Hypoxia-Inducible Factor-1α Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1α is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIF-1α can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1α is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1α in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HIF-1α by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1α significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1α expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1α promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1α within tumor compartments, we generated cells with combined disruptions of both HIF-1α and vascular endothelial growth factor (VEGF). In all xenografts, disruption of VEGF led to marked expansion of the hypoxic compartments and growth delay. Nonetheless, the presence or absence of HIF-1α did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1α is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1α is a positive factor for cell proliferation and survival under hypoxic conditions in vitro, but does not grossly contribute to the tumor hypoxic compartments in vivo. (Cancer Res 2006; 66(3): 1684-93)
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HCT116 cells are dependent on HIF for generation of tumors in xenograft models.
“To determine whether SirT3 modulates the progression and maintenance of tumors, we preformed studies taking advantage of the fact that HCT116 cells are dependent on HIF for the generation of tumors in xenograft models (Dang et al., 2006).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Dang et al., 2006
Suppression of HIF-1α decreases cell growth rates in vitro and in vivo.
“HIF-dependent genes stimulate cell proliferation (45), and the suppression of HIF-1 𝛂 has been shown to decrease cell growth rates in vitro and in vivo (14).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [14]
Decreasing HIF transcriptional activity through antisense, dominant-negative, or short interfering RNA constructs slows tumor progression.
“Conversely, decreasing HIF transcriptional activity through antisense, dominant-negative, or short interfering RNA constructs (12, 14, 27, 30, 39) slows tumor progression.”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [14]
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- Authors
- Dang, D. T., Chen, F., Gardner, L. B., Cummins, J. M., Rago, C., Bunz, F., Kantsevoy, S. V., & Dang, L. H.
- Affiliations
- University of Michigan (US)
- NYU Langone Health (US)
- Sidney Kimmel Cancer Center (US)
- Johns Hopkins University (US)
- Venue
- Cancer Research
- Published
- 2006-02-01
- Volume
- 66
- Issue
- 3
- Pages
- 1684-1693
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1972944556
- Cited by
- 122
- References
- 53
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 9 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 6
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K22CA111897)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK059970, K08DK59970)
- 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-1α, colon cancer, cell proliferation, tumor hypoxia, tumor xenografts, vascular endothelial growth factor, HCT116 cells, RKO cells, tumor growth inhibition
- MeSH terms
- Animals, Cell Survival, Colonic Neoplasms, DNA, Neoplasm, Female, Glycolysis, Humans, Mice, Nude, Transplantation, Heterologous, Cell Hypoxia, Vascular Endothelial Growth Factor A, HCT116 Cells, Cell Growth Processes, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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