IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway.
IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway.
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DOI：
10.1158/1541-7786.mcr-11-0271
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Kumar P
中科院分区：
文献类型：
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作者：
Yadav A;Kumar B;Datta J;Teknos TN;Kumar P
上皮-间质转化（Epithelial-mesenchymal transition，EMT）是肿瘤转移级联反应中的一个关键过程，其特征是细胞间连接和细胞极性的丧失，导致细胞获得迁移和侵袭特性。然而，在头颈部癌症中启动这种复杂EMT过程的精确分子事件知之甚少。越来越多的证据表明，肿瘤微环境在促进肿瘤细胞EMT中起重要作用。我们先前已经表明，头颈部肿瘤在肿瘤相关内皮细胞中表现出显著更高的Bcl-2表达，并且在SCID小鼠模型中，肿瘤相关内皮细胞中单独的Bcl-2过表达足以增强口腔鳞状细胞癌的肿瘤转移。在这项研究中，我们表明，内皮细胞表达Bcl-2（EC-Bcl-2），当与头颈部肿瘤细胞（CAL 27）共培养，显着增强EMT相关的变化，主要是通过分泌IL-6的肿瘤细胞。在CAL 27细胞或永生化口腔上皮细胞（IOE）中用重组IL-6或稳定IL-6过表达处理显著诱导间充质标志物波形蛋白的表达，同时通过JAK/STAT 3/Snail信号通路抑制E-钙粘蛋白表达。这些EMT相关变化进一步与增强的肿瘤和IOE细胞散射和运动性相关。STAT 3敲低通过抑制FAK活化显著逆转IL-6介导的肿瘤和IOE细胞运动。此外，在SCID小鼠异种移植模型中，过表达IL-6的肿瘤细胞显示淋巴结和肺转移显著增加。总之，这些结果证明了IL-6在介导头颈部肿瘤细胞中的EMT并增加其转移潜力中的新功能。
Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. However, the precise molecular events that initiate this complex EMT process in head and neck cancers are poorly understood. Increasing evidence suggests that tumor microenvironment plays an important role in promoting EMT in tumor cells. We have previously shown that head and neck tumors exhibit significantly higher Bcl-2 expression in tumor-associated endothelial cells and overexpression of Bcl-2 alone in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a SCID mouse model. In this study, we show that endothelial cells expressing Bcl-2 (EC-Bcl-2), when co-cultured with head and neck tumor cells (CAL27), significantly enhance EMT-related changes in tumor cells predominantly by the secretion of IL-6. Treatment with recombinant IL-6 or stable IL-6 overexpression in CAL27 cells or immortalized oral epithelial cells (IOE) significantly induced the expression of mesenchymal marker, vimentin, while repressing E-cadherin expression via the JAK/STAT3/Snail signaling pathway. These EMT-related changes were further associated with enhanced tumor and IOE cell scattering and motility. STAT3 knock-down significantly reversed IL-6-mediated tumor and IOE cell motility by inhibiting FAK activation. Furthermore, tumor cells overexpressing IL-6 showed marked increase in lymph node and lung metastasis in a SCID mouse xenograft model. Taken together, these results demonstrate a novel function for IL-6 in mediating EMT in head and neck tumor cells and increasing their metastatic potential.