miR-577 Regulates TGF-β Induced Cancer Progression through a SDPR-Modulated Positive-Feedback Loop with ERK-NF-κB in Gastric Cancer
miR-577 Regulates TGF-β Induced Cancer Progression through a SDPR-Modulated Positive-Feedback Loop with ERK-NF-κB in Gastric Cancer
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miR-577 通过 SDPR 调节的 ERK-NF-kappa B 正反馈环调节胃癌中 TGF-β 诱导的癌症进展
DOI：
10.1016/j.ymthe.2019.02.002
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发表时间：
2019-06-05
影响因子：
12.4
通讯作者：
Liao, Wangjun
中科院分区：
文献类型：
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作者：
Luo, Yuhao;Wu, Jianhua;Liao, Wangjun
转化生长因子β（TGF-β）驱动上皮-间充质转化（EMT），在癌症转移中起重要作用。microRNA（miRNAs）和TGF-β之间的串扰经常被观察到并参与TGF-β诱导的EMT。在这里，我们确定miR-577在胃癌（GC）中显著上调。miR-577表达与胃癌转移状态和患者预后不良正相关。功能分析表明，miR-577通过诱导EMT和干细胞样特性促进转移和化学抗性。此外，TGF-β促进miR-577的表达，并且miR-577参与TGF-β介导的癌症转移。从机制上讲，TGF-B通过NF-κ B介导的转录激活miR-577，而miR-577通过靶向血清剥夺蛋白反应（SDPR）增强TGF-β信号传导，SDPR直接与ERK相互作用以阻断ERK-NF-κ B途径，从而形成反馈环以驱动肿瘤转移。阐明了TGF-β网络诱导EMT的合理机制。我们的研究结果表明，TGF-β-miR-577-SDPR轴可能是一个潜在的预后标志物和治疗胃癌转移的靶点。
Transforming growth factor beta (TGF-beta) drives epithelial-mesenchymal transition (EMT), playing vital roles in cancer metastasis. The crosstalk between microRNAs (miRNAs) and TGF-beta are frequently observed and involved in TGF-beta-induced EMT. Here, we determine that miR-577 is significantly upregulated in gastric cancer (GC). miR-577 expression is positively correlated with GC metastasis status and poor patient prognosis. Functional assays demonstrate that miR-577 promotes metastasis and chemoresistance by inducing EMT and stemness-like properties. Moreover, TGF-beta promotes the expression of miR-577, and miR-577 participates TGF-beta-mediated cancer metastasis. Mechanistically, TGF-b activates miR-577 via NF-kappa B-mediated transcription, and miR-577 enhances TGF-beta signaling by targeting the serum deprivation protein response (SDPR), which directly interacts with ERK to inactivate the ERK-NF-kappa B pathway, hence forming a feedback loop to drive tumor metastasis. A plausible mechanism of EMT induction by the TGF-beta network is elucidated. Our findings suggest that the TGF-beta-miR-577-SDPR axis may be a potential prognostic marker and therapeutic target against cancer metastasis in GC.