Department of Anatomy, Shanxi Medical University, Taiyuan, PR China.
Cancer Lett. 2010 Apr 1;290(1):87-95. doi: 10.1016/j.canlet.2009.09.001. Epub 2009 Sep 30.
ECRG2 is a novel tumor suppressor gene that shows sequence similarity to KAZAL-type serine protease inhibitor. We have previously demonstrated ECRG2 inhibits migration/invasion of lung cancer PG cells. However, the mechanism by which ECRG2 performs these activities remains unknown. In this study, we found that ECRG2 inhibits proteolysis activity of uPA/plasmin and MMP2, and substantially reduces the ability of HT1080 and HCT-116 cells to invade ECM. Moreover, we demonstrated ECRG2 prevents the cleavage of uPAR, disrupts the association of sD2D3 with FPRL1, and that disruption impairs FPRL1 function. Conversely, depletion of ECRG2 not only markedly increased proteolysis activity of uPA/plasmin and MMP2 but also enhanced the association of uPAR with FPRL1, stimulated cell migration/invasion. Together, our results provide evidence that ECRG2 regulates invasion/migration partly through ECM degradation and uPA/uPAR/FPRL1 pathway, and may represent a novel therapeutic target for cancer.
ECRG2 是一种新型肿瘤抑制基因，与 KAZAL 型丝氨酸蛋白酶抑制剂具有序列相似性。我们之前已经证明 ECRG2 可以抑制肺癌 PG 细胞的迁移/侵袭。然而，ECRG2 发挥这些作用的机制尚不清楚。在这项研究中，我们发现 ECRG2 抑制 uPA/纤溶酶和 MMP2 的蛋白水解活性，并显著降低 HT1080 和 HCT-116 细胞侵袭 ECM 的能力。此外，我们证明 ECRG2 可以防止 uPAR 的裂解，破坏 sD2D3 与 FPRL1 的结合，而破坏结合会损害 FPRL1 功能。相反，ECRG2 的耗竭不仅显著增加了 uPA/纤溶酶和 MMP2 的蛋白水解活性，而且增强了 uPAR 与 FPRL1 的结合，刺激了细胞迁移/侵袭。总之，我们的研究结果表明，ECRG2 通过 ECM 降解和 uPA/uPAR/FPRL1 途径部分调节侵袭/迁移，可能成为癌症的一个新的治疗靶点。
