title: Novel tissue-specific mechanism of regulation of angiogenesis and cancer growth in response to hyperglycemia.
abstract: BACKGROUND
  Hyperglycemia is an independent risk factor for the development of vascular diabetic complications, which are characterized by endothelial dysfunction and tissue-specific aberrant angiogenesis. Tumor growth is also dependent on angiogenesis. Diabetes affects several cancers in a tissue-specific way. For example, it positively correlates with the incidence of breast cancer but negatively correlates with the incidence of prostate cancer. The tissue-specific molecular mechanisms activated by hyperglycemia that control angiogenesis are unknown. Here we describe a novel tissue- and cell-specific molecular pathway that is activated by high glucose and regulates angiogenesis.
  
  
  RESULTS
  We have identified microRNA 467 (miR-467) as a translational suppressor of thrombospondin-1 (TSP-1), a potent antiangiogenic protein that is implicated in the pathogenesis of several diabetic complications. miR-467 was upregulated by hyperglycemia in a tissue-specific manner. It was induced by high glucose in microvascular endothelial cells and in breast cancer cells, where it suppressed the production of TSP-1 by sequestering mRNA in the nonpolysomal fraction. Mutation of the miR-467 binding site in TSP-1 3' UTR or miR-467 inhibitor relieved the translational silencing and restored TSP-1 production. In in vivo angiogenesis models, miR-467 promoted the growth of blood vessels, and TSP-1 was the main mediator of this effect. Breast cancer tumors showed increased growth in hyperglycemic mice and expressed higher levels of miR-467. The antagonist of miR-467 prevented the hyperglycemia-induced tumor growth.
  
  
  CONCLUSIONS
  Our results demonstrate that miR-467 is implicated in the control of angiogenesis in response to high glucose, which makes it an attractive tissue-specific potential target for therapeutic regulation of aberrant angiogenesis and cancer growth in diabetes.
authors: Department of Molecular Cardiology and Joseph J Jacob Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Sanghamitra
authors: S
authors: Bhattacharyya
authors: Kristina
authors: K
authors: Sul
authors: Irene
authors: I
authors: Krukovets
authors: Carla
authors: C
authors: Nestor
authors: Jianbo
authors: J
authors: Li
authors: Olga Stenina
authors: OS
authors: Adognravi
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D003920:Diabetes Mellitus / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; C569061:MIRN467 microRNA, mouse; D035683:MicroRNAs; D019700:Thrombospondin 1
keywords: complications of diabetes; microRNA; thrombospondin‐1; translational regulation