MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA
MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA
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DOI：
10.1128/mcb.00941-08
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发表时间：
2008-11-15
影响因子：
5.3
通讯作者：
Cheng, Jin Q.
中科院分区：
文献类型：
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作者：
Kong, William;Yang, Hua;Cheng, Jin Q.
转化生长因子β (tgf - β)信号传导促进晚期恶性肿瘤的转移。虽然已知许多蛋白质编码基因参与了这一过程，但关于微rna （mirna）在tgf - β诱导的细胞迁移和侵袭中的作用的信息仍然有限。通过杂交基于515-miRNA寡核苷酸的微阵列文库，共发现28个mirna在tgf - β处理的正常小鼠乳腺（NMuMG）上皮细胞中显著失调，而Smad4敲除的NMuMG细胞则没有。在上调的miRNA中，miR-155是最显著升高的miRNA。tgf - β通过Smad4诱导miR-155表达和启动子活性。miR-155的敲低抑制tgf - β诱导的上皮-间质转化（EMT）和紧密连接溶解，以及细胞迁移和侵袭。此外，miR-155的异位表达降低了RhoA蛋白并破坏了紧密连接的形成。重新引入没有3'非翻译区的RhoA cDNA在很大程度上逆转了miR-155和tgf - β诱导的表型。此外，在浸润性乳腺癌组织中经常检测到miR-155水平升高。这些数据表明，miR-155可能通过靶向RhoA在tgf - β诱导的EMT和细胞迁移和侵袭中发挥重要作用，并表明它是乳腺癌干预的潜在治疗靶点。
Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs)in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.