Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis
Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis
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DOI：
10.1111/j.1349-7006.2009.01322.x
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发表时间：
2009-12-01
期刊：
影响因子：
5.7
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
--
作者：
Amano, Hideki;Ito, Yoshiya;Majima, Masataka
环氧合酶（考克斯）-2与肿瘤预后不良相关，并促进肿瘤转移。然而，这种现象的确切机制仍然未知。我们以前曾报道，宿主间质前列腺素E2（PGE（2））-前列腺素E2受体（EP）3信号传导对肿瘤相关血管生成和肿瘤生长至关重要。在这里，我们测试了EP 3受体是否在肿瘤转移中起关键作用。将刘易斯肺癌（LLC）细胞静脉内注射到WT小鼠和用考克斯-2抑制剂NS-398处理的小鼠中。非选择性考克斯抑制剂阿司匹林减少肺转移，但考克斯-1抑制剂SC 560没有。与PBS处理的小鼠相比，NS-398处理的小鼠中基质金属蛋白酶（MMP）-9和血管内皮生长因子（VEGF）-A的表达受到抑制。与WT小鼠相比，EP 3受体敲除（EP 3-/-）小鼠中含有LLC集落的肺显著减少。MMP-9和VEGF-A在EP 3-/-小鼠肺转移灶中表达下调。免疫组化研究显示，MMP-9表达内皮细胞显着减少，在EP 3-/-小鼠与WT小鼠相比。当用EP 1、EP 2、EP 3或EP 4的激动剂处理HUVEC时，仅EP 3激动剂增强MMP-9表达。这些结果表明，内皮细胞上的EP 3受体信号传导对于MMP-9上调是必需的，MMP-9上调增强肿瘤转移和血管生成。EP 3受体拮抗剂可能有助于防止肿瘤转移。（Cancer Sci 2009; 100：2318-2324）。
Cyclooxygenase (COX)-2 is known to correlate with poor cancer prognosis and to contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal prostaglandin E-2 (PGE(2))-prostaglandin E2 receptor (EP)3 signaling appears critical for tumor-associated angiogenesis and tumor growth. Here we tested whether the EP3 receptor has a critical role in tumor metastasis. Lewis lung carcinoma (LLC) cells were intravenously injected into WT mice and mice treated with the COX-2 inhibitor NS-398. The nonselective COX inhibitor aspirin reduced lung metastasis, but the COX-1 inhibitor SC560 did not. The expression of matrix metalloproteinases (MMP)-9 and vascular endothelial growth factor (VEGF)-A was suppressed in NS-398-treated mice compared with PBS-treated mice. Lungs containing LLC colonies were markedly reduced in EP3 receptor knockout (EP3-/-) mice compared with WT mice. The expression of MMP-9 and VEGF-A was downregulated in metastatic lungs of EP3-/- mice. An immunohistochemical study revealed that MMP-9-expressing endothelial cells were markedly reduced in EP3-/- mice compared with WT mice. When HUVEC were treated with agonists for EP1, EP2, EP3, or EP4, only the EP3 agonist enhanced MMP-9 expression. These results suggested that EP3 receptor signaling on endothelial cells is essential for the MMP-9 upregulation that enhances tumor metastasis and angiogenesis. An EP3 receptor antagonist may be useful to protect against tumor metastasis. (Cancer Sci 2009; 100: 2318-2324).