Dataset Information

Global microRNA depletion suppresses tumor angiogenesis.

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.

SUBMITTER: Chen S

PROVIDER: S-EPMC4035535 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Global microRNA depletion suppresses tumor angiogenesis.

Chen Sidi S Xue Yuan Y Wu Xuebing X Le Cong C Bhutkar Arjun A Bell Eric L EL Zhang Feng F Langer Robert R Sharp Phillip A PA

Genes & development 20140501 10

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 derepr ...[more]

PMID: 24788094

Similar Datasets

Project description:Tumor neovascularization/tumor angiogenesis is a pathophysiological process in which new blood vessels are formed from existing blood vessels in the primary tumors to supply adequate oxygen and nutrition to cancer cells for their proliferation and metastatic growth to the distant organs. Therefore, controlling tumor angiogenesis is an attractive target for cancer therapy. Structural abnormalities of the vasculature (i.e., leakiness due to the abnormal lining of pericytes on the microvessels) are one of the critical features of tumor angiogenesis that sensitizes vascular cells to cytokines and helps circulating tumor cells to metastasize to distant organs. Our goal is to repurpose the drugs that may prevent tumor angiogenesis or normalize the vessels by repairing leakiness via recruiting pericytes or both. In this study, we tested whether aspirin (ASA), which could block primary tumor growth, regulates tumor angiogenesis. We investigated the effects of low (1 mM) and high (2.5 mM) doses of ASA (direct effect), and ASA-treated or untreated triple negative breast cancer (TNBC) cells' conditioned media (indirect effect) on endothelial cell physiology. These include in vitro migration using modified Boyden chamber assay, in vitro capillary-like structure formation on Matrigel, interactions of pericytes-endothelial cells and cell permeability using in vitro endothelial permeability assay. We also examined the effect of ASA on various molecular factors associated with tumor angiogenesis. Finally, we found the outcome of ASA treatment on in vivo tumor angiogenesis. We found that ASA-treatment (direct or indirect) significantly blocks in vitro migration and capillary-like structure formation by endothelial cells. Besides, we found that ASA recruits pericytes from multipotent stem cells and helps in binding with endothelial cells, which is a hallmark of normalization of blood vessels, and decreases in vitro permeability through endothelial cell layer. The antiangiogenic effect of ASA was also documented in vivo assays. Mechanistically, ASA treatment blocks several angiogenic factors that are associated with tumor angiogenesis, and suggesting ASA blocks paracrine-autocrine signaling network between tumor cells and endothelial cells. Collectively, these studies implicate aspirin with proper dose may provide potential therapeutic for breast cancer via blocking as well as normalizing tumor angiogenesis.

Dataset Information

Global microRNA depletion suppresses tumor angiogenesis.

Publications

Global microRNA depletion suppresses tumor angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets