Medulloblastoma (MB) is the most common malignant brain tumor in childhood and represents the main cause of cancer-related death in this age group. The phosphoinositide 3-kinase (PI3K) pathway has been shown to play an important role in the regulation of medulloblastoma cell survival and proliferation, but the molecular mechanisms and downstream effectors underlying PI3K signaling still remain elusive. The impact of RNA interference (RNAi)-mediated silencing of PI3K isoforms p110 alpha and p110 delta on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110 alpha silencing in comparison to silencing of the closely related p110 delta isoform was revealed. Among these genes, the leukemia inhibitory factor receptor alpha (LIFR alpha) was validated as a novel p110 alpha target in medullo-blastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFR alpha expression downstream of p110 alpha. Targeting the LIFR alpha by RNAi, or by using neutralizing reagents impaired medulloblastoma cell proliferation in vitro and induced a tumor volume reduction in vivo. An analysis of primary tumors revealed that LIFR alpha and p110 alpha expression were elevated in the sonic hedgehog (SHH) subgroup of medulloblastoma, indicating its clinical relevance. Together, these data reveal a novel molecular signaling network, in which PI3K isoform p110 alpha controls the expression of LIFR alpha via c-Myc and miR-125b to promote MB cell proliferation.