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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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“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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Toward Multi-Targeted Platinum and Ruthenium Drugs—A New Paradigm in Cancer Drug Treatment Regimens?
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“…HIF-1 expression has been shown to be correlated with poor outcome in patient with head and neck cancer, nasopharyngeal carcinoma, colorectal, pancreatic, breast, cervical, osteosarcoma, endometrial, ovarian, bladder, glioblastoma, and gastric carcinomas (for review, see Rankin and Giaccia, 2008).”
BackgroundMechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D
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“Activation of HIF-1a 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).”
BackgroundSomatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia
Zhuang, Z., Yang, C., Lorenzo, F., Merino, M., Fojo, T., Kebebew, E., Popovic, V., Stratakis, C. A., Prchal, J. T., & Pacak, K. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1205119 · Cited by 397
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Mechanisms of drug resistance in HCC
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“[106,107] When HIF-1 α and HIF-2 α are upregulated in the HCC tumor microenvironment, they control processes regulating tumor progression and response to drug therapy.”
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Marengo, B., Nitti, M., Furfaro, A. L., Colla, R., Ciucis, C. D., Marinari, U. M., Pronzato, M. A., Traverso, N., & Domenicotti, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/6235641 · Cited by 327
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HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers
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“Thus, HIF1A may affect several key steps in colon tumorigenesis, including angiogenesis, metabolism, proliferation, and invasion.(49) Our observational results certainly support the “oncogenic” role of HIF1A in colorectal cancer.”
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Joseph, J. P., Harishankar, M. K., Pillai, A. A., & Devi, A. (2018) · Oral Oncology · doi:10.1016/j.oraloncology.2018.03.004 · Cited by 282
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“Hypoxia-inducible factors (HIFs) are transcription factors that control the expression of numerous genes known to regulate glucose uptake, angiogenesis, cell proliferation, apoptosis, and autophagy (17).”
BackgroundContextual Synthetic Lethality of Cancer Cell Kill Based on the Tumor Microenvironment
Chan, N. H. L., Pires, I. M., Bencokova, Z., Coackley, C. L., Luoto, K. R., Bhogal, N., Lakshman, M., Gottipati, P., Oliver, F. J., Helleday, T., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2352 · Cited by 250
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“Where the relationships between hypoxia, EMT and cancer are concerned, it is well known that hypoxia is a major and common feature of almost any clinically relevant human solid malignant tumor, including cancer of the breast, prostate, lung, pancreas, rectum, brain, uterine cervix, melanomas, liver, soft tissue sarcom…”
InfluentialThe oncofetal H19 RNA connection: Hypoxia, p53 and cancer
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“These HIF-1 and/or HIF-2 target genes participate in many biological processes, including erythropoiesis, angiogenesis, metabolic reprograming, cell-cycle regulation, and tumor progression (Gordan and Simon, 2007; Rankin and Giaccia, 2008).”
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“There is strong evidence to suggest that some variants have contrasting functions (Rankin and Giaccia, 2008).”
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“Accordingly, hypoxia-inducible factor (HIF) contributes to tumor progression in a positive feedback loop.(11,12)”
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Physiological and Genetic Adaptations to Diving in Sea Nomads
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“HIF levels are found to be elevated in a variety of cancers [34, 35].”
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“Promoter analysis revealed that HIF-1 α directly regulates more than 60 target genes, and genes induced by HIF-1 α in hypoxic conditions are similar to those induced in normoxic conditions [63-67] .”
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“…to oxygen deprivation, hypoxia inducible factors (HIFs) mediate multiple protective mechanisms, which together act to maintain oxygen homeostasis through reducing oxidative metabolism and oxygen consumption (Gordan and Simon, 2007; Papandreou et al., 2006; Rankin and Giaccia, 2008; Semenza, 2010).”
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“The biological functions of HIF-1 are primarily controlled by the stability of HIF-1, which is tightly regulated by oxygen tension [9].”
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BackgroundHypoxia-inducible factor-2 regulates vascular tumorigenesis in mice
Rankin, E. B., Rha, J., Unger, T. L., Wu, C., Shutt, H. P., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2008) · Oncogene · doi:10.1038/onc.2008.160 · Cited by 149
Self-citationVorrink, S. U., & Domann, F. E. (2014) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2014.05.001 · Cited by 150
“Elevated levels of HIF-1α and HIF-2α are often found in malignant tumors and are thought to play a role in tumorigenesis and poor patient outcome (Rankin and Giaccia, 2008).”
