Prostaglandin E2 receptor 4 mediates renal cell carcinoma intravasation and metastasis.
Prostaglandin E2 receptor 4 mediates renal cell carcinoma intravasation and metastasis.
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DOI：
10.1016/j.canlet.2017.01.007
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发表时间：
2017-04-10
期刊：
影响因子：
9.7
通讯作者：
Daaka Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Thayele Purayil H;Black JB;Fetto F;Lynch LD;Masannat JN;Daaka Y
转移性肾细胞癌（RCC）的治疗选择有限。在这项研究中，我们研究前列腺素E2（PGE 2）受体4（EP 4）对肾癌转移的影响。我们发现在两种RCC细胞系ACHN和SN 12 C中敲低EP 4并不影响小鼠异种移植肿瘤的摄取或生长速率，但通过减少肿瘤内渗来减少转移。使用鸡胚绒毛尿囊膜（CAM）测定，我们证实阻断EP 4信号传导抑制肿瘤内渗。体外研究表明，EP 4的表达和活性与肾细胞癌细胞的跨内皮迁移（TEM）有关。基因表达分析和验证试验表明，EP 4敲低降低了粘附分子P-选择素的配体CD 24的表达。在EP 4敲低的RCC中，CD 24的强制表达拯救了细胞的TEM能力。药理学抑制或敲低内皮P-选择素阻断EP 4介导的癌细胞TEM，并且在CAM测定中抑制P-选择素防止RCC肿瘤内渗。我们的研究结果表明，抑制EP 4减弱RCC的浸润和转移，下调CD 24和P-选择素参与肿瘤的浸润，这意味着这些分子作为治疗晚期RCC的治疗靶点的潜力。
Treatment options for metastatic renal cell carcinoma (RCC) are limited. In this study, we investigated impact of prostaglandin E2 (PGE2) receptor 4 (EP4) on RCC metastasis. We found that knockdown of EP4 in two RCC cell lines, ACHN and SN12C, does not affect xenograft tumor take or growth rate in mice, but reduces metastasis by decreasing tumor intravasation. Using chick chorioallantoic membrane (CAM) assay, we confirmed that blockade of EP4 signaling inhibits tumor intravasation. In vitro studies associated EP4 expression and activity with RCC cell transendothelial migration (TEM). Gene expression analysis and validation assays showed that EP4 knockdown decreases expression of CD24, a ligand to the adhesion molecule P-selectin. Forced expression of CD24 in EP4 knockdown RCC rescues TEM capacity of the cells. Pharmacologic inhibition or knockdown of endothelial P-selectin blocks EP4-mediated cancer cell TEM, and inhibition of P-selectin prevents RCC tumor intravasation in CAM assay. Our results demonstrate that inhibition of EP4 attenuates the RCC intravasation and metastasis by downregulating CD24 and that P-selectin participates in tumor intravasation, implying a potential for these molecules as therapeutic targets for advanced RCC treatment.