Slug Is a Downstream Mediator of Transforming Growth Factor-β1-Induced Matrix Metalloproteinase-9 Expression and Invasion of Oral Cancer Cells
Slug Is a Downstream Mediator of Transforming Growth Factor-β1-Induced Matrix Metalloproteinase-9 Expression and Invasion of Oral Cancer Cells
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DOI：
10.1002/jcb.22309
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发表时间：
2009-10-15
影响因子：
4
通讯作者：
Munshi, Hidayatullah G.
中科院分区：
文献类型：
--
作者：
Joseph, Mathew J.;Dangi-Garimella, Surabbi;Munshi, Hidayatullah G.
蜗牛转录因子家族成员通过诱导上皮-间质转化、促进侵袭和增加基质金属蛋白酶（MMP）表达在口腔癌的进展中发挥重要作用。虽然Snail （Snai1）是该家族中最具特征和研究最广泛的成员，但Slug （Snai2）在口腔癌进展中的作用和调控尚不清楚。在本报告中，我们发现转化生长因子- β 1 （tgf - β 1）增加了三永生化口腔角质形成细胞和恶性口腔鳞状细胞癌（OSCC）细胞中的Slug水平。抑制ERK1/2信号通路，而非pi3激酶信号通路，可阻断tgf - β 1诱导的恶性UMSCC1细胞中Slug的表达。为了进一步研究Slug在OSCC进展中的作用，我们产生了诱导表达Slug蛋白的UMSCC1细胞。在UMSCC1细胞中诱导Slug不会抑制E-cadherin水平或调节UMSCC1细胞的个体运动。相反，Slug增强了UMSCC1细胞的队列迁移和Matrigel侵袭。Slug增加了MMP-9水平，MMP-9特异性siRNA阻断了Slug诱导的Matrigel侵袭。有趣的是，蛞蝓特异性siRNA减弱了tgf - β 1诱导的MMP-9表达和Matrigel侵袭。这些数据表明tgf - β 1通过ERK1/2信号通路增加了Slug，从而促进了OSCC的进展。j .细胞。中国生物医学工程学报，2009,31(2):526 - 536。(C) 2009 Wiley-Liss, Inc。
Members of Snail family of transcription factors play an important role in oral cancer progression by inducing epithelial-mesenchymal transition, by promoting invasion and by increasing matrix metalloproteinase (MMP) expression. Although Snail (Snai1) is the best characterized and the most extensively studied member of this family, the role and regulation of Slug (Snai2) in oral cancer progression is less well understood. In this report, we show that transforming growth factor-beta 1 (TGF-beta 1) increases Slug levels in tert-immortalized oral keratinocytes and in malignant oral squamous cell carcinoma (OSCC) cells. Inhibiting ERK1/2 signaling, but not PI3-kinase signaling, blocked TGF-beta 1-induced Slug expression in the malignant UMSCC1 cells. To further examine the role of Slug in OSCC progression, we generated UMSCC1 cells with inducible expression of Slug protein. Induction of Slug in UMSCC1 cells did not repress E-cadherin levels or regulate individual movement of UMSCC1 cells. Instead, Slug enhanced cohort migration and Matrigel invasion by UMSCC1 cells. Slug increased MMP-9 levels and MMP-9-specific siRNA blocked Slug-induced Matrigel invasion. Interestingly, Slug-specific siRNA attenuated TGF-beta 1-induced MMP-9 expression and Matrigel invasion. These data demonstrate that TGF-beta 1 increases Slug via ERK1/2 signaling, and thereby contributes to OSCC progression. J. Cell. Biochem. 108: 726-736, 2009. (C) 2009 Wiley-Liss, Inc.