Study of the molecular mechanism of neural tumor formation mediatedby NF1 gene deficiency

点击翻译按钮获取中文摘要

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that predisposesindividuals to developing benign neurofibromas and malignant peripheral nerve sheathtumors (MPNSTs). The molecular mechanism of NF1-associated tumor pathogenesis has beenlargely unknown, and the strategy of medical treatments for NF1 tumors has not beenestablished. To identify the molecular marker/target in malignant tumors mediated by NF1gene deficiency, we established the NF1 gene knockdown (KD) system in neural cells asa NF1 disease model, and analyzed the expression profiles of genes/proteins by anintegrated proteomics. Of 4000 non-redundant proteins semi-quantitatively identified,we extracted 38 molecular signals which were abnormally upregulated in NF1 KD cellscompared with control cells. These proteins were mostly related to cell motility,apoptosis, and cell differentiation, and including several novel protein networks inneuronal cells, such as TCTP(Translationally Controlled Tumor Protein)-mTOR signal andDynein-GR-COX1 signal. We confirmed that these signals were significantly up-regulatedin NF1-deficient neural cells via the activation of MAPK/PI3K-AKT signaling in responseto growth factors. The knockdown or inhibitor treatments of these signals suppressed theviability and differentiation of NF1 disease model/tumor cells. These results suggestthat these novel NF1-related signals are functionally implicated in the tumorigenesisand it’s progression, and serves as a diagnostic biomarker/therapeutic target for NF1tumors.