MicroRNA deregulation in peripheral nerve sheath tumor progression.

Abstract

10526 Background: Malignant peripheral nerve sheath tumors (MPNST) constitute a group of malignant tumors that arise from schwann cells of the peripheral nerve sheath. Neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, affecting 1 in 3000 individuals worldwide, arises on a background of germ-line mutations of NF1. Neurofibromas (NF) are the benign counterpart of MPNST, but currently little is known of the mechanism involved in the transformation from benign to malignant disease. The aim of this study was to identify a molecular signature, which would distinguish NF from MPNST, and could then be exploited for the development of therapeutic agents against specific targets implicated in the disease. Methods: The cohort consisted of 10 NF and 10 MPNST, all obtained from individuals with NF1. Schwann cells isolated from 4 nerves from patients without nerve sheath disease acted as controls. An Agilent Human miRNA microarray was used in the study. Results: We identified a set of miRNAs for which the expression was deregulated in our index cases. Of the 7 most significantly deregulated miRNAs (miR-340, 139-5p, let7g, 210, 30e, 29c*, 29c), 6 were independently confirmed by TaqMan Expression Assays in the same panel of cases. Of these, miR-29c was the most significantly down-regulated in MPNST compared to NF (p=1.083e-05). COL1A1, COL21A1, COL5A2, and TDG were then predicted as potential miR-29c target genes using TargetScan and PITA, data mining of our previous gene expression data and reports from the literature. These genes were found to be significantly up-regulated in MPNST when compared to NF. The gene expression level of miR-29c and the target genes were confirmed in a further blinded study of 20 MPNST and 20 NF. Using a synthetic mimic for miR-29c and a GFP retroviral construct containing the pri-miR29c in an MPNST cell line exhibiting very low endogenous expression of miR-29c (SNF96.2), we demonstrated that the expression of these target genes is suppressed upon exogenous expression of miR-29c. Conclusions: using miRNA microarray we have generated a robust molecular signature that distinguishes MPNST from NF. Further functional studies of miR-29c are required to determine if these findings can be exploited for therapeutic use. No significant financial relationships to disclose.