Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells
Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells
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DOI：
10.1038/sj.onc.1208729
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发表时间：
2005-07-28
期刊：
影响因子：
8
通讯作者：
O'Connor, KL
中科院分区：
文献类型：
--
作者：
Chen, M;O'Connor, KL
在晚期乳腺癌中，α 6 β 4整合素与迁移和侵袭表型相关。在我们目前的研究中，我们表明，α 6 β 4整合素在MDA-MB- 435乳腺癌细胞中的表达导致自分泌运动因子自分泌运动因子的表达增加，如通过Affyssin基因芯片、实时定量RT-PCR和免疫印迹分析所确定的。我们进一步证明，从整合素α 6 β 4表达细胞分泌增加的自分泌运动因子通过其将溶血磷脂酰胆碱（LPC）转化为溶血磷脂酸（LPA）的能力来增强趋化性，并占条件培养基的运动活性的80%。通过使用特异性靶向自分泌运动因子、整合素β 4、NFAT 1和NFAT 5的siRNA，我们确定了MDA- MB- 435细胞中自分泌运动因子的整合素α 6 β 4依赖性过表达是由NFAT 1介导的，而不是NFAT 5。最后，我们通过电泳迁移率变动分析表明，在自分泌运动因子启动子中发现的两个共有NFAT结合位点强烈且特异性地结合来自整合素a6 b4表达细胞的NFAT 1。总之，我们发现α 6 β 4整联蛋白通过上调和激活NFAT 1增强自分泌运动因子的表达。这些观察首次突出了NFAT转录因子可以促进整合素α 6 β 4信号传导下游的侵袭性和运动性表型的机制。
In advanced breast carcinomas, the alpha 6 beta 4 integrin is associated with a migratory and invasive phenotype. In our current study, we show that expression of the a6b4 integrin in MDA- MB- 435 breast carcinoma cells leads to increased expression of the autocrine motility factor autotaxin, as determined by Affymetrix gene chip, realtime quantitative RT-PCR and immunoblot analyses. We further demonstrate that increased autotaxin secretion from integrin a6b4 expressing cells acts to enhance chemotaxis through its ability to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and accounts for 80% of the motogenic activity of the conditioned medium. We determine that integrin alpha 6 beta 4dependent overexpression of autotaxin in MDA- MB- 435 cells is mediated by NFAT1, but not NFAT5, through the use of siRNAs that specifically target autotaxin, integrin beta 4, NFAT1 and NFAT5. Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin a6b4 expressing cells. In summary, we find that the a6b4 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1. The se observations highlight for the first time a mechanism by which NFAT transcription factors can facilitate an invasive and motile phenotype downstream of integrin a6b4 signaling.