The DOI matches its Crossref record; 105 of the 105 references it cites were found in a registry or an index.
The role of hypoxia-inducible factors in tumorigenesis
Open accessAbstract
Hypoxia-inducible factors (HIFs) are essential mediators of the cellular oxygen-signaling pathway. They are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-alpha) and a constitutive beta subunit (HIF-beta) that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that control glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, and apoptosis. In most experimental models, the HIF pathway is a positive regulator of tumor growth as its inhibition often results in tumor suppression. In clinical samples, HIF is found elevated and correlates with poor patient prognosis in a variety of cancers. In summary, HIF regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy, making it a critical regulator of the malignant phenotype.
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In the citing paper
“HIF-1 also controls the expression of genes involved in tumor cell immor- talization, stem cell maintenance/de-differentiation, genetic in- stability, autocrine growth, invasion/metastasis, and treatment failure (6, 7).”
From Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth (2008) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“Activation of HIF-1α will directly augment the transcription of genes involved in angiogenesis and metastasis, such as VEGF, MMP-9, lysyl oxidase and carbonic anhydrase IX (Rankin and Giaccia, 2008).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Rankin and Giaccia, 2008
In the citing paper
“Clinically, hypoxia is associated with HIF activation, metastasis, and resistance to chemotherapy and radiotherapy, as well as poor patient survival”
From Hypoxic control of metastasis (2016) · cites this paper as [4]
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Citations
Cites
1 retracted
Lysyl oxidase is essential for hypoxia-induced metastasis
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., & Giaccia, A. J. (2006) · Nature · doi:10.1038/nature04695 · Cited by 1,309
Self-citationRetractedHanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425
Stem cells, cancer, and cancer stem cells
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001) · Nature · doi:10.1038/35102167 · Cited by 9,738
Angiogenesis in cancer and other diseases
Carmeliet, P., & Jain, R. K. (2000) · Nature · doi:10.1038/35025220 · Cited by 9,070
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 1×
“Hydroxylation of conserved proline residues within the HIF-a ODD by prolyl-4hydroxylase domain (PHD)-containing proteins mediates pVHL binding and degradation.(20,21) Under hypoxia, HIF-a subunits are stabilized and translocate to the nucleus, where they heterodimerize with ARNT and bind to HREs located within regulat…”
BackgroundIdentification of the von Hippel-Lindau Disease Tumor Suppressor Gene
Latif, F., Tory, K., Gnarra, J. R., Yao, M., Duh, F.-M. C., Orcutt, M. L., Stackhouse, T. M., Kuzmin, I., Modi, W. S., Geil, L., et al. (1993) · Science · doi:10.1126/science.8493574 · Cited by 2,971
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Decoding osteosarcoma pathogenesis: the pivotal influence of m 6 A modification
Huang, C., Han, Z., Su, J., Zhang, M. X., Lin, Y., He, H., Tang, Y., Guo, P., Wang, Y., & Chen, H. T. (2026) · Epigenetics · doi:10.1080/15592294.2026.2705608 · Cited by 1
“VHL inactivation causes VEGF and PDGF to be constitutively activated, and these factors further target the downstream glutamine transporter SLC1A5 to promote glutamine metabolism [95]; SLC1A5 is a key target of FTO.”
Imran, H., Basit, A., & Farid, F. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12408-3
“Given the rapid degradation of HIF-1α during reoxygenation, temporal assessment of its expression would have strengthened the mechanistic interpretation [4].”
Gogitidze, G.-J. (2026) · Biology · doi:10.3390/biology15161362
“HIF-1 α represents an upstream environmental regulator that links hypoxia to vasculogenic activation by inducing VEGF, CXCL12/CXCR4, angiopoietins, and other mediators responsible for endothelial progenitor cell recruitment and vascular adaptation [11,32].”
Carrero, Y. N., & Mosquera, J. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1922814
“Evidence indicates that these oncoproteins, especially E6 and E7 promote the expression of VEGF and other angiogenesis factors, such as IL-8, which can promote tumor angiogenesis through a HIF-1 a /VEGF pathway in human cervical carcinoma cells and in non-small cell lung cancers (106, 107).”
Liu, Y., & Shi, P. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105616
Metadata
- Authors
- Rankin, E. B., & Giaccia, A. J.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Giaccia, A J
- Venue
- Cell Death & Differentiation
- Published
- 2008-02-15
- Volume
- 15
- Issue
- 4
- Pages
- 678-685
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3050610
- OpenAlex
- W2014245338
- Cited by
- 806
- References
- 105
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 30 · 2023: 34 · 2022: 43 · 2021: 42 · 2020: 39 · 2019: 38 · 2018: 33 · 2017: 44 · 2016: 45 · 2015: 48 · 2014: 56 · 2013: 51 · 2012: 46
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA067166, T32CA009151)
- 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
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia-inducible factor, carcinogenesis, oxygen signaling, hypoxia-inducible factor alpha, angiogenesis, cancer metabolism, tumor growth, metastasis, radiation response, tumor differentiation, prognosis, apoptosis, cell proliferation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adaptation, Physiological, Animals, Hypoxia, Cell Differentiation, Energy Metabolism, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Oxygen, Signal Transduction, Cell Hypoxia, Cell Proliferation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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