HIF2α cooperates with RAS to promote lung tumorigenesis in mice
Open accessAbstract
Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2alpha and a mutant form of Kras (KrasG12D) that induces lung tumors. Mice expressing both Hif2a and KrasG12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only KrasG12D. Additionally, tumors expressing both KrasG12D and Hif2a were more invasive, demonstrated features of epithelial- mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2alpha can promote expression of markers of EMT, and define HIF2alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC.
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Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types.
“Hypoxia or overexpression of HIF is sufficient to induce EMT and invasion in multiple cell types”
From Hypoxic control of metastasis (2016) · cites this paper as [68]
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- Authors
- Kim, W. Y., Perera, S., Zhou, B., Carretero, J., Yeh, J. J., Heathcote, S. A., Jackson, A. L., Nikolinakos, P., Ospina, B., Naumov, G., Brandstetter, K. A., Weigman, V. J., Zaghlul, S., Hayes, D. N., Padera, R. F., Heymach, J. V., Kung, A. L., Sharpless, N. E., Kaelin, W. G., & Wong, K.-K.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Dana-Farber Cancer Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kim, William Y.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-08-03
- Volume
- 119
- Issue
- 8
- Pages
- 2160-2170
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2719950
- OpenAlex
- W1971886895
- Cited by
- 141
- References
- 90
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 10 · 2017: 13 · 2016: 11 · 2015: 15 · 2014: 10 · 2013: 10 · 2012: 12
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Melanoma Research Foundation
- Melanoma Research Alliance
- Flight Attendant Medical Research Institute
- National Institutes of Health
- Gillings School of Public Health
- University of North Carolina at Chapel Hill
- National Institute on Aging (AG2400401, K08AG024004)
- National Cancer Institute (R01CA122794, K08CA097203)
- Lineberger Comprehensive Cancer Center, 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 › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- HIF-2α, Ras, KRAS G12D, non-small cell lung cancer, lung carcinogenesis, epithelial-mesenchymal transition, tumor angiogenesis, endothelial progenitor cells, tumor invasion, vascular endothelial growth factor, VEGFR2, hypoxia, conditional mouse model, tumor progression
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Organic Cation Transporter 3, Animals, Cell Differentiation, Endothelium, Humans, Lung Neoplasms, Mesoderm, Mice, Inbred C57BL, Neoplasm Invasiveness, Proto-Oncogene Proteins p21(ras), Gene Expression Profiling, Organic Cation Transport Proteins, Mice, Basic Helix-Loop-Helix Proteins
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