Inhibition of microRNA-126 to Prevent Kasabach-Merritt Phenomenon in Endothelial Cell Tumors

Hemangioendothelioma (HE) is a type of endothelial cell tumor. Kasabach-Merritt Phenomenon (KMP) can develop in infants with HEs and has a mortality rate of 20%. Infants with KMP die from consumptive coagulopathy with sequestration of blood and platelets in the tumor. Treatments for HE include chemotherapy agents, such as vincristine, that have high risk side effects. The purpose of this work was to test whether microRNA-126 (miR126) inhibition prevents KMP through repression of mammalian Target of Rapamycin (mTOR). mTOR is a protein kinase that promotes angiogenesis, which increases susceptibility to KMP. p85ß/PIK3R2 is a protein that represses mTOR. Hemangioendothelioma endothelial (EOMA) cells, a validated HE model in 126P/3 mice, have high levels of expression for miR126 and mTOR, which were measured using qPCR and western blots. EOMA cells were transfected with miR126 inhibitors or control inhibitors to measure, using qPCR and western blots, expression of p-85ß and mTOR. Results indicated that inhibition of miR126 increased p85ß expression, which decreased mTOR expression. To analyze miR126 inhibition in vivo, 126P/3 mice were injected subcutaneously with EOMA cells and treated with either miR126 inhibitors or control inhibitors. Blood testing did not indicate significant decreases in hemoglobin, hematocrit, and platelets levels in the control inhibitor group, as excepted for KMP, compared to the miR126 inhibitor. Overall, in vitro activation of mTOR is miR126 dependent because miR126 silences p-85ß, resulting in mTOR activation. Inhibition of miR126 results in decreased mTOR expression by de-repression of p-85β. Further murine studies are being preformed to understand miR126 inhibition on KMP. By determining the effects of miR126, we will be closer to discovering a safe and effective treatment for KMP. This will improve lives and decrease KMP mortality.National Institute of Health/National Institute of General Medical Sciences grantNo embargoAcademic Major: Biolog