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HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells
Open accessAbstract
Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.
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“hypoxic tumor cells evade innate immune recognition through the up-regulation of CD47, a cell surface molecule that interacts with signal regulatory protein alpha (SIRP α) on the surface of macrophages to block phagocytosis”
From Hypoxic control of metastasis (2016) · cites this paper as [58]
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Metadata
- Authors
- Zhang, H., Lu, H., Xiang, L., Bullen, J. W., Zhang, C., Samanta, D., Gilkes, D. M., He, J., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-10-28
- Volume
- 112
- Issue
- 45
- Pages
- E6215-23
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4653179
- OpenAlex
- W1853160207
- Cited by
- 420
- References
- 62
- Citations by year
- 2026: 22 · 2025: 33 · 2024: 62 · 2023: 46 · 2022: 57 · 2021: 48 · 2020: 52 · 2019: 29 · 2018: 31 · 2017: 17 · 2016: 21 · 2015: 1
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-09-25)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society (122437-RP-12-090-01-COUN)
- U.S. Department of Defense (W81XWH-12-1-0464)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- HIF-1, CD47, breast cancer, phagocytosis evasion, macrophages, cancer stem cells, hypoxia, transcriptional regulation, mammospheres, patient mortality, prognostic factors
- MeSH terms
- Analysis of Variance, Breast Neoplasms, Female, Humans, Luciferases, Phagocytosis, Neoplastic Stem Cells, Immunoblotting, Gene Expression Regulation, Neoplastic, DNA Primers, Tumor Escape, RNA, Small Interfering, Cell Line, Tumor, Chromatin Immunoprecipitation, Hypoxia-Inducible Factor 1, CD47 Antigen, Real-Time Polymerase Chain Reaction
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