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MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors

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Final rept. 15 Aug 2010-14 Aug 2013

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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-betaSMAD 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.

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  • Medicine and Medical Research

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