MRP-1/CD9 gene transduction downregulates Wnt signal pathways
MRP-1/CD9 gene transduction downregulates Wnt signal pathways
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DOI：
10.1038/sj.onc.1208063
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发表时间：
2004-09-30
期刊：
影响因子：
8
通讯作者：
Miyake, M
中科院分区：
文献类型：
--
作者：
Huang, CL;Liu, DG;Miyake, M
运动相关蛋白-1（MRP-1/CD 9）是一种跨膜糖蛋白，参与细胞粘附、运动、增殖和分化。它具有作为肿瘤转移抑制剂的功能作用。在肿瘤进展过程中，MRP-1/CD 9基因表达的降低导致肿瘤细胞具有高转移潜力。然而，MRP-1/CD 9的作用机制仍不清楚。我们研究了MRP-1/CD 9基因转导到肿瘤细胞株HT 1080和A549中的相关基因表达的变化，使用微阵列分析和实时PCR。因此，我们已经证明MRP-1/CD 9基因转导可以下调几个Wnt家族基因的表达，如Wnt 1，Wnt 2b 1和Wnt 5a，以及它们的靶基因，包括WISP-1（Wnt-1诱导的分泌蛋白1），WISP-3，c-Myc，血管内皮生长因子-A和基质金属蛋白酶-26。Western blot分析显示MRP-1/CD 9基因转导下调Wnt 1蛋白及其靶蛋白的表达。此外，中和性抗MRP-1/CD 9单克隆抗体抑制MRP-1/CD 9转染细胞中Wnt信号通路的下调。目前的研究表明，MRP-1/CD 9信号位于Wnt信号通路的上游。因此，MRP-1/CD 9可能通过下调Wnt 1表达抑制上皮细胞向间质细胞转化，并可能通过下调Wnt 5a表达抑制肿瘤转移。
Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/ CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/ CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/ CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/ CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.