Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α
Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α
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DOI：
10.1007/s10585-010-9360-x
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发表时间：
2011-02-01
影响因子：
4
通讯作者：
Krueger, Achim
中科院分区：
文献类型：
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作者：
Schelter, Florian;Halbgewachs, Birgit;Krueger, Achim
“蛋白酶网”代表蛋白酶、其抑制剂和效应分子的网络，作为组织稳态的关键决定因素而出现。该网络的不平衡，例如由金属蛋白酶组织抑制剂-1（TIMP-1）的升高的宿主水平引起的，已经显示通过诱导肝细胞生长因子（HGF）途径增加靶器官对分散转移的易感性。缺氧诱导因子-1 α亚基（HIF-1 α）的表达增加也与肿瘤进展相关，并且还已知通过上调HGF受体Met诱导HGF信号传导，即在典型应激条件下，如缺氧。在这里，我们的目的是确定一个可能的转移促进TIMP-1，HIF-1 α和HGF信号之间的联系。我们发现，在TIMP-1过表达的同基因DBA/2小鼠中，L-CI.5s T淋巴瘤细胞的肝转移期间，HIF-1 α和HIF-1-信号传导增加。在体外，暴露于重组TIMP-1的L-CI.5s细胞显示TIMP-1本身能够诱导HIF-1 α和HIF-1-信号传导。HIF-1 α的敲低鉴定了肿瘤细胞衍生的HIF-1 α作为这种TIMP-1诱导的体外侵袭性的介质。在体内，HIF-1 α敲低显著损害Met表达以及Met磷酸化，并抑制分散的肝转移。此外，HGF依赖性TIMP-1促进的Met磷酸化和HGF依赖性TIMP-1诱导的体外侵袭性由HIF-1 α介导。我们的结论是，TIMP-1在肿瘤细胞的微环境中的水平升高，可以通过诱导HIF-1 α依赖的HGF信号传导促进转移。蛋白酶抑制剂（TIMP-1）和经典的应激相关因子（HIF-1 α）之间的这种联系是迄今尚未发现的“蛋白酶网络”对组织稳态的影响，对转移具有重要意义。
The "protease web", representing the network of proteases, their inhibitors, and effector molecules, arises as a pivotal determinant of tissue homeostasis. Imbalances of this network, for instance caused by elevated host levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), have been shown to increase the susceptibility of target organs to scattered metastasis by inducing the hepatocyte growth factor (HGF) pathway. Increased expression of the hypoxia-inducible factor-1 alpha-subunit (HIF-1 alpha) is also associated with tumour progression and is also known to induce HGF-signaling via up-regulation of the HGF-receptor Met, namely under canonical stress conditions like lack of oxygen. Here, we aimed to identify a possible metastasis-promoting connection between TIMP-1, HIF-1 alpha, and HGF-signaling. We found that HIF-1 alpha and HIF-1-signaling were increased during liver metastasis of L-CI.5s T-lymphoma cells in TIMP-1 overexpressing syngeneic DBA/2 mice. In vitro, exposure of L-CI.5s cells to recombinant TIMP-1 revealed that TIMP-1 itself was able to induce HIF-1 alpha and HIF-1-signaling. Knock-down of HIF-1 alpha identified tumour cell-derived HIF-1 alpha as mediator of this TIMP-1-induced invasiveness in vitro. In vivo, HIF-1 alpha knock-down significantly impaired Met expression as well as Met phosphorylation and inhibited scattered liver metastasis. Furthermore, HGF-dependent TIMP-1-promoted Met phosphorylation and HGF-dependent TIMP-1-induced invasiveness in vitro was mediated by HIF-1 alpha. We conclude that elevated levels of TIMP-1 in the microenvironment of tumour cells can promote metastasis by inducing HIF-1 alpha-dependent HGF-signaling. This connection between a protease inhibitor (TIMP-1) and a classically stress-related factor (HIF-1 alpha) is a so far undiscovered impact of the "protease web" on tissue homeostasis with important implications for metastasis.