Abstract 57: Hyperglycemia-Induced miR-467 Regulates Angiogenesis and Tumor Growth in a Tissue-Specific Manner

Abstract

Recent emerging evidence suggests that diabetes is associated with increased incidence of several cancers (e.g., breast, bladder, pancreas, liver) but decreased incidence of others (e.g., prostate). We suggest that the tissue-specific association with cancers is caused by a tissue-specific regulation of angiogenesis in diabetic patients. A well-known aberrant angiogenesis of diabetes (increased neovascularization in some tissues, e.g., retina and kidney, and deficient angiogenesis causing ischemia in others, e.g., skin and myocardium) has been recognized for many years and is the cause of diabetic microvascular complications (retinopathy, neuropathy, cardiomyopathy, and nephropathy). However, the molecular mechanisms of the tissue-specific diabetic angiogenesis are unknown. We have discovered a novel tissue-specific mechanism that is activated by hyperglycemia: the levels of microRNA-467 (miR-467) are upregulated in response to hyperglycemia in mouse breast cancer but not in prostate cancer. miR-467 inhibits production of a potent anti-angiogenic protein thrombospondin-1 (TSP-1), and, as a result, angiogenesis is increased in a tissue-specific manner. Our preliminary data identified miR-467 as a regulator of TSP-1 production and angiogenesis in response to hyperglycemia, established a correlation between hyperglycemia-induced tumor growth and miR-467 and TSP-1 in vivo , confirmed the effect of miR-467 on angiogenesis in vivo and the effect of miR-467 antagonist on hyperglycemia-induced tumor growth. In a mouse breast cancer model, hyperglycemia increased the tumor size 8 fold (0.24 g ± 0.012 vs 0.03 ± 0.002, p = 0.003), miR-467 levels 4 fold increase, and angiogenesis 7-fold (endothelial marker CD31), but decreased TSP-1 levels > 3-fold. When miR-467 antagonist was expressed in breast cancer cells, the changes detected in response to hyperglycemia (increase in angiogenesis, size of tumors and miR-467 levels and decrease in TSP-1 level) were completely prevented. We described a tissue-specific mechanism of diabetes-induced cancer growth, which suggests a novel breakthrough approach to block hyperglycemia-induced cancer angiogenesis and growth without affecting physiological angiogenesis.