BackgroundInfluentialTiwari, A., Tashiro, K., Dixit, A. K., Soni, A., Vogel, K., Hall, B., Shafqat, I., Slaughter, J. R., Param, N. J., Le, A., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.07.046 · Cited by 145
Xue, M., Li, X., Li, Z., & Chen, W. (2014) · Tumor Biology · doi:10.1007/s13277-014-1925-x · Cited by 142
Zhao, D., Zhai, B., He, C., Tan, G., Jiang, X. L., Pan, S., Dong, X., Wei, Z., Ma, L., Qiao, H., et al. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.01.026 · Cited by 146
Hypoxia as a biomarker for radioresistant cancer stem cells
Peitzsch, C., Perrin, R. L., Hill, R. P., Dubrovska, A., & Kurth, I. (2014) · International Journal of Radiation Biology · doi:10.3109/09553002.2014.916841 · Cited by 143
“Th at regulates the transcription of genes, which are involved in angiogenesis, metabolism, proliferation, invasion and metastasis to maintain oxygen homeostasis and to gain additional growth advantage (Rankin and Giaccia 2008).”
BackgroundRole of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies
Rapisarda, A., & Melillo, G. (2009) · Drug Resistance Updates · doi:10.1016/j.drup.2009.03.002 · Cited by 142
Rofstad, E. K., Galappathi, K., & Mathiesen, B. S. (2014) · Neoplasia · doi:10.1016/j.neo.2014.07.003 · Cited by 139
“that tumor hypoxia and interstitial hypertension cause up-regulation of VEGF-A, VEGF-C, and other proangiogenic factors [18,40,41].”
BackgroundKrishnan, A. V., & Feldman, D. (2009) · Endocrine Related Cancer · doi:10.1677/erc-09-0139 · Cited by 139
Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo
Milovanova, T. N., Bhopale, V. M., Sorokina, E. M., Moore, J. S., Hunt, T. K., Hauer‐Jensen, M., Velazquez, O. C., & Thom, S. R. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91054.2008 · Cited by 139
Differential Hypoxic Regulation of Hypoxia-Inducible Factors 1α and 2α
Lin, Q., Cong, X., & Yun, Z. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0053 · Cited by 138
“SK-N-BE2C cells were incubated at 1% O2 for 24 hours and were used for chromatin immunoprecipitation (ChIP) analysis according to our previously published protocol (19, 20).”
BackgroundMethodInfluentialYang, T., Yao, Q., Cao, F., Liu, Q., Liu, B., & Wang, X. (2016) · International Journal of Nanomedicine · doi:10.2147/ijn.s109695 · Cited by 140
“The best studied member is HIF-1α, which forms a transcriptionally active heterodimeric complex with HIF-1β.(11,12) Under normoxic conditions, the expression of HIF-1α is maintained at very low levels since it is effectively directed to a degradation cascade.”
Bigos, K. J. A., Quiles, C. G., Lunj, S., Smith, D. J., Krause, M., Troost, E. G. C., West, C., Hoskin, P., & Choudhury, A. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1331355 · Cited by 146
“HIF-3 does not have a transactivation domain like HIF-1/HIF-2 but instead contains a polypeptide that represses HRE-responsive gene expression (49).”
BackgroundHypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2
Suzuki, M. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1207 · Cited by 137
Lee, J.-Y., Park, J.-H., Choi, H.-J., Won, H.-Y., Joo, H., Shin, D.-H., Park, M. K., Han, B., Kim, K. P., Lee, T. J., et al. (2017) · Oncogene · doi:10.1038/onc.2017.158 · Cited by 134
Emerging role of nuclear protein 1 (NUPR1) in cancer biology
Chowdhury, U. R., Samant, R. S., Fodstad, Ø., & Shevde, L. A. (2009) · Cancer and Metastasis Reviews · doi:10.1007/s10555-009-9183-x · Cited by 131
Programming DNA Nanoassembly for Enhanced Photodynamic Therapy
Pan, M., Jiang, Q., Sun, J., Xu, Z., Zhou, Y., Zhang, L., & Liu, X. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201912574 · Cited by 136
Menrad, H., Werno, C., Schmid, T., Copanaki, E., Deller, T., Dehne, N., & Brüne, B. (2010) · Hepatology · doi:10.1002/hep.23597 · Cited by 137
“However, HIF-2 appears to be relevant for the ‘‘chronic phase’’ to stimulate proliferation and erythropoiesis.(6,7) HIFs also control the balance of necrotic and apoptotic events.”
BackgroundPadi, S. K. R., Zhang, Q., Rustum, Y. M., Morrison, C., & Guo, B. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.04.012 · Cited by 131
“As the tumor grows larger, the center core is subjected to hypoxia and HIF-1a expression is increased to promote angiogenesis, growth, survival, metastasis, and to regulate anaerobic glucose metabolism.(39) Several hundred genes are induced in hypoxia and the massive transcriptional reorganization might be the result…”
BackgroundMechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals
Cummins, E. P., Strowitzki, M. J., & Taylor, C. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00003.2019 · Cited by 140
“The role of HIF during tumor development has been expertly reviewed (96, 99, 163, 176).”
BackgroundBeclin 1 deficiency is associated with increased hypoxia-induced angiogenesis
Lee, S., Kim, H.-P., Jin, Y., Choi, A. M. K., & Ryter, S. W. (2011) · Autophagy · doi:10.4161/auto.7.8.15598 · Cited by 130
“HIFs regulate the expression of genes involved in energy metabolism, neovascularization, proliferation and cell migration, and thus act as promoters of tumor growth.(13,14) Autophagy, a homeostatic program for organelle or protein turnover and nutrient recycling, has recently been implicated as a physiological respons…”
BackgroundThe role of hypoxia-inducible factor-2 in digestive system cancers
Zhao, J., Du, F., Shen, G., Zheng, F., & Xu, B. (2015) · Cell Death & Disease · doi:10.1038/cddis.2014.565 · Cited by 122
Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy
Augustin, R. C., Leone, R. D., Naing, A., Fong, L. H., Bao, R., & Luke, J. J. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004089 · Cited by 131
Metabolic rivalry: circadian homeostasis and tumorigenesis
Kinouchi, K., & Sassone‐Corsi, P. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0291-9 · Cited by 128
Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea
Almendros, I., Montserrat, J. M., Torres, M., Bonsignore, M. R., Chimenti, L., Navajas, D., & Farré, R. (2012) · Sleep Medicine · doi:10.1016/j.sleep.2012.08.012 · Cited by 123
“Interestingly, it is well known that hypoxia (a hallmark challenge in OSA) enhances tumor growth [4–7].”
BackgroundThe Ubiquitin Ligase Siah2 and the Hypoxia Response
Nakayama, K., Qi, J., & Ronai, Z. A. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0458 · Cited by 124
Policastro, L. L., Ibañez, I. L., Notcovich, C., Duran, H. A., & Podhajcer, O. L. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4367 · Cited by 120
“Fast proliferating cells growing within the tumor limit O2 diffusion from their vascular network and trigger the tumor response to hypoxia (33, 78, 201, 318), by activating broad-action transcription factors named hypoxia-inducible factors (HIFs) (201, 264).”
Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma
Lu, X.-X. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i12.1912 · Cited by 120
Prolyl 4‐hydroxylases, master regulators of the hypoxia response
Myllyharju, J. (2013) · Acta Physiologica · doi:10.1111/apha.12096 · Cited by 123
“1; Rankin & Giaccia 2008, Majmundar et al. 2010, Myllyharju & Schipani 2010, Greer et al. 2012, Semenza 2012a).”
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“In addition to modulating metabolism, hypoxia regulates cell growth, differentiation state, angiogenesis, and invasion (13, 14).”
BackgroundMechanisms linking pathogens-associated inflammation and cancer
Porta, C., Riboldi, E., & Sica, A. (2011) · Cancer Letters · doi:10.1016/j.canlet.2010.10.012 · Cited by 119
“Hypoxia-inducible factors (HIF) are key mediators of the cellular oxygen-signaling pathway [68].”
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Zinc Downregulates HIF-1α and Inhibits Its Activity in Tumor Cells In Vitro and In Vivo
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“hallmark of rapidly growing solid tumors [1].”
FM19G11, a New Hypoxia-inducible Factor (HIF) Modulator, Affects Stem Cell Differentiation Status
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Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses
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“Vascular endothelial growth factor (VEGF) is an important pro-angiogenic HIF1 target gene and a central player in angiogenic signaling (Rankin and Giaccia, 2008).”
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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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