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HIF1α and HIF2α independently activate SRC to promote melanoma metastases
Open accessAbstract
Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells. Using a Pten-deficient, Braf-mutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1α or HIF2α abrogates metastasis without affecting primary tumor formation. HIF1α and HIF2α drive melanoma invasion and invadopodia formation through PDGFRα and focal adhesion kinase-mediated (FAK-mediated) activation of SRC and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1α and HIF2α activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.
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“whereas inactivation of HIF decreases the metastatic potential of tumor cells”
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Metadata
- Authors
- Hanna, S. C., Krishnan, B., Bailey, S. T., Moschos, S. J., Kuan, P.-F., Shimamura, T., Osborne, L. D., Siegel, M. B., Duncan, L. M., O’Brien, E. T., Superfine, R., Miller, C. R., Simon, M. C., Wong, K.-K., & Kim, W. Y.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Loyola University Chicago (US)
- Harvard University (US)
- University of Pennsylvania (US)
- Corresponding author
- Kim, William Y.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-04-08
- Volume
- 123
- Issue
- 5
- Pages
- 2078-2093
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3635738
- OpenAlex
- W2085551560
- Cited by
- 147
- References
- 41
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 11 · 2020: 16 · 2019: 13 · 2018: 11 · 2017: 16 · 2016: 13 · 2015: 15 · 2014: 21 · 2013: 5
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense (W81XWH, W81XWH0920042)
- Damon Runyon Cancer Research Foundation
- Melanoma Research Foundation
- Melanoma Research Alliance
- National Institutes of Health (5u54ca151652-05, NIH-R01, W81XWH)
- National Cancer Institute (R01CA166480, U54‐CA151652, CA120964, CA163896, CA141576, R01CA122794, R01CA140594, CA 140594, R33CA155618, CA 122794, R01CA142794, P01CA154303, R01CA163896, P50CA093683, P01CA120964, P30CA016086, U01CA141576, CA 166480)
- National Institute of General Medical Sciences (T32GM007092)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034987)
- National Institute of Environmental Health Sciences (P30ES010126)
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- HIF-1α, HIF-2α, melanoma metastasis, Src kinase, hypoxia-inducible factor, tumor invasion, invadopodia, PDGFRA, focal adhesion kinase, extracellular matrix remodeling, MT1-MMP, MMP-2, tumor cell motility
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Hypoxia, Extracellular Matrix, Humans, Melanoma, Microscopy, Fluorescence, Mutation, Neoplasm Metastasis, Oncogenes, Skin Neoplasms, Gene Expression Regulation, Neoplastic, RNA, Small Interfering, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, PTEN Phosphohydrolase, Mice, Focal Adhesion Protein-Tyrosine Kinases, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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