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.