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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. and Jumpertz, S. and Erdem, M. and Egners, A. and Warzecha, K.T. and Fragoulis, A. and Kuehl, A.A. and Kramann, R. and Neuss, S. and Rudolph, I. and Endermann, T. and Zasada, C. and Apostolova, I. and Gerling, M. and Kempa, S. and Hughes, R. and Lewis, C.E. and Brenner, W. and Malinowski, M.B. and Stockmann, M. and Schomburg, L. and Faller, W. and Sansom, O.J. and Tacke, F. and 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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