Cusanelli, Emilio (2009) miR34a targets the Notch pathway in medulloblastoma. [Tesi di dottorato] (Inedito)

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Abstract

Medulloblastoma (MB) is a highly aggressive cancer that mostly affects children, through developmental impairment of the cerebellum. Several miR34a targets belong to the Notch pathway, a signaling pathway that is involved in cerebellum development and that is aberrantly activated during MB tumorigenesis. We show here that miR34a over-expression transiently down-regulates the Notch ligand Delta-like 1 (DLL1) protein levels and also results in Notch1 activation and Notch2 signaling inhibition, an effect that we see in the MB Daoy and D283-MED cells. Moreover, ectopic expression of miR34a in MB cells results in impairment of proliferation rate and soft agar colony formation, while inducing apoptosis and differentiation processes. Noteworthy, the induction of apoptosis was inhibited by ectopic expression of DLL1, suggesting the involvement of DLL1 down-regulation in this process. We also provide evidences that the endogenous expression of miR34a can down-regulate DLL1 protein levels and contribute to the p53-induced apoptosis in Daoy cells, upon doxorubicin stimulation. Induction of miR34a correlates with DLL1 protein down-regulation also in neuroblastoma and breast cancer cells and expression of miR34b and miR34c can contribute to the DLL1 down-regulation. Finally, we report that miR34a, miR34b and miR34c, are down-regulated in human MB tumors. These results suggest that miR34a has an onco-suppressor function in MB and that it can thus be targeted for future therapeutic applications.

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