Glioblastoma multiforme, which belongs to high-grade gliomas, is the most common and serious primary gliomas in adults. Malignant gliomas are highly mobile, invasive, and difficult to completely resect through surgery. Therefore, radiation and chemotherapy generally follow surgical treatment as adjuvant therapies. Temozolomide (TMZ), which is able to penetrate the blood-brain barrier, is an alkylating agent of the imidazotetrazine series and the major chemotherapeutic drug in the clinical treatment of malignant gliomas. However, the drug resistance of TMZ decreases the therapeutic effects on the patients. Besides, the course of TMZ treatment will last a lifetime which may cause a financial burden. Therefore, to further identify the adjuvant drugs with TMZ or substitutes may enhance the efficacy and application of temozolomide in clinical therapy of glioblastoma. MicroRNAs comprise a novel class of endogenous, small, non-coding RNAs. MicroRNAs control gene expressions