title: Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours.
abstract: 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.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. subree@umn.edu
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Venugopal
authors.initials: V
authors.lastname: Thayanithy
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: Shirley
authors.initials: S
authors.lastname: Zhu
authors.forename: Erinn
authors.initials: E
authors.lastname: Downs-Kelly
authors.forename: Kelli
authors.initials: K
authors.lastname: Montgomery
authors.forename: John R
authors.initials: JR
authors.lastname: Goldblum
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D016000:Cluster Analysis; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D009455:Neurofibroma; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012334:RNA, Neoplasm / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors