MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors.

摘要

One of the main hurdles to develop effective therapy for malignant peripheral nerve sheath tumors (MPNST) is the lack of understanding of molecular mechanisms regulating cancer genes and metastasis. Oncogenic epithelial-to-mesenchymal transition (EMT) is a critical step for metastasis and is closely related with transcriptional changes of many key genes involved in cell polarity, cell-cell adhesion, and cell migration. Multiple abnormal signaling in this pathways and processes can initiate, promote, and maintain EMT process. To understand the molecular networks that regulates EMT pathway and promote metastasis in MPNST, we systematically analyzed the microRNA (miRNA) mediated gene regulatory networks using miRNA and MRNA expression profiles generated from normal Schwan cells, MPNSTs tumor tissues and cell lines. Both negative- and positive- correlation networks based on gene and miRNA expression data were generated. These correlations were further mined by referring to various relational database (protein-protein interactions, canonical pathways, transcription factor-to-target prediction) and genomics data (copy-number alteration, differential DNA methylation). We identified six candidate network modules, which potentially control the preferential activation of TGF-beta/SMAD signaling to TGFbeta/ non-SMAD signaling and the induction of cancer cell stemness. By applying different levels of data integration and exploration, we could identify several units which take part in EMT of MPNST. Reconstructed networks suggests that miRNAs actively participate in transcription control of cancer genes and cause aberrant modification of core pathways responsible for transformation and metastasis. MPNST development.