EA 6305, Université François Rabelais de Tours, Tours F-37032, France ; Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, Tours F-37032, France.
FEBS Open Bio. 2013 Jun 27;3:291-301. doi: 10.1016/j.fob.2013.06.004. Print 2013.
Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin, a protease which is involved in tumour progression by activating (MMPs). This therefore makes TFPI-2 a potential inhibitor of invasiveness and the development of metastases. In this study, low levels of TFPI-2 expression were found in 65% of patients with small cell lung cancer (SCLC), the most aggressive type of lung cancer. To study the impact of TFPI-2 in tumour progression, TFPI-2 was overexpressed in NCI-H209 SCLC cells which were orthotopically implanted in nude mice. Investigations showed that TFPI-2 inhibited lung tumour growth. Such inhibition could be explained in vitro by a decrease in tumour cell viability, blockade of G1/S phase cell cycle transition and an increase in apoptosis shown in NCI-H209 cells expressing TFPI-2. We also demonstrated that TFPI-2 upregulation in NCI-H209 cells decreased MMP expression, particularly by downregulating MMP-1 and MMP-3. Moreover, TFPI-2 inhibited phosphorylation of the MAPK signalling pathway proteins involved in the induction of MMP transcripts, among which MMP-1 was predominant in SCLC tissues and was inversely expressed with TFPI-2 in 35% of cases. These results suggest that downregulation of TFPI-2 expression could favour the development of SCLC.
组织因子途径抑制剂-2（TFPI-2）是纤溶酶的有效抑制剂，纤溶酶通过激活（MMPs）参与肿瘤进展。因此，TFPI-2 成为侵袭性和转移发展的潜在抑制剂。在这项研究中，发现在 65%的小细胞肺癌（SCLC）患者中 TFPI-2 表达水平较低，SCLC 是最具侵袭性的肺癌类型。为了研究 TFPI-2 在肿瘤进展中的作用，在 NCI-H209 SCLC 细胞中过表达 TFPI-2，这些细胞被原位植入裸鼠中。研究表明，TFPI-2 抑制肺肿瘤生长。在体外，通过降低肿瘤细胞活力、阻断 G1/S 期细胞周期转换以及增加表达 TFPI-2 的 NCI-H209 细胞中的细胞凋亡来解释这种抑制作用。我们还证明，NCI-H209 细胞中 TFPI-2 的上调降低了 MMP 的表达，特别是通过下调 MMP-1 和 MMP-3。此外，TFPI-2 抑制了参与 MMP 转录诱导的 MAPK 信号通路蛋白的磷酸化，其中 MMP-1 在 SCLC 组织中占主导地位，在 35%的病例中与 TFPI-2 呈负相关表达。这些结果表明，TFPI-2 表达下调可能有利于 SCLC 的发展。
