The Phosphoinositide 3-Kinase p110? Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

ABSTRACT: 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? and p110? on global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110? silencing in comparison to silencing of the closely related p110? isoform was revealed. Among these genes, the leukemia inhibitory factor receptor ? (LIFR ?) was validated as a novel p110? target in medulloblastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFR? expression downstream of p110?. Targeting the LIFR? 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? and p110? 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? controls the expression of LIFR? via c-Myc and miR-125b to promote MB cell proliferation.

SUBMITTER: Salm F 

PROVIDER: S-EPMC4411098 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature