Pan Mei-Ren, Hou Ming-Feng, Chang Hui-Chiu, Hung Wen-Chun
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
J Biol Chem. 2008 Apr 25;283(17):11155-63. doi: 10.1074/jbc.M710038200. Epub 2008 Mar 4.
Recent studies demonstrate that cyclooxygenase-2 (COX-2) expression is frequently associated with lymph node metastasis. However, the mechanism by which COX-2 increases the invasion of cancer cells to lymph node is unclear. CCR7 is a chemokine receptor that plays important roles in the mediation of migration of leukocytes and dendritic cells toward lymphatic endothelial cells (LECs) that express receptor ligand CCL21. We found that treatment of prostaglandin E(2) or ectopic expression of COX-2 in MCF-7 cells up-regulated CCR7 expression. On the contrary, knockdown of COX-2 by small hairpin RNA reduced CCR7 in COX-2-overexpressing MDA-MB-231 cells. Interaction of CCR7 and CCL21 was important for the migration of breast cancer cells toward LECs because antibodies against these two molecules inhibited the migration. We also found that COX-2 increased CCR7 expression via the EP2 and EP4 receptor in breast cancer cells. EP2 and EP4 agonists stimulated CCR7 in MCF-7 cells, whereas antagonists or small hairpin RNA of EP2 and EP4 attenuated CCR7 in MDA-MB-231 cells. Protein kinase A and AKT kinase were involved in COX-2-induced CCR7. Pathological analysis demonstrated that COX-2 overexpression was associated with CCR7, EP2, and EP4 expressions in breast tumor tissues. In addition, CCR7 expression in COX-2-overexpressing tumors was significantly correlated with lymph node metastasis. Collectively, we suggest that CCR7 is a down-stream target for COX-2 to enhance the migration of breast cancer cells toward LECs and to promote lymphatic invasion.
近期研究表明，环氧化酶-2（COX-2）的表达常与淋巴结转移相关。然而，COX-2增加癌细胞向淋巴结侵袭的机制尚不清楚。CCR7是一种趋化因子受体，在介导白细胞和树突状细胞向表达受体配体CCL21的淋巴管内皮细胞（LEC）迁移中起重要作用。我们发现，用前列腺素E2处理或在MCF-7细胞中异位表达COX-2会上调CCR7的表达。相反，用小发夹RNA敲低COX-2可降低COX-2过表达的MDA-MB-231细胞中的CCR7。CCR7与CCL21的相互作用对乳腺癌细胞向LEC的迁移很重要，因为针对这两种分子的抗体可抑制迁移。我们还发现，COX-2通过乳腺癌细胞中的EP2和EP4受体增加CCR7的表达。EP2和EP4激动剂可刺激MCF-7细胞中的CCR7，而EP2和EP4的拮抗剂或小发夹RNA可减弱MDA-MB-231细胞中的CCR7。蛋白激酶A和AKT激酶参与了COX-2诱导的CCR7。病理分析表明，COX-2的过表达与乳腺肿瘤组织中CCR7、EP2和EP4的表达相关。此外，COX-2过表达肿瘤中的CCR7表达与淋巴结转移显著相关。总体而言，我们认为CCR7是COX-2的下游靶点，可增强乳腺癌细胞向LEC的迁移并促进淋巴侵袭。
