Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Biochem Pharmacol. 2011 Feb 1;81(3):379-87. doi: 10.1016/j.bcp.2010.11.001. Epub 2010 Nov 9.
An important event in the development of tumors is angiogenesis, or the formation of new blood vessels. Angiogenesis is also known to be involved in tumor cell metastasis and is dependent upon the activity of the vascular endothelial growth factor (VEGF) signaling pathway. Studies of mice in which the EP3 prostanoid receptors have been genetically deleted have shown a role for these receptors in cancer growth and angiogenesis. In the present study, human colon cancer HCA-7 cells were used as a model system to understand the potential role of EP3 receptors in tumor cell migration. We now show that stimulation of HCA-7 cells with PGE₂ enhanced the up-regulation of VEGF receptor-1 (VEGFR-1) expression by a mechanism involving EP3 receptor-mediated activation of phosphatidylinositol 3-kinase and the extracellular signal-regulated kinases. Moreover, the PGE₂ stimulated increase in VEGFR-1 expression was accompanied by an increase in the cellular migration of HCA-7 cells. Given the known involvement of VEGFR-1 in cellular migration, our results suggest that EP3 receptors may contribute to tumor cell metastasis by increasing cellular migration through the up-regulation of VEGFR-1 signaling.
肿瘤发展中的一个重要事件是血管生成，即新血管的形成。血管生成也被认为参与肿瘤细胞转移，并且依赖于血管内皮生长因子 (VEGF) 信号通路的活性。对 EP3 前列腺素受体基因缺失的小鼠的研究表明，这些受体在癌症生长和血管生成中发挥作用。在本研究中，我们用人结肠癌细胞 HCA-7 作为模型系统，以了解 EP3 受体在肿瘤细胞迁移中的潜在作用。我们现在表明，PGE₂刺激 HCA-7 细胞增强了 VEGFR-1 表达的上调，这一机制涉及 EP3 受体介导的磷酸肌醇 3-激酶和细胞外信号调节激酶的激活。此外，PGE₂ 刺激的 VEGFR-1 表达增加伴随着 HCA-7 细胞的细胞迁移增加。鉴于 VEGFR-1 已知参与细胞迁移，我们的结果表明，EP3 受体可能通过上调 VEGFR-1 信号来增加细胞迁移，从而促进肿瘤细胞转移。
