The 120 kDa cell-binding fragment of fibronectin up-regulates migration of αvβ6-expressing cells by increasing matrix metalloproteinase-2 and-9 secretion
The 120 kDa cell-binding fragment of fibronectin up-regulates migration of αvβ6-expressing cells by increasing matrix metalloproteinase-2 and-9 secretion
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DOI：
10.1111/j.1600-0722.2007.00481.x
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发表时间：
2007-12-01
影响因子：
1.9
通讯作者：
Whawell, Simon A.
中科院分区：
文献类型：
--
作者：
Al-Hazmi, Nadia;Thomas, Gareth J.;Whawell, Simon A.
细胞外基质、整合素表达和蛋白酶分泌的变化发生在伤口愈合和癌症中，这些系统被认为在这些过程中起着至关重要的作用。在这项研究中，我们进行了实验来检测上皮细胞与120 kDa细胞结合的纤维连接蛋白片段的相互作用。与全长分子相比，120 kDa片段显著增加了细胞迁移，但仅限于过表达β -6整合素（VB6）的细胞。这涉及基质金属蛋白酶（MMPs） 2和9的上调，其水平在120 kDa片段上镀的VB6细胞的上清中增加。用金属蛋白酶-1组织抑制剂（TIMP-1）和化学抑制剂（Ro32-3580）抑制MMP活性导致纤维连接蛋白片段迁移的显著减少。在体外，该片段可以通过纯化的MMP-9与全长纤维连接蛋白孵育产生。仅在伤口愈合和癌症中可见的β 6整合素亚基的表达增强了上皮细胞对120 kDa纤维连接蛋白片段的运动性和MMP分泌。然后，这些酶可以进一步降解纤维连接蛋白以产生额外的片段，从而形成一个正反馈循环，这可能在疾病过程中具有重要意义。
Changes in the extracellular matrix, integrin expression, and protease secretion occur in wound healing and cancer and these systems are thought to play a crucial role in such processes. In this study, experiments were performed to examine the interaction of epithelial cells with the 120 kDa cell-binding fibronectin fragment. Cell migration was significantly increased in response to the 120 kDa fragment when compared with the full-length molecule, but only in cells overexpressing the beta-6 integrin (VB6). This involved the up-regulation of matrix metalloproteinases (MMPs) 2 and 9, the levels of which are increased in the supernatant from VB6 cells plated on the 120 kDa fragment. Inhibition of MMP activity with both tissue inhibitor of metalloproteinase-1 (TIMP-1) and a chemical inhibitor (Ro32-3580) resulted in a significant reduction in migration on the fibronectin fragment. In vitro this fragment can be generated by incubating full-length fibronectin with purified MMP-9.Expression of the beta 6 integrin subunit, which is only seen in wound healing and cancer, enhances the motility of and MMP secretion by epithelial cells in response to the 120 kDa fibronectin fragment. These enzymes can then further degrade fibronectin to generate additional fragments, leading to the creation of a positive feedback loop, which may be of significance in disease processes.