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Genes Dev DOI:10.1101/gad.239681.114

Global microRNA depletion suppresses tumor angiogenesis.

Publication TypeJournal Article
Year of Publication2014
AuthorsChen, S, Xue, Y, Wu, X, Le, C, Bhutkar, A, Bell, EL, Zhang, F, Langer, R, Sharp, PA
JournalGenes Dev
Date Published2014 May 15
KeywordsAnimals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, DEAD-box RNA Helicases, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Genotype, Mice, Mice, Nude, MicroRNAs, Neovascularization, Pathologic, Ribonuclease III, Transcriptome

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.


Alternate JournalGenes Dev.
PubMed ID24788094
PubMed Central IDPMC4035535
Grant ListR01-CA133404 / CA / NCI NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
R01 EB006365 / EB / NIBIB NIH HHS / United States
EB006365 / EB / NIBIB NIH HHS / United States
P01 CA042063 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
EB016101-01A1 / EB / NIBIB NIH HHS / United States
R01 CA133404 / CA / NCI NIH HHS / United States
DP1 MH100706 / MH / NIMH NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 EB016101 / EB / NIBIB NIH HHS / United States