Medulloblastoma is the most common malignant brain tumor in children. Hedgehog group MB accounts for 30% MB cases in human, predominately resulting from aberrant activation of hedgehog pathway in cerebellar granule neuron precursors. Hedgehog pathway activation is also required for the progression of MB tumor cells. However, it remains elusive how tumor cells sustain activation of the hedgehog pathway. Our studies revealed that MB tumor cells highly express Nestin, an intermediate filament protein that is commonly considered as a stem cell marker. By physical interaction, Nestin inhibits the inhibitory effect of Gli3, thereby facilitating hedgehog pathway activation in MB tumor cells. Nestin expression in tumor cells relies on leukotriene biosynthesis, and inhibition of leukotriene synthesis by antagonists of 5-lipoxygenase, significantly represses Nestin expression and hedgehog signaling in tumor cells, and suppresses MB growth. These studies demonstrate the important functions of Nestin in MB tumorigenesis, revealing leukotriene biosynthesis as a promising therapeutic target for MB treatment.

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