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| Item Type: | Article |
|---|---|
| Title: | Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis |
| Creators Name: | Rohwer, N., Jumpertz, S., Erdem, M., Egners, A., Warzecha, K.T., Fragoulis, At., Kühl, A.A., Kramann, R., Neuss, S., Rudolph, I., Endermann, T., Zasada, C., Apostolova, I., Gerling, M., Kempa, S., Hughes, R., Lewis, C.E., Brenner, W., Malinowski, M.B., Stockmann, M., Schomburg, L., Faller, W., Sansom, O.J., Tacke, F., Morkel, M. and Cramer, T. |
| Abstract: | The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment. |
| Keywords: | alpha Subunit Hypoxia-Inducible Factor 1, Colorectal Neoplasms, Inbred C57BL Mice, Intestinal Mucosa, Macrophages, Oncogenes, Protein Stability, Tumor Microenvironment, Animals, Mice |
| Source: | Oncogene |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Volume: | 38 |
| Number: | 28 |
| Page Range: | 5670-5685 |
| Date: | 11 July 2019 |
| Official Publication: | https://doi.org/10.1038/s41388-019-0816-4 |
| External Fulltext: | View full text on external repository or document server |
| PubMed: | View item in PubMed |
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