Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer
| Autor: | Thomas Brabletz, Jason T. George, Herbert Levine, Jochen Maurer, Mohit Kumar Jolly, Samir M. Hanash, Satyendra C. Tripathi, Marc P. Stemmler, Dongya Jia, Bogdan-Tiberius Preca |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Medical technology lcsh:Biotechnology Biomedical Engineering Biophysics Bioengineering Invited Articles Biology Biomaterials 03 medical and health sciences 0302 clinical medicine lcsh:TP248.13-248.65 Epithelial–mesenchymal transition Autocrine signalling Transcription factor CD44 Phenotype 3. Good health Cell biology Epithelial Splicing Regulatory Protein 1 Crosstalk (biology) 030104 developmental biology lcsh:R855-855.5 Tumor progression Special Topic: Bioengineering of Cancer 030220 oncology & carcinogenesis biology.protein |
| Zdroj: | APL Bioengineering 2(3), 031908 (2018). doi:10.1063/1.5024874 special issue: "Special Topic: Bioengineering of Cancer" APL Bioengineering APL Bioengineering, Vol 2, Iss 3, Pp 031908-031908-15 (2018) |
| ISSN: | 2473-2877 |
| DOI: | 10.1063/1.5024874 |
| Popis: | Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process; rather, cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1—a key transcription factor driving EMT—can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing epithelial splicing regulatory protein 1 (ESRP1), hyaluronic acid synthase 2 (HAS2), and CD44 which maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by experiments showing that knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlate with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition. |
| Databáze: | OpenAIRE |
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