Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway
Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway
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DOI：
10.1007/s11060-011-0549-x
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发表时间：
2011-09-01
影响因子：
3.9
通讯作者：
Fillmore, H. L.
中科院分区：
文献类型：
--
作者：
Anand, M.;Van Meter, T. E.;Fillmore, H. L.
多形性胶质母细胞瘤（GBM）是一种侵袭性癌症，生存率很低。导致预后不良的一个关键因素是胶质瘤细胞以弥漫性方式侵入局部脑组织的能力。在参与侵袭过程的多种蛋白酶中，基质金属蛋白酶-1 （matrix metalloproteinase-1, MMP-1）已被确定为多种癌症的重要促成因子。MMP-1除了具有切割初级细胞外基质（ECM）底物的传统作用外，与基质金属蛋白酶家族的其他成员一样，MMP-1还可以激活潜在形式的生物活性分子，启动下游的促侵袭和促癌信号机制。MMP-1的表达受多种生长因子的调控，包括表皮生长因子（EGF）。由于表皮生长因子受体（EGFR）在GBM中异常过表达，我们希望更详细地研究GBM细胞中EGF驱动MMP-1表达和侵袭的信号机制。经EGF处理的T98G细胞在EGFR激活后诱导MMP-1表达。通过药理学和遗传学方法抑制EGFR消除了这种诱导。丝裂原活化蛋白激酶（MAPK）信号的抑制导致egf诱导的MMP-1的抑制，而pi3激酶/AKT信号与egfr介导的MMP-1诱导无关。抑制EGFR信号传导也导致T98G侵袭减少。这些数据表明，在T98G细胞中，EGFR介导的MMP-1调节主要通过MAPK途径，抑制EGFR和MMP-1可导致T98G细胞侵袭减少。
Glioblastoma multiforme (GBM) is an aggressive cancer with a poor survival rate. A key component that contributes to the poor prognosis is the capacity of glioma cells to invade local brain tissue in a diffuse manner. Among various proteases that aid in the process of invasion, matrix metalloproteinase-1 (MMP-1) has been identified as an important contributory factor in various cancers. Apart from its traditional role in cleaving its primary extracellular matrix (ECM) substrates, and like other members of the matrix metalloproteinase family, MMP-1 can activate latent forms of bio-active molecules initiating downstream pro-invasive and pro-oncogenic signaling mechanisms. MMP-1 expression is regulated by several growth factors including epidermal growth factor (EGF). Due to the fact that the epidermal growth factor receptor (EGFR) is aberrantly overexpressed in GBM, we wanted to examine in greater detail the signaling mechanisms by which MMP-1 expression and invasion is driven by EGF in GBM cells. T98G cells treated with EGF resulted in an induction of MMP-1 expression following EGFR activation. Inhibition of EGFR by both pharmacologic and genetic approaches abrogated this induction. Repression of the mitogen activated protein kinase (MAPK) signaling led to the inhibition of EGF-induced MMP-1 whereas the PI3-kinase/AKT signaling was not associated with EGFR-mediated MMP-1 induction. Inhibition of EGFR signaling also led to a decrease in T98G invasion. These data suggest that EGFR mediated MMP-1 regulation is mainly via the MAPK pathway in T98G cells and inhibition of EGFR and MMP-1 results in a decrease in T98G cell invasion.