Notch signaling mediates hypoxia-induced tumor cell migration and invasion
Open accessAbstract
Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood. Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial–mesenchymal transition (EMT), increased motility, and invasiveness. Inhibition of Notch signaling abrogated hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch could substitute for hypoxia to induce these processes. Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT. First, Notch directly up-regulated Snail-1 expression by recruitment of the Notch intracellular domain to the Snail-1 promoter, and second, Notch potentiated hypoxia-inducible factor 1α (HIF-1α) recruitment to the lysyl oxidase ( LOX ) promoter and elevated the hypoxia-induced up-regulation of LOX, which stabilizes the Snail-1 protein. In sum, these data demonstrate a complex integration of the hypoxia and Notch signaling pathways in regulation of EMT and open up perspectives for pharmacological intervention with hypoxiainduced EMT and cell invasiveness in tumors.
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The HIF pathway indirectly promotes EMT through Notch, TGF-β, integrin-linked kinase, certain tyrosine kinase receptors, Wnt, and Hedgehog.
“The HIF pathway also indirectly promotes EMT through a number of cell signaling pathways, including Notch (74, 75), TGF-β (76), integrin-linked kinase (77), certain tyrosine kinase receptors (48), Wnt (73), and Hedgehog (78, 79).”
From Hypoxic control of metastasis (2016) · cites this paper as [75]
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- Authors
- Sahlgren, C., Gustafsson, M. V., Jin, S., Poellinger, L., & Lendahl, U.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-04-29
- Volume
- 105
- Issue
- 17
- Pages
- 6392-6397
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2359811
- OpenAlex
- W2035396934
- Cited by
- 823
- References
- 41
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 34 · 2023: 41 · 2022: 36 · 2021: 46 · 2020: 38 · 2019: 40 · 2018: 58 · 2017: 53 · 2016: 58 · 2015: 60 · 2014: 61 · 2013: 51 · 2012: 57
- FWCI
- 26.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- TU/e Research Portal (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- Notch signaling, tumor hypoxia, epithelial-mesenchymal transition, tumor cell migration, tumor invasion, SNAI1, HIF-1α, lysyl oxidase, protein stabilization, metastasis, transcriptional regulation
- MeSH terms
- Snail Family Transcription Factors, Cell Movement, Epithelium, Humans, Ligands, Mesoderm, Neoplasm Invasiveness, Neoplasms, RNA, Messenger, Transcription Factors, Signal Transduction, Down-Regulation, Cell Hypoxia, Cadherins, Up-Regulation, Gene Expression Regulation, Neoplastic, Extracellular Matrix Proteins, Cell Line, Tumor, Receptors, Notch
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