RGD Reference Report - Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. - Rat Genome Database

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Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.

Authors: Miller, SJ  Lan, ZD  Hardiman, A  Wu, J  Kordich, JJ  Patmore, DM  Hegde, RS  Cripe, TP  Cancelas, JA  Collins, MH  Ratner, N 
Citation: Miller SJ, etal., Oncogene. 2010 Jan 21;29(3):368-79. doi: 10.1038/onc.2009.360. Epub 2009 Nov 9.
RGD ID: 11561959
Pubmed: PMID:19901965   (View Abstract at PubMed)
PMCID: PMC2809821   (View Article at PubMed Central)
DOI: DOI:10.1038/onc.2009.360   (Journal Full-text)

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas without effective therapeutics. Bioinformatics was used to identify potential therapeutic targets. Paired Box (PAX), Eyes Absent (EYA), Dachsund (DACH) and Sine Oculis (SIX) genes, which form a regulatory interactive network in Drosophila, were found to be dysregulated in human MPNST cell lines and solid tumors. We identified a decrease in DACH1 expression, and increases in the expressions of PAX6, EYA1, EYA2, EYA4, and SIX1-4 genes. Consistent with the observation that half of MPNSTs develop in neurofibromatosis type 1 (NF1) patients, subsequent to NF1 mutation, we found that exogenous expression of the NF1-GTPase activating protein-related domain normalized DACH1 expression. EYA4 mRNA was elevated more than 100-fold as estimated by quantitative real-time PCR in most MPNST cell lines. In vitro, suppression of EYA4 expression using short hairpin RNA reduced cell adhesion and migration and caused cellular necrosis without affecting cell proliferation or apoptotic cell death. MPNST cells expressing shEYA4 either failed to form tumors in nude mice or formed very small tumors, with extensive necrosis but similar levels of proliferation and apoptosis as control cells. Our findings identify a role of EYA4 and possibly interacting SIX and DACH proteins in MPNSTs and suggest the EYA4 pathway as a rational therapeutic target.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
neurilemmoma  IEP 11561959mRNA:increased expression:Schwann cell (human)RGD 
neurilemmoma  ISOSIX1 (Homo sapiens)11561959; 11561959mRNA:increased expression:Schwann cell (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Six1  (SIX homeobox 1)

Genes (Mus musculus)
Six1  (sine oculis-related homeobox 1)

Genes (Homo sapiens)
SIX1  (SIX homeobox 1)


Additional Information