MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis
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Abstract
Hypoxia-inducible factor-1α (HIF-1α) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1α, acting through direct binding to the HIF-1α 3′ untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α–mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c–overexpressing cells exhibited dramatically reduced HIF-1α levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. Cancer Res; 70(7); 2675–85
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miR-519c is highly associated with the reversion of multidrug resistance by targeting ABCG2 mRNA.
“where miR-519c has been demonstrated to be highly associated with the reversion of MDR by targeting the ABCG2 mRNA.19–21”
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- Authors
- Cha, S.-T., Chen, P.-S., Johansson, G., Chu, C.-Y., Wang, M.-Y., Jeng, Y.-M., Yu, S.-L., Chen, J.-S., Chang, K.-J., Jee, S.-H., Tan, C.-T., Lin, M.-T., & Kuo, M.-L.
- Affiliations
- National Taiwan University (TW)
- ORCID
- Venue
- Cancer Research
- Published
- 2010-03-31
- Volume
- 70
- Issue
- 7
- Pages
- 2675-2685
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2086595831
- Cited by
- 202
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 13 · 2022: 8 · 2021: 14 · 2020: 9 · 2019: 19 · 2018: 7 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 16 · 2013: 22 · 2012: 21
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-15)
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Taiwan University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- HIF-1α, tumor angiogenesis, hepatocyte growth factor, Akt signaling, microRNA biogenesis, 3' untranslated region, post-transcriptional regulation, endothelial tube formation, metastasis, tumor growth
- MeSH terms
- Adenocarcinoma, Animals, Breast Neoplasms, Humans, Lung Neoplasms, Male, Mice, Inbred BALB C, Neovascularization, Pathologic, RNA Processing, Post-Transcriptional, 3' Untranslated Regions, MicroRNAs, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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