MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer.
MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer.
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DOI：
10.18632/oncotarget.4702
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Yan GR
中科院分区：
文献类型：
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作者：
Chen D;Dang BL;Huang JZ;Chen M;Wu D;Xu ML;Li R;Yan GR
我们先前的蛋白质组学研究显示，硫氧还蛋白相互作用蛋白（TXNIP）被miR-373下调。然而，人们对miR-373降低TXNIP以刺激转移的机制知之甚少。在这项研究中，我们发现miR-373促进乳腺癌中的上皮向间质转化（EMT）。MiR-373通过与TXNIP的3′UTR结合来抑制TXNIP，这进而诱导癌细胞EMT和转移。TXNIP共表达逆转了miR-373诱导的EMT、迁移、侵袭和转移的增强，但TXNIP-3′UTR不逆转。MiR-373通过TXNIP依赖性活性氧（ROS）减少刺激EMT、迁移和侵袭。在机制上，miR-373通过TXNIP途径上调并激活HIF 1 α-TWIST信号轴。因此，TWIST通过与miR-371-373簇的启动子结合来诱导miR-373表达。在临床上，miR-373与TXNIP呈负相关，与HIF 1 α和TWIST呈正相关，miR-373-TXNIP-HIF 1 α-TWIST信号轴的激活与乳腺癌患者的不良结局相关。该信号轴可能是乳腺癌患者的独立预后因素。
Our previous proteomics study revealed that thioredoxin-interacting protein (TXNIP) was down-regulated by miR-373. However, little is known of the mechanism by which miR-373 decreases TXNIP to stimulate metastasis. In this study, we show that miR-373 promotes the epithelial-to-mesenchymal transition (EMT) in breast cancer. MiR-373 suppresses TXNIP by binding to the 3′UTR of TXNIP, which in turn, induces cancer cell EMT and metastasis. TXNIP co-expression, but not the TXNIP-3′UTR, reverses the enhancement of EMT, migration, invasion and metastasis induced by miR-373. MiR-373 stimulates EMT, migration and invasion through TXNIP-dependent reactive oxygen species (ROS) reduction. Mechanistically, miR-373 up-regulates and activates the HIF1α-TWIST signaling axis via the TXNIP pathway. Consequently, TWIST induces miR-373 expression by binding to the promoter of the miR-371-373 cluster. Clinically, miR-373 is negatively associated with TXNIP and positively associated with HIF1α and TWIST, and activation of the miR-373-TXNIP-HIF1α-TWIST signaling axis is correlated with a worse outcome in patients with breast cancer. This signaling axis may be an independent prognostic factor for patients with breast cancer.