Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity
Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity
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DOI：
10.1038/onc.2014.418
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发表时间：
2015-09-17
期刊：
影响因子：
8
通讯作者：
Choi, H. S.
中科院分区：
文献类型：
--
作者：
Kim, J. Y.;Lim, S-C;Choi, H. S.
白细胞介素-1（IL-1）家族的细胞因子，例如IL-1 α/β和IL-18，在宿主防御和疾病的先天性和适应性免疫反应中具有多效性活性。深入了解它们的生物学功能有助于开发新的治疗方法来治疗人类炎症性疾病。IL-33是细胞因子IL-1家族的重要成员，并且是IL-1受体家族成员ST 2受体的配体。然而，IL-33/ST 2轴在乳腺癌的肿瘤生长和转移中的作用仍不清楚。在这里，我们证明，IL-33是一个关键的肿瘤促进剂在上皮细胞增殖和乳腺肿瘤发生。IL-33通过正常上皮细胞和乳腺癌细胞中的ST 2-COT相互作用剂量和时间依赖性地增加癌症大坂甲状腺（COT）磷酸化。IL-33/ST 2/COT级联诱导MEK-ERK（MEK-细胞外信号调节激酶）、JNK-cJun（cJun N-末端激酶-cJun）和STAT 3（信号转导和转录激活因子3）信号通路的激活，随后增加AP-1和STAT 3转录活性。当ST 2和COT的小干扰RNA被导入细胞时，IL-33诱导的AP-1和stat 3活性显著降低，与对照细胞不同。COT活性的抑制导致IL-33诱导的上皮细胞转化减少，并且IL-33、ST 2和COT在乳腺癌细胞中的敲低减弱了乳腺癌细胞的致瘤性。与这些观察结果一致，ST 2水平与人乳腺癌中COT表达呈正相关。这些发现为IL-33/ST 2/COT信号通路在肿瘤微环境中支持癌症相关炎症的作用提供了新的视角。因此，靶向该途径的治疗方法可以有效抑制乳腺癌的发生。
Cytokines of the interleukin-1 (IL-1) family, such as IL-1 alpha/beta and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose-and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.