The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma.
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 global gene expression was investigated by DNA microarray analysis in medulloblastoma cell lines. A subset of genes with selectively altered expression upon p110α silencing in comparison to silencing of the closely related p110δ isoform was revealed. Among these genes, the leukemia inhibitory factor receptor α (LIFR α) was validated as a novel p110α target in medulloblastoma. A network involving c-Myc and miR-125b was shown to be involved in the control of LIFRα expression downstream of p110α. Targeting the LIFRα 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 LIFRα and p110α 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 p110α controls the expression of LIFRα via c-Myc and miR-125b to promote MB cell proliferation.
Department of Clinical Research, Division of Pediatric Hematology/Oncology, University of Bern, Bern, Switzerland.
Fabiana
F
Salm
Department of Clinical Research, Division of Pediatric Hematology/Oncology, University of Bern, Bern, Switzerland.
Valeriya
V
Dimitrova
Department of Pediatrics and Department of Pediatric Hematology and Oncology, Georg August University Goettingen, Goettingen, Germany.
André O
AO
von Bueren
Department of Clinical Research, Division of Pediatric Hematology/Oncology, University of Bern, Bern, Switzerland.
Paulina
P
Ćwiek
Functional Genomics Center Zurich, ETH and University of Zurich, Zurich, Switzerland.
Hubert
H
Rehrauer
Institute of Anatomy, University of Bern, Bern, Switzerland.
Valentin
V
Djonov
Institute of Biochemistry and Molecular Medicine, University of Bern, Swiss National Centre of Competence in Research TransCure, University of Bern, Bern, Switzerland; Swiss National Centre of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Pascale
P
Anderle
Department of Clinical Research, Division of Pediatric Hematology/Oncology, University of Bern, Bern, Switzerland.
Alexandre
A
Arcaro
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D053606:Receptors, OSM-LIF; D058543:Class Ia Phosphatidylinositol 3-Kinase