Cleveland Clinic researchers investigated the effect of systemic administration of an antagonist of microRNA-467 on hyperglycemia-induced local angiogenesis. 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. microRNA-467 was upregulated by hyperglycemia in a tissue-specific manner.
In vivo studies showed beneficial effect of preventing prevented hyperglycemia-induced angiogenesis and growth of mouse and human breast cancer tumors while didn’t affect angiogenesis in a skin wound healing mouse model indicating specificity to diabetes associated breast cancer. This treatment can have potential in treatment of breast cancer patients who also have diabetes.
Inhibition of hyperglycemia-induced angiogenesis and breast cancer tumor growth by systemic injection of microRNA-467 antagonist
Krukovets I1, Legerski M1, Sul P1, Stenina-Adognravi O2.[expand title=”Show Affiliations”]
1Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.
2Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA [email protected].[/expand]
Abnormal angiogenesis in multiple tissues is a key characteristic of the vascular complications of diabetes. However,angiogenesis may be increased in one tissue but decreased in another in the same patient at the same time point in the disease. The mechanisms of aberrant angiogenesis in diabetes are not understood. There are no selective therapeutic approaches to target increased neovascularization without affecting physiologic angiogenesis and angiogenesis in ischemic tissues. We recently reported a novel miRNA-dependent pathway that up-regulates angiogenesis in response to hyperglycemia in a cell- and tissue-specific manner. The goal of the work described herein was to test whether systemic administration of an antagonist of microRNA-467 would prevent hyperglycemia-induced local angiogenesis in a tissue-specific manner. We examined the effect of the antagonist on hyperglycemia-induced tumor growth and angiogenesis and on skin wound healing in mouse models of diabetes. Our data demonstrated that the systemic injection of the antagonist prevented hyperglycemia-induced angiogenesis and growth of mouse and human breast cancer tumors, where the microRNA-467 pathway was active in hyperglycemia. In tissues where the microRNA-467-dependent mechanism was not activated by hyperglycemia, there was no effect of the antagonist: the systemic injection did not affect skin wound healing or the growth of prostate tumors. The data show that systemic administration of the microRNA-467 antagonist could be a breakthrough approach in the treatment and prevention of diabetes-associated breast cancer in a tissue-specific manner without affecting physiologic angiogenesis and angiogenesis in ischemic tissues.
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