COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer.
COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer.
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DOI：
10.1038/sj.bjc.6603067
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发表时间：
2006-04-24
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
COX-2或VEGF-C的表达增加与某些癌症的进展性疾病相关。本研究利用COX-2表达不同的几种人乳腺癌细胞系（MCF-7、T-47D、Hs578T和MDA-MB-231）和10例人乳腺癌标本，研究COX-2和前列腺素E （EP）受体在VEGF-C表达或分泌中的作用，以及COX-2或VEGF-C表达与淋巴管生成的关系。我们发现COX-2 mRNA的表达与乳腺癌细胞系中VEGF-C的表达或分泌水平以及乳腺癌组织中VEGF-C的表达有很强的相关性。淋巴内皮选择性标志物LYVE-1的表达也与乳腺癌组织中COX-2或VEGF-C的表达呈正相关。COX-1/2或COX-2抑制剂抑制VEGF-C的表达和分泌，或COX-2 siRNA下调COX-2，确立了COX-2在乳腺癌细胞VEGF-C合成中的刺激作用。EP1和EP4受体拮抗剂抑制VEGF-C的产生，表明EP1和EP4在内源性PGE2上调VEGF-C中的作用。最后，在Her-2/neu、Src和p38 MAPK激酶抑制剂的存在下，MDA-MB-231细胞的VEGF-C分泌被抑制，这表明VEGF-C合成需要这些激酶。这些结果首次证明了COX-2在人乳腺癌中VEGF-C合成（从而淋巴管生成）中的调节作用，至少部分是由EP1/EP4受体介导的。
Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE2. Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.
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影响因子：
7.5
作者：
Kyzas, PA;Stefanou, D;Agnantis, NJ
通讯作者：
Agnantis, NJ
影响因子：
6.4
作者：
Mattila, MMT;Ruohola, JK;Härkönen, PL
通讯作者：
Härkönen, PL
DOI：
10.1111/j.1440-1746.2004.03348.x
发表时间：
2004-06-01
影响因子：
4.1
作者：
Byeon, JS;Jung, HY;Kim, JS
通讯作者：
Kim, JS
影响因子：
3.8
作者：
Kinoshita, J;Kitamura, K;Sugimachi, K
通讯作者：
Sugimachi, K
影响因子：
4.8
作者：
Courter, DL;Lomas, L;Giachelli, CM
通讯作者：
Giachelli, CM