous ovarian carcinoma
miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-κB in high-grade serous ovarian carcinoma
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miR-130a 在高级别浆液性卵巢癌中通过靶向 TSC1 上调 mTOR 通路并被 NF-κ B 反式激活
DOI：
10.1038/cdd.2017.129
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发表时间：
2017-12-01
影响因子：
12.4
通讯作者：
Liu, Zhaojian
中科院分区：
文献类型：
--
作者：
Wang, Yuqiong;Zhang, Xiyu;Liu, Zhaojian
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的激活与上皮性卵巢癌的不良预后有关。TSC1-TSC2复合体是mTOR信号传导的关键负调控因子。在这里，我们证明TSC1在高级别浆液性卵巢癌（HGSOC）中经常下调，TSC1的低表达水平与肿瘤的晚期有关。接下来，我们通过靶向TSC1的3'UTR，确定了miR-130a是TSC1的负调控因子。miR-130a在HGSOC中过表达，可驱动卵巢癌细胞增殖和侵袭转移。miR-130a还能减弱雷帕霉素/饥饿诱导的自噬。TSC1异位表达可阻断miR-130a对细胞增殖、迁移和自噬的影响。最后，我们发现miR-130a的表达可以被炎症因子上调，并被NF-kappa b反激活。因此，我们的研究结果建立了炎症和mTOR信号之间的串扰，该串扰是由miR-130a介导的，可能在HGSOC的发生和进展中起关键作用。
Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells. miR-130a could also attenuate rapamycin/starvation-induced autophagy. Ectopic TSC1 expression could block the effects of miR-130a on cell proliferation, migration and autophagy. Finally, we found that miR-130a expression could be upregulated by inflammatory factors and was transactivated by NF-kappa B. Therefore, our findings establish a crosstalk between inflammation and mTOR signaling that is mediated by miR-130a, which might have a pivotal role in the initiation and progression of HGSOC.