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; Dimitrova, Valeriya; von Bueren, André O; Cwiek, Paulina; Rehrauer, Hubert; Djonov, Valentin; Anderle, Pascale; Arcaro, Alexandre (2015). The Phosphoinositide 3-Kinase p110α Isoform Regulates Leukemia Inhibitory Factor Receptor Expression via c-Myc and miR-125b to Promote Cell Proliferation in Medulloblastoma. PLoS ONE, 10(4), e0123958. Public Library of Science 10.1371/journal.pone.0123958

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Tiefenau Hospital (discontinued) > Forschungsgruppe Hämatologie/Onkologie (Pädiatrie) (discontinued)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)

UniBE Contributor:

Salm, Fabiana; Dimitrova, Valeriya; Cwiek, Paulina; Djonov, Valentin; Anderle, Pascale and Arcaro, Alexandre

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Ruslan Hlushchuk

Date Deposited:

23 Feb 2016 09:32

Last Modified:

23 Feb 2016 09:32

Publisher DOI:

10.1371/journal.pone.0123958

PubMed ID:

25915540

BORIS DOI:

10.7892/boris.76432

URI:

https://boris.unibe.ch/id/eprint/76432

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