CXCR4 Promotes Oral Squamous Cell Carcinoma Migration and Invasion through Inducing Expression of MMP-9 and MMP-13 via the ERK Signaling Pathway
CXCR4 Promotes Oral Squamous Cell Carcinoma Migration and Invasion through Inducing Expression of MMP-9 and MMP-13 via the ERK Signaling Pathway
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CXCR4通过ERK信号通路诱导MMP-9和MMP-13表达促进口腔鳞状细胞癌迁移和侵袭
DOI：
10.1158/1541-7786.mcr-10-0386
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发表时间：
2011-02-01
影响因子：
5.2
通讯作者：
Li, Longjiang
中科院分区：
文献类型：
--
作者：
Yu, Tao;Wu, Yingying;Li, Longjiang
口腔鳞状细胞癌细胞迁移和侵袭的增加是淋巴结和远处器官转移发展的关键事件。虽然趋化因子受体CXCR 4及其配体基质细胞衍生因子-1 α在肿瘤侵袭中发挥重要作用，但其确切作用和潜在的潜在机制仍不清楚。在本研究中，我们发现敲低CXCR 4显著降低Tca 8113细胞的迁移和侵袭能力，同时降低MMP-9和MMP-13的表达。通过特异性拮抗剂TN 14003抑制配体与CXCR 4的结合也导致癌细胞迁移和侵袭减少。由于蛋白酶（例如基质金属蛋白酶（MMP））对细胞外基质和基底膜的降解对于癌细胞的迁移和侵袭至关重要，我们研究了几种MMPs的表达，发现功能性MMP-9和MMP-13的表达在CXCR 4敲除细胞中选择性降低。更重要的是，CXCR 4敲低细胞的细胞迁移和侵袭的减少被MMP-9或MMP-13的外源性表达完全拯救，表明这两种MMP是CXCR 4介导的信号传导的下游靶点。此外，我们发现CXCR 4沉默的Tca 8113细胞中磷酸化的细胞外信号调节激酶（ERK）水平显著降低，提示ERK可能是CXCR 4调节Tca 8113细胞MMP-9和MMP-13表达的潜在介质。综上所述，我们的研究结果强烈提示CXCR 4通过调节MMP-9和MMP-13的表达促进Tca 8113迁移和侵袭的潜在机制，可能通过激活ERK信号通路。Mol Cancer Res; 9（2）; 161-72. (C)2011年AACR。
The increased migration and invasion of oral squamous cell carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. Although the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 alpha, have been found to play an important role in tumor invasion, its precise role and potential underlying mechanisms remain largely unknown. In this study, we showed that knockdown of CXCR4 significantly decreased Tca8113 cells migration and invasion, accompanied with the reduction of MMP-9 and MMP-13 expression. Inhibition of ligand binding to CXCR4 by a specific antagonist TN14003, also led to reduced cancer cell migration and invasion. Because the degradation of the extracellular matrix and the basement membrane by proteases, such as matrix metalloproteinases (MMP) is critical for migration and invasion of cancer cells, we investigated the expression of several MMPs and found that the expression of functional MMP-9 and MMP-13 was selectively decreased in CXCR4 knockdown cells. More importantly, decreased cell migration and invasion of CXCR4 knockdown cells were completely rescued by exogenous expression of MMP-9 or MMP-13, indicating that the two MMPs are downstream targets of CXCR4-mediated signaling. Furthermore, we found the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in CXCR4-silenced cells, suggesting that ERK may be a potential mediator of CXCR4-regulated MMP-9 and MMP-13 expression in Tca8113 cells. Taken together, our results strongly suggest the underlying mechanism of CXCR4 promoting Tca8113 migration and invasion by regulating MMP-9 and MMP-13 expression perhaps via activation of the ERK signaling pathway. Mol Cancer Res; 9(2); 161-72. (C) 2011 AACR.