期刊
GENES & DEVELOPMENT
卷 28, 期 10, 页码 1054-1067出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.239681.114
关键词
microRNA; Dicer; angiogenesis; hypoxia; CRISPR/Cas9; gene regulation
资金
- Swedish Research Council
- National Institutes of Health [R01-CA133404, EB016101-01A1, EB006365]
- Massachusetts Institute of Technology-Harvard Center for Cancer Nanotechnology Excellence [U54 CA151884]
- National Cancer Institute
- Koch Institute Support (core) [P30-CA14051]
- Damon Runyon Cancer Research Fellow [DRG-2117-12]
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 39 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.
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