Global microRNA depletion suppresses tumor angiogenesis
Author(s)Chen, Sidi; Xue, Yuan; Wu, Xuebing; Le, Cong; Bhutkar, Arjun (AJ); Bell, Eric L.; Zhang, Feng; Langer, Robert; Sharp, Phillip A.; Wu, Xuebing; ... Show more Show less
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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.
Departmentdelete; David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Computational and Systems Biology Program; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemical Engineering
Genes & Development
Cold Spring Harbor Laboratory Press
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.
Final published version