Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII
Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII
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DOI：
10.1158/0008-5472.can-06-1803
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Miyagi, Yohei
中科院分区：
文献类型：
--
作者：
Koizume, Shiro;Jin, Neng-Shou;Miyagi, Yohei
凝血因子VII（fVII）在肝脏中生理合成并释放到血液中。fVII与血管损伤部位的组织因子（TF）结合触发凝血和止血。TF/fIIa复合物在癌细胞表面的形成在癌症生物学中起重要作用。虽然fVII是由肝细胞癌合成的，但仍不清楚TF/fVIIa复合物的形成和促迁移信号如何发生在大多数其他血管外癌症中。在这里，我们通过逆转录-PCR分析表明，非肝癌细胞系组成型表达fVII mRNA，内源性合成的fVIIa触发这些细胞的凝血激活。癌细胞中的fVIIa表达在缺氧条件下是可诱导的，并且在染色质免疫沉淀分析中缺氧诱导因子-2 α结合FVII基因的启动子区。卵巢癌细胞系中组成型fVII表达增强了迁移和侵袭。增强的运动性被抗TF抗体、Xa因子抑制和抗蛋白酶激活受体-1抗体治疗阻断，证实TF/fVIIa通过触发细胞信号传导刺激迁移。这项研究表明，异位合成的fVII癌细胞是足以支持proinvasive因子Xa介导的蛋白酶激活受体-1信号，这条途径是诱导缺氧。
Blood coagulation factor VII (fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2 alpha bound the promoter region of the FVII gene in chromatin immuno-precipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti-protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa-mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia.