Myeloid Zinc Finger 1 (MZF1) Maintains the Mesenchymal Phenotype by Down-regulating IGF1R/p38 MAPK/ERα Signaling Pathway in High-level MZF1-expressing TNBC cells
العنوان: | Myeloid Zinc Finger 1 (MZF1) Maintains the Mesenchymal Phenotype by Down-regulating IGF1R/p38 MAPK/ERα Signaling Pathway in High-level MZF1-expressing TNBC cells |
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المؤلفون: | Chia Jen Lee, Ching Wen Hu, Kok Tong Tan, Ching Shiang Chi, Fu Mei Huang, Kun I. Lin, Chia Herng Yue, Jer-Yuh Liu, Ying Ru Pan |
المصدر: | Anticancer Research. 39:4149-4164 |
بيانات النشر: | Anticancer Research USA Inc., 2019. |
سنة النشر: | 2019 |
مصطلحات موضوعية: | Cancer Research, Epithelial-Mesenchymal Transition, Kruppel-Like Transcription Factors, Triple Negative Breast Neoplasms, Protein degradation, p38 Mitogen-Activated Protein Kinases, Receptor, IGF Type 1, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, ELK1, Cell Movement, Cell Line, Tumor, Humans, Neoplasm Invasiveness, Promoter Regions, Genetic, ets-Domain Protein Elk-1, Chemistry, Estrogen Receptor alpha, Myeloid zinc finger 1, Receptors, Somatomedin, Cell migration, General Medicine, Transfection, Cadherins, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Female, Signal transduction, Chromatin immunoprecipitation, Signal Transduction |
الوصف: | Background/aim Signaling regulation of myeloid zinc finger 1 (MZF1) has been implicated in the progression of many human malignancies; however, the mechanistic action of MZF1 in triple-negative breast cancer (TNBC) progression remains elusive. In this study, the aim was to investigate the molecular mechanisms of MZF1 and its functional role in TNBC cellular migration and invasion. Materials and methods Hs578T and MDA-MB-231 cells were transfected to stably express the acidic domain of MZF1 (MZF160-72), or were transfected with MZF1-specific or ELK1-specific short hairpin RNA (shRNA). Changes in cell morphology and distributions of cellular proteins were observed and subsequently migration and invasion were measured by wound healing and transwell assays. Expression levels of epithelial-mesenchymal transition (EMT)-related genes were carried out using immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. Data of transcriptional regulation were obtained from promoter-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Results Herein, we found that MZF1 in high-level MZF1-expressing TNBC cells is associated with cell migration, invasion, and mesenchymal phenotype. MZF1 interacted with the promoter region of insulin-like growth factor 1 receptor (IGF1R) to drive invasion and metastasis of high-level MZF1-expressing TNBC cells. Exogenous expression of the acidic domain of MZF1 repressed the binding of endogenous MZF1 to IGF1R promoter via blocking the interaction with ETS-like gene 1 (ELK1). This blockage not only caused MZF1 protein degradation, but also restrained ELK1 nuclear localization in high-level MZF1-expressing TNBC cells. MZF1, but not ELK1, was necessary for the retention of mesenchymal phenotype by repressing IGF1R promoter activity in TNBC cells expressing high levels of MZF1. Activation of the IGF1R-driven p38MAPK-ERα-slug-E-cadherin signaling axis mediated the conversion of mesenchymal cell to epithelial phenotype, caused by MZF1 destabilization. These results suggest that MZF1 is an oncogenic inducer. Conclusion Blocking of the MZF1/ELK1 interaction to reduce MZF1 protein stability by saturating the endogenous MZF1/ELK1 binding domains might be a promising therapeutic strategy for the treatment of high-level MZF1-expressing TNBC. |
تدمد: | 1791-7530 0250-7005 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3bdb206751ead5152e3f0a9200b88729 https://doi.org/10.21873/anticanres.13574 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....3bdb206751ead5152e3f0a9200b88729 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 17917530 02507005 |
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