Journal Article

Hypoxia-inducible factor (HIF)-1α directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF)

Zhi-Bo Han, He Ren, Hui Zhao, Ying Chi, Ke Chen, Bin Zhou, Yong-jun Liu, Lei Zhang, Bin Xu, Bin Liu, Renchi Yang and Zhong-Chao Han

in Carcinogenesis

Volume 29, issue 10, pages 1853-1861
Published in print October 2008 | ISSN: 0143-3334
Published online March 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn066
Hypoxia-inducible factor (HIF)-1α directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF)

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Stem cell factor (SCF) plays important roles in tumor growth and angiogenesis. However, its regulatory mechanism remains largely undefined. Here, we report that hypoxia upregulated the expression of SCF in MCF-7 breast cancer cells in both messenger RNA and protein levels. When hypoxia-inducible factor (HIF)-1α expression was knocked down by RNA interference, the MCF-7 cell expression of SCF was decreased significantly. Furthermore, the SCF receptor, c-kit phosphorylation was significantly strengthened by the condition culture media from hypoxic MCF-7 and MCF-7-c cells. The survival of A549 cells was more dependent on SCF under hypoxia. Analysis of SCF promoter 5′-flanking region revealed a potential hypoxia-response element (HRE; 5′-GCGTG-3′) located at −68 to −64 relative to the transcriptional start site. Chromatin immunoprecipitation assay demonstrated that HIF-1α directly bound to this region under normoxia, and this binding activity was significantly enhanced under hypoxia. Overexpression of HIF-1α significantly upregulated the expression of luciferase reporter gene under control of the SCF promoters in both MCF-7 cells and human embryonic kidney 293 cells, but mutation of the HRE site completely blocked this effect. Epidermal growth factor was also able to enhance the SCF expression under normoxia in MCF-7 cells, which was dependent on HIF-1α. Taken together, our data demonstrated that HIF-1α was a key regulator of SCF expression in breast cancer cells. Hypoxia and epidermal growth factor receptor signal coexisted in the tumor microenvironment and might promote angiogenesis through HIF-1α-mediated upregulation of SCF and other angiogenic factors.

Journal Article.  6686 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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