miR-5003-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization and direct targeting of E-cadherin
miR-5003-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization and direct targeting of E-cadherin
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DOI：
10.1093/jmcb/mjw026
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发表时间：
2016-10-01
影响因子：
5.5
通讯作者：
Han, Young-Hoon
中科院分区：
文献类型：
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作者：
Kwak, Seo-Young;Yoo, Je-Ok;Han, Young-Hoon
转移扩散的最初步骤之一是上皮-间充质转化(EMT)。沿着这一路线，microRNAs(MiRNAs)已被证明在不同阶段发挥着肿瘤进展的重要调节作用。因此，我们对调节EMT的miRNAs进行了功能筛选，并鉴定了几个候选的miRNAs。其中，我们证明了miR-5003-3p诱导了EMT特有的细胞特征。MIR-5003-3p通过蛋白稳定诱导E-钙粘蛋白的转录抑制因子Snail表达上调。MDM2被确定为miR-5003-3p的直接靶点，其下调可诱导钉螺稳定。E-钙粘蛋白也是miR-5003-3p的直接靶点，增强了miR-5003-3p的EMT促进功能。组织芯片原位杂交和免疫组织化学分析显示，miR-5003-3p在配对转移性乳腺癌组织中的表达高于在原发导管癌组织中的表达，且与MDM2和E-cadherin的表达呈负相关。此外，在尾静脉注射实验中，miR-5003-3P可促进小鼠肺内转移结节的形成。综上所述，我们的结果提示miR-5003-3p通过双重调节Snail稳定性和E-cadherin来促进EMT，从而发挥转移激活剂的作用，因此可能成为转移癌的潜在治疗靶点。
One of the initial steps in metastatic dissemination is the epithelial-mesenchymal transition (EMT). Along this line, microRNAs (miRNAs) have been shown to function as important regulators of tumor progression at various stages. Therefore, we performed a functional screening for EMT-regulating miRNAs and identified several candidate miRNAs. Among these, we demonstrated that miR-5003-3p induces cellular features characteristic of EMT. miR-5003-3p induced upregulation of Snail, a key EMT-promoting transcription factor and transcriptional repressor of E-cadherin, through protein stabilization. MDM2 was identified as a direct target of miR-5003-3p, the downregulation of which induced Snail stabilization. E-cadherin was also demonstrated to be a direct target of miR-5003-3p, reinforcing the EMT-promoting function of miR-5003-3p. In situ hybridization and immunohistochemical analyses using tissue microarrays revealed that miR-5003-3p expression was higher in paired metastatic breast carcinoma tissues than in primary ductal carcinoma tissues, and was inversely correlated with the expression of MDM2 and E-cadherin. Furthermore, miR-5003-3p enhanced the formation of metastatic nodules in the lungs of mice in a tail vein injection experiment. Collectively, our results suggest that miR-5003-3p functions as a metastasis activator by promoting EMT through dual regulation of Snail stability and E-cadherin, and may therefore be a potential therapeutic target in metastatic cancers.