Document Detail


Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours.
MedLine Citation:
PMID:  19890883     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumour metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative down-regulation of miR-34a in most MPNSTs compared to neurofibromas. In vitro studies using the cell lines MPNST-14 (NF1 mutant) and MPNST-724 (from a non-NF1 individual) show that exogenous expression of p53 or miR-34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR-34a and other miRNAs. Our data show that p53 inactivation and subsequent loss of expression of miR-34a may significantly contribute to the MPNST development. Collectively, our findings suggest that deregulation of miRNAs has a potential role in the malignant transformation process in peripheral nerve sheath tumours.
Authors:
Subbaya Subramanian; Venugopal Thayanithy; Robert B West; Cheng-Han Lee; Andrew H Beck; Shirley Zhu; Erinn Downs-Kelly; Kelli Montgomery; John R Goldblum; Pancras C W Hogendoorn; Christopher L Corless; Andre M Oliveira; Sarah M Dry; Torsten O Nielsen; Brian P Rubin; Jonathan A Fletcher; Christopher D M Fletcher; Matt van de Rijn
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of pathology     Volume:  220     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-09     Completed Date:  2010-02-22     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  58-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Apoptosis / genetics
Cell Adhesion / genetics
Cell Proliferation
Cluster Analysis
Down-Regulation
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, p53*
Humans
Male
MicroRNAs / metabolism*
Middle Aged
Neoplasm Proteins / genetics,  metabolism
Nerve Sheath Neoplasms / genetics*,  metabolism,  pathology,  secondary
Neurofibroma
Oligonucleotide Array Sequence Analysis / methods
RNA, Neoplasm / metabolism*
Receptor, Epidermal Growth Factor / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction / methods
Signal Transduction / genetics
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
P50 CA127003/CA/NCI NIH HHS; P50 CA127003-03/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/MIRN34 microRNA, human; 0/MicroRNAs; 0/Neoplasm Proteins; 0/RNA, Neoplasm; 0/Tumor Suppressor Protein p53; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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