Induction of Ras by SAF ‐1/ MAZ through a feed‐forward loop promotes angiogenesis in breast cancer
| Autor: | Alpana Ray, Bimal K. Ray |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Vascular Endothelial Growth Factor A
Chromatin Immunoprecipitation Cancer Research Angiogenesis Breast Neoplasms Biology breast cancer Cell Line Tumor Anti-apoptotic Ras signalling cascade Humans Gene silencing Radiology Nuclear Medicine and imaging Promoter Regions Genetic Transcription factor Original Research Tumor microenvironment fungi VEGF expression SAF-1 DNA-Binding Proteins Vascular endothelial growth factor A Cell Transformation Neoplastic Oncology Gene Knockdown Techniques Cancer cell ras Proteins Cancer research Female Chromatin immunoprecipitation Ras Signal Transduction Transcription Factors |
| Zdroj: | Cancer Medicine |
| ISSN: | 2045-7634 |
| DOI: | 10.1002/cam4.362 |
| Popis: | In the majority of breast cancers, overexpression and hyperactivation of Ras in the tumor microenvironment play significant role in promoting cancer cell growth, angiogenesis, and metastasis. We have previously shown that vascular endothelial growth factor (VEGF) expression in triple negative breast cancer cells is regulated, at least in part, by SAF-1 (serum amyloid A activating factor 1) transcription factor. In this study we show that transformation of normal MCF-10A breast epithelial cells by constitutively active, oncogenic Ras, induces the DNA-binding activity and transcription function of SAF-1. Furthermore, we show that inhibition of MEK/MAPK-signaling pathway prevents Ras-mediated activation of SAF-1. Interestingly, silencing of SAF-1 expression in breast cancer cells by SAF-1-specific short hairpin RNAs (shRNAs) significantly reduced H-Ras and K-Ras mRNA level. We show that SAF-1 is a direct transcriptional regulator of H-Ras and K-Ras and overexpression of SAF-1 increases H-Ras and K-Ras gene expression. Chromatin immunoprecipitation (ChIP) analyses demonstrated in vivo interaction of SAF-1 at highly purine-rich sequences present at the proximal promoter region, upstream of the transcription start site, in H-Ras and K-Ras genes. Previous studies have shown that these sequences are nuclease hypersensitive and capable of forming G4 quadruplex structure. Together, our results show the presence of a novel transactivating loop, in which, Ras and SAF-1 are interconnected. These findings will help defining molecular mechanisms of abnormal overexpression of Ras in breast tumors, which seldom show genetic Ras mutations. |
| Databáze: | OpenAIRE |
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