Dataset Information

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

ACCESS DATA

Publications

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

Salm Fabiana F Dimitrova Valeriya V von Bueren André O AO Ćwiek Paulina P Rehrauer Hubert H Djonov Valentin V Anderle Pascale P Arcaro Alexandre A

PloS one 20150427 4

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 p110α and p110δ on g ...[more]

PMID: 25915540

Similar Datasets

Project description:BackgroundVisceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic targets. Recently, we found that mice with an inactivating knock-in mutation in the p110? isoform of pi3k, (p110?(d910a)) are hyper resistant to L. major, develop minimal cutaneous lesion and rapidly clear their parasite. Here, we investigated whether pi3k signaling also regulates resistance to L. donovani, one of the causative agents of visceral leishmaniasis.Methodology/principal findingsWT and p110?(D910A) mice (on a BALB/c background) were infected with L. donovani. At different time points, parasite burden and granuloma formation were assessed. T and B cell responses in the liver and spleen were determined. In addition, Tregs were expanded in vivo and its impact on resistance was assessed. We found that p110?(D910A) mice had significantly reduced splenomegaly and hepatomegaly and these organs harbored significantly fewer parasites than those of WT mice. Interestingly, infected p110?(D910A) mice liver contains fewer and less organized granulomas than their infected WT counterparts. Cells from p110?(D910A) mice were significantly impaired in their ability to produce cytokines compared to WT mice. The percentage and absolute numbers of Tregs in infected p110?(D910A) mice were lower than those in WT mice throughout the course of infection. In vivo expansion of Tregs in infected p110?(D910A) mice abolished their enhanced resistance to L. donovani infection.Conclusions/significanceOur results indicate that the enhanced resistance of p110?(D910A) mice to L. donovani infection is due to impaired activities of Tregs. They further show that resistance to Leishmania in the absence of p110? signaling is independent of parasite species, suggesting that targeting the PI3K signaling pathway may be useful for treatment of both visceral and cutaneous leishmaniasis.

Dataset Information

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

Publications

The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure