The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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”
From Hypoxic control of metastasis (2016) · cites this paper as [47]
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Cites
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“For example, HIF activates proangiogenic genes, such as VEGFA, PDGFB, and IL-8, genes that regulate cellular pH, such as carbonic anhydrase 9 (CA9), and genes that regulate glycolytic cellular metabolism, such as lactate dehydrogenase A (LDHA) and phosphofructokinase (PFK) (4, 5).”
BackgroundHypoxia — a key regulatory factor in tumour growth
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Self-citationDifferential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386
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Research works printed but not linked: 1
- Blancher, 2001, Cancer Res., 61, 7349
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Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340
Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis
Pittayapruek, P., Meephansan, J., Prapapan, O., Komine, M., & Ohtsuki, M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060868 · Cited by 1,099
Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET
Rankin, E. B., Fuh, K. C., Castellini, L., Viswanathan, K., Finger, E. C., Diep, A. N., LaGory, E. L., Kariolis, M. S., Chan, A., Lindgren, D., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404848111 · Cited by 269
Melanocytic nevi and melanoma: unraveling a complex relationship
Damsky, W., & Bosenberg, M. (2017) · Oncogene · doi:10.1038/onc.2017.189 · Cited by 263
Hypoxia: Signaling the Metastatic Cascade
Rankin, E. B., Nam, J.-M., & Giaccia, A. J. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.05.006 · Cited by 249
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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