Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours.
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.
Subramanian
Subbaya
S
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. subree@umn.edu
Thayanithy
Venugopal
V
West
Robert B
RB
Lee
Cheng-Han
CH
Beck
Andrew H
AH
Zhu
Shirley
S
Downs-Kelly
Erinn
E
Montgomery
Kelli
K
Goldblum
John R
JR
Hogendoorn
Pancras C W
PC
Corless
Christopher L
CL
Oliveira
Andre M
AM
Dry
Sarah M
SM
Nielsen
Torsten O
TO
Rubin
Brian P
BP
Fletcher
Jonathan A
JA
Fletcher
Christopher D M
CD
van de Rijn
Matt
M
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
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors