Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan.
Department of Respiratory Medicine and Infectious Disease, Graduate School of Medical and Dental Sciences, Niigata University, Japan.
Mol Oncol. 2017 Sep;11(9):1241-1262. doi: 10.1002/1878-0261.12098. Epub 2017 Jul 11.
Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1-regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL-6 and IL-8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid-derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.
锌指 E 盒结合蛋白 1（ZEB1）和 ZEB2 诱导上皮-间充质转化（EMT）并增强癌症进展。然而，ZEB1 和 ZEB2 对转录的全局调控观点尚未阐明。在这里，我们使用染色质免疫沉淀测序和 RNA 测序鉴定了乳腺癌细胞中 ZEB1 调节的炎症表型，随后对 ZEB1 结合基因进行了基因集富集分析（GSEA）。敲低 ZEB1 和/或 ZEB2 导致与癌症患者预后不良相关的炎症细胞因子的编码基因下调，包括 IL6 和 IL8，因此表明 ZEB1 和 ZEB2 在调节炎症细胞因子的产生方面具有相似的功能。抗体阵列和 ELISA 实验证实 ZEB1 控制了 IL-6 和 IL-8 蛋白的产生。ZEB1 调节的分泌蛋白增强了乳腺癌细胞的增殖和肿瘤生长。乳腺癌细胞中的 ZEB1 表达也影响了细胞培养中成纤维细胞的生长，以及体内肿瘤中髓源性抑制细胞的积累。这些发现为 ZEB1 通过炎症细胞因子介导的 EMT 起始在癌症进展中的作用提供了新的见解。
