Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression
Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression
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DOI：
10.1074/jbc.m608428200
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发表时间：
2007-02-16
影响因子：
4.8
通讯作者：
Stack, M. Sharon
中科院分区：
文献类型：
--
作者：
Barbolina, Maria V.;Adley, Brian P.;Stack, M. Sharon
晚期卵巢癌的特征是弥散的腹膜内转移作为I型和III胶原蛋白富含蛋白胶原蛋白层的次要病变的锚。卵巢癌细胞优先粘附在间质胶原蛋白上，胶原蛋白诱导的整联蛋白聚集在上调跨膜胶原酶膜1型基质金属蛋白酶（MT1-MMP）的表达。胶原式活性在腹膜内转移中很重要，通过间皮细胞层增强侵袭，并在富含胶原蛋白的基质中定植。这项研究的目的是阐明胶原蛋白粘附和MT1-MMP表达之间的潜在机械联系。我们的结果表明，在三维胶原蛋白凝胶上培养细胞，但不是薄层胶原蛋白或合成三维水凝胶，导致转录因子Egr1的快速诱导。通过SRC激酶依赖性途径的整合素信号对于EGR1诱导是必需的。使用小的干扰RNA对EGR1表达进行沉默，废除了胶原蛋白诱导的MT1-MMP表达，并抑制了三维胶原蛋白凝胶的细胞侵袭。这些数据支持腹膜内转移的模型，其中胶原蛋白结合素的胶原蛋白粘附和聚类通过SRC激酶激活整联蛋白介导的信号传导，以诱导EGR1的表达，从而导致MT1-MMP启动子的转录激活以及随后的MT1-MMP-cati-cataliz colagagen Invisasion in 。该模型强调了卵巢癌细胞与卵巢肿瘤微环境中卵巢癌细胞与间质性胶原蛋白之间的独特相互作用在诱导基因表达变化的变化，从而增强腹膜内转移性进展。
Late stage ovarian cancer is characterized by disseminated intraperitoneal metastasis as secondary lesions anchor in the type I and III collagen-rich submesothelial matrix. Ovarian carcinoma cells preferentially adhere to interstitial collagen, and collagen-induced integrin clustering up-regulates the expression of the transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP). Collagenolytic activity is important in intraperitoneal metastasis, potentiating invasion through the mesothelial cell layer and colonization of the submesothelial collagen-rich matrix. The objective of this study was to elucidate a potential mechanistic link between collagen adhesion and MT1-MMP expression. Our results indicate that culturing cells on three-dimensional collagen gels, but not thin layer collagen or synthetic three-dimensional hydrogels, results in rapid induction of the transcription factor EGR1. Integrin signaling through a SRC kinase-dependent pathway is necessary for EGR1 induction. Silencing of EGR1 expression using small interfering RNA abrogated collagen-induced MT1-MMP expression and inhibited cellular invasion of three-dimensional collagen gels. These data support a model for intraperitoneal metastasis wherein collagen adhesion and clustering of collagen binding integrins activates integrin-mediated signaling via SRC kinases to induce expression of EGR1, resulting in transcriptional activation of the MT1-MMP promoter and subsequent MT1-MMP-catalyzed collagen invasion. This model highlights the role of unique interactions between ovarian carcinoma cells and interstitial collagens in the ovarian tumor microenvironment in inducing gene expression changes that potentiate intraperitoneal metastatic progression.