A Fra-1-dependent, matrix metalloproteinase driven EGFR activation promotes human lung epithelial cell motility and invasion.
A Fra-1-dependent, matrix metalloproteinase driven EGFR activation promotes human lung epithelial cell motility and invasion.
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DOI：
10.1002/jcp.21410
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发表时间：
2008-08
影响因子：
5.6
通讯作者：
Reddy, Sekhar P.
中科院分区：
文献类型：
--
作者：
Adiseshaiah, Pavan;Vaz, Michelle;Machireddy, Narsa;Kalvakolanu, Dhananjaya V.;Reddy, Sekhar P.
我们和其他人已经证明了呼吸道致癌物对肺上皮细胞中Fra-1转录因子(AP-1的二聚体伙伴)水平的持续高诱导。FRA-1在多种人类肿瘤和癌细胞中经常过表达。我们最近发现FrA-1显著促进人肺上皮细胞的生长、运动和侵袭，但这种增强的确切分子机制尚不清楚。由于基质金属蛋白酶(MMPs)在伤口愈合和肺癌转移中起关键作用，我们验证了Fra-1通过激活MMPs促进肺上皮细胞运动和侵袭的假说。我们的研究表明，基质金属蛋白酶-9和基质金属蛋白酶-2激活的信号在调节Fra-1诱导的肺上皮细胞生长和侵袭中起关键作用。异位Fra-1显著刺激基质金属蛋白酶-2和基质金属蛋白酶-9的mRNA表达。抑制基质金属蛋白酶-2和基质金属蛋白酶-9活性显著减弱由Fra-1驱动的细胞运动和侵袭。此外，Fra-1以一种依赖于基质金属蛋白酶的方式诱导EGFR的磷酸化，并且EGFR特异性的抑制剂能够阻断Fra-1增强的细胞运动和侵袭。综上所述，我们的数据提示Fra-1通过诱导MMPs的活性，特别是MMP2和MMP9的活性，以及EGFR激活的信号转导来增强肺癌上皮细胞的运动和侵袭能力。
We and others have shown a persistently high induction of Fra-1 transcription factor (a dimeric partner of AP-1) levels by respiratory carcinogens in pulmonary epithelial cells. Fra-1 is frequently overexpressed in various human tumors and cancer cells. We have recently shown that Fra-1 significantly promotes growth, motility, and invasion of human pulmonary epithelial cells, the precise molecular mechanisms by which this enhancement occurs are unclear. Because matrix metalloproteinases (MMPs) play key roles in wound healing and lung tumor metastasis, we tested the hypothesis that Fra-1 promotes lung epithelial cell motility and invasion via MMP activation. We show here that MMP-9 and MMP-2 activated signaling plays a critical role in regulating Fra-1-induced lung epithelial cell growth and invasion. Ectopic Fra-1 markedly stimulates MMP-2 and MMP-9 mRNA expression. Inhibition of MMP-2 and MMP-9 activity significantly attenuated Fra-1-driven cell motility and invasion. Furthermore, Fra-1 induced EGFR phosphorylation in an MMP-dependent manner, and an EGFR-specific inhibitor was able to block Fra-1-enhanced cell motility and invasion. Taken together, our data suggest that Fra-1 enhances lung cancer epithelial cell motility and invasion by inducing the activity of MMPs, in particular MMP-2 and MMP-9, and EGFR-activated signaling.
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