Novel Tissue‐Specific Mechanism of Regulation of Angiogenesis and Cancer Growth in Response to Hyperglycemia

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. METHODS AND 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.