COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells
COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells
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COX-2通过介导癌细胞与骨髓源性抑制细胞之间的相互作用促进鼻咽癌转移
DOI：
10.1080/2162402x.2015.1044712
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发表时间：
2015-01-01
期刊：
影响因子：
7.2
通讯作者：
Li, Jiang
中科院分区：
文献类型：
--
作者：
Li, Ze-Lei;Ye, Shu-Biao;Li, Jiang
骨髓源性抑制细胞（MDSCs）的扩增是肿瘤的常见特征，但其生物学作用和分子机制尚不清楚。在这里，我们研究了MDSC扩增和鼻咽癌（NPC）肿瘤细胞转移之间的分子联系。我们证明，MDSCs扩增，并与肿瘤考克斯-2表达和血清IL-6水平升高，在NPC患者呈正相关。重要的是，考克斯-2和MDSC是患者无病生存期（DFS）的不良预测因子。敲低肿瘤考克斯-2表达阻碍了IL-6阻断的功能性TW 03介导的MDSC细胞（T-MDSC）诱导。我们发现，T-MDSCs通过触发细胞间接触的上皮-间质转化（EMT）促进NPC细胞迁移和侵袭，并且T-MDSCs在体内增强肿瘤实验性肺转移。有趣的是，T-MDSC和NPC细胞之间的接触增强了肿瘤考克斯-2的表达，随后激活了β-catenin/TCF 4通路，导致癌细胞的EMT。阻断转化生长因子β（TGFβ）或诱导型一氧化氮合酶（iNOS）可显著抑制T-MDSC诱导的NPC细胞考克斯-2表达和EMT评分的上调，而TGFβ或L-精氨酸补充剂可上调NPC细胞考克斯-2表达和EMT评分。这些结果表明，考克斯-2是介导MDSCs与肿瘤细胞相互作用的关键因子，提示抑制考克斯-2或MDSCs具有抑制NPC转移的潜力。
The expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and T-MDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the β-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor β (TGFβ) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFβ or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.