ZEB1-regulated inflammatory phenotype in breast cancer cells.

Abstract

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.

• Authors: Akihiro Katsura, Yusuke Tamura, Satoshi Hokari, Mayumi Harada, Masato Morikawa, Tsubasa Sakurai, Kei Takahashi, Anna Mizutani, Jun Nishida, Yuichiro Yokoyama, Yasuyuki Morishita, Takashi Murakami, Shogo Ehata, Kohei Miyazono, Daizo Koinuma
• Journal: Molecular oncology (Mol Oncol) Vol. 11 Issue 9 Pg. 1241-1262 (09 2017) ISSN: 1878-0261 [Electronic] United States
• PMID: 28618162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Biomarkers, Tumor
• Chemokines
• Culture Media, Conditioned
• DNA, Neoplasm
• Transforming Growth Factor beta
• ZEB2 protein, human
• Zinc Finger E-box Binding Homeobox 2
• Zinc Finger E-box-Binding Homeobox 1

Topics

• Animals
• Base Sequence
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemokines (metabolism)
• Culture Media, Conditioned (pharmacology)
• DNA, Neoplasm (metabolism)
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Inflammatory Breast Neoplasms (genetics, metabolism, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• Myeloid Cells (drug effects, metabolism)
• Paracrine Communication (drug effects)
• Phenotype
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (pharmacology)
• Zinc Finger E-box Binding Homeobox 2 (metabolism)
• Zinc Finger E-box-Binding Homeobox 1 (genetics, metabolism)