Study On The Function And Mechanism Of EIF4E In Self-Renewal Of Glioma-Initiating Cell

Brain tumors account for about 2% of all cancers and remain a formidable cancer problem that has seen few therapeutic advances during the last 40 years. Gliomas represent 40-60% of primary tumours of the brain, are predominantly malignant. Glioma results from unregulated expansion of a self-renewing glioma-initiating cell population. Glioma-initiating cells also contribute to solid tumor angiogenesis, metastasis, and resistance to chemotherapy and radiotherapy. These cells have many of the properties that can be ascribed to stem cells, namely the expression of neural stem-cell markers, and more importantly, the properties of self-renewal, extensive proliferation, and the ability to differentiate into more mature neural lineages. Understanding the difference of self-renewal between glioma-initiating cells and normal stem cells contributes to the identification of molecular targets for future therapies.Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem (iPS) cells and plays significantly roles in sustaining self-renewal of neural stem cells and glioma-initiating cells. This raises the questions of whether the expression or regulation of Sox2 is different between glioma-initiating cells and normal stem cells. Here, we find that Sox2 is significantly increased at translational level in a subset of human glioma-initiating cells as compared with normal neural stem cells.Further investigation reveals that Sox2 is a direct translational target of eukaryotic Initiation Factor-4E (eIF4E), which is significantly activated in glioma-initiating cells. eIF4E is the least abundant among these translation initiation factors and is considered to be the rate limiting factor for cap-dependent translation initiation. Higher level of eIF4E preferentially enhances the selective synthesis of oncogenic proteins and is also involved in nuclear-cytoplasmic export and RNA processing. eIF4E is elevated in many solid tumors such as breast, bladder, colon, head and neck, lymphomas, prostate, cervix and lung cancers. Our studies show a positive correlation between Sox2 and eIF4E expression in glioma tissues. Down-regulation of eIF4E significantly inhibits the self-renewal of glioma-initiating cells in a Sox2-depedent manner. Our studies further reveal that the agents salinomycin and tunicamycin inhibit the activity of eIF4E and reduce the self-renewal of glioma-initiating cells. Our results establish eIF4E signaling through Sox2 as a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a therapeutic strategy for glioma.