The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis
The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis
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TNF-α/IL-33/ST2L信号介导的肿瘤细胞与活化成纤维细胞之间的相互作用促进胃癌转移
DOI：
10.1038/s41388-019-1078-x
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Su，Liping
中科院分区：
文献类型：
--
作者：
Zhou，Quan;Wu，Xiongyan;Su，Liping
胃癌（gastric cancer，GC）具有局部浸润广泛、远处转移和预后差的特点.在大多数情况下，GC进展与细胞因子的异常表达或由肿瘤-间质相互作用介导的信号级联激活相关。然而，这些相互作用促进GC进展的机制知之甚少。在这项研究中，我们发现IL-33及其受体ST 2L在人GC中上调，并作为GC患者生存不良的预后标志物。在与GC细胞和癌症相关成纤维细胞（CAFs）的共培养模型中，我们进一步证明CAFs衍生的IL-33通过以ST 2L依赖性方式激活ERK 1/2-SP1-ZEB 2通路诱导上皮-间质转化（EMT）来增强GC细胞的迁移和侵袭。此外，胃癌细胞通过TNFR 2-NF-κB-IRF-1途径释放的促炎细胞因子TNF-α可诱导CAFs分泌IL-33。此外，CAF中IL-33表达或GC细胞中ST 2L表达的沉默抑制了裸鼠中GC细胞的腹膜播散和转移潜力。总之，这些结果表征了由TNF-α/IL-33/ST 2L信号传导介导的上皮-基质之间的相互作用在GC进展中的关键作用，并为靶向该途径治疗GC转移提供了理论基础。
Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor–stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial–mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.