Global microRNA depletion suppresses tumor angiogenesis
Name
Chen-2014-Global microRNA depl.pdf
Size
2.61 MB
Format
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Checksum (MD5)
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Author(s)
Chen, Sidi
Xue, Yuan
Le, Cong
Bhutkar, Arjun (AJ)
Bell, Eric L.
Zhang, Feng
Langer, Robert
Sharp, Phillip A.
Wu, Xuebing, Ph. D. Massachusetts Institute of Technology
Wu, Xuebing, Ph. D. Massachusetts Institute of Technology
Date Issued
May 2014
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Chen, S., Y. Xue, X. Wu, C. Le, A. Bhutkar, E. L. Bell, F. Zhang, R. Langer, and P. A. Sharp. “Global microRNA Depletion Suppresses Tumor Angiogenesis.” Genes & Development 28, no. 10 (May 15, 2014): 1054–1067.
Version
Final published version
Abstract
MicroRNAs delicately regulate the balance of angiogenesis. Here we show that depletion of all microRNAs suppresses tumor angiogenesis. We generated microRNA-deficient tumors by knocking out Dicer1. These tumors are highly hypoxic but poorly vascularized, suggestive of deficient angiogenesis signaling. Expression profiling revealed that angiogenesis genes were significantly down-regulated as a result of the microRNA deficiency. Factor inhibiting hypoxia-inducible factor 1 (HIF-1), FIH1, is derepressed under these conditions and suppresses HIF transcription. Knocking out FIH1 using CRISPR/Cas9-mediated genome engineering reversed the phenotypes of microRNA-deficient cells in HIF transcriptional activity, VEGF production, tumor hypoxia, and tumor angiogenesis. Using multiplexed CRISPR/Cas9, we deleted regions in FIH1 3′ untranslated regions (UTRs) that contain microRNA-binding sites, which derepresses FIH1 protein and represses hypoxia response. These data suggest that microRNAs promote tumor responses to hypoxia and angiogenesis by repressing FIH1.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommerical
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DOI of Published Version
https://doi.org/10.1101/gad.239681.114
