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Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis

Item Type:Preprint
Title:Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis
Creators Name:Rohwer, N., Jumpertz, S., Erdem, M., Egners, A., Warzecha, K.T., Fragoulis, A., Kuehl, 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/b-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 and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1a in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1a and suggests that hypoxia and HIF-1a 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.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:273045
Date:28 February 2018
Official Publication:https://doi.org/10.1101/273045

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