Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression
Open accessAbstract
BACKGROUND: Hypoxia-inducible factor 1 alpha (HIF-1alpha) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1alpha during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. METHODS: Immunohistochemistry and Western blot is used to analyse HIF-1alpha expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1alpha inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. RESULTS: In normal mucosa, HPP and TA-LGD HIF-1alpha was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1alpha were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1alpha overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1alpha expression was strongly accumulated in perinecrotic regions. In these cases HIF-1alpha activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1alpha was also seen in periinflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1alpha expression and nuclear translocation. CONCLUSION: We conclude that HIF-1alpha expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic activation of HIF-1alpha in invasive tumors underlines a dual role of HIF-1alpha by regulating both pro-survival and pro-death processes. HIF-1alpha up-regulation in response to LPS-mediated stimulation and periinflammatory expression in invasive carcinomas suggest its involvement in inflammatory events. These patterns of HIF-1alpha inducibility could contribute indirectly to the acquisition of a metastatic phenotype.
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HIF-1α protein is overexpressed in various common solid malignant tumors including breast, colon, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas compared to their respective normal tissues.
“The HIF-1α protein is overexpressed in various common solid malignant tumors including breast, colon, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas compared to their respective normal tissues.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Simiantonaki et al., 2008
The Results report HIF-1α protein in colorectal carcinomas but not adjacent normal mucosa. The Background reports enhanced expression during prostate, gastric, and breast carcinogenesis. Our copy does not establish the claimed comparison with normal tissue for lung, skin, ovarian, pancreatic, or renal carcinomas. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMany benign tumors show very little or no HIF-1α expression.
“In contrast, many benign tumors show very little or no HIF-1α expression (Zhong et al., 1999;Daponte et al., 2008;Simiantonaki et al., 2008;Mayer et al., 2008b).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Simiantonaki et al., 2008
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- Authors
- Simiantonaki, N., Taxeidis, M., Jayasinghe, C., Kurzik-Dumke, U., & Kirkpatrick, C. J.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Simiantonaki, Nektaria
- Venue
- BMC Cancer
- Published
- 2008-11-04
- Volume
- 8
- Issue
- 1
- Pages
- 320-320
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC2584660
- OpenAlex
- W2080457089
- Cited by
- 81
- References
- 50
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 8 · 2013: 9 · 2012: 5
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- hypoxia-inducible factor-1α, colorectal carcinogenesis, colorectal adenocarcinoma, tumor progression, serrated pathway, hyperplastic polyps, sessile serrated adenoma, tumor necrosis, lipopolysaccharide, inflammation, metastasis, nuclear translocation, colorectal cancer cell lines
- MeSH terms
- Cell Transformation, Neoplastic, Colonic Polyps, Humans, Immunohistochemistry, Lipopolysaccharides, Neoplasm Metastasis, Precancerous Conditions, Colorectal Neoplasms, Disease Progression, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit
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