Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells
Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells
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DOI：
10.1074/jbc.m710038200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Hung, Wen-Chun
中科院分区：
文献类型：
--
作者：
Pan, Mei-Ren;Hou, Ming-Feng;Hung, Wen-Chun
近年来研究表明，环氧合酶-2（考克斯-2）的表达与淋巴结转移密切相关。然而，考克斯-2增加癌细胞对淋巴结的侵袭的机制尚不清楚。CCR 7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CCL 21的淋巴管内皮细胞（LEC）迁移中起重要作用。我们发现前列腺素E-2处理或考克斯-2在MCF-7细胞中的异位表达上调了CCR 7的表达。相反，在考克斯-2过表达的MDA-MB-231细胞中，通过小发夹RNA敲低考克斯-2减少了CCR 7。CCR 7和CCL 21的相互作用对于乳腺癌细胞向LEC的迁移是重要的，因为针对这两种分子的抗体抑制了迁移。我们还发现，考克斯-2增加乳腺癌细胞中通过EP 2和EP 4受体CCR 7的表达。在MCF- 7细胞中，EP 2和EP 4激动剂刺激CCR 7，而EP 2和EP 4的拮抗剂或小发夹RNA在MDA-MB-231细胞中减弱CCR 7。蛋白激酶A和AKT激酶参与了考克斯-2诱导的CCR 7。病理学分析表明，乳腺癌组织中考克斯-2的过表达与CCR 7、EP 2和EP 4的表达相关。另外，在考克斯-2过表达的肿瘤中，CCR 7的表达与淋巴结转移显著相关。总的来说，我们认为CCR 7是考克斯-2的下游靶点，以增强乳腺癌细胞向LEC的迁移，并促进淋巴管浸润。
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 downstream target for COX-2 to enhance the migration of breast cancer cells toward LECs and to promote lymphatic invasion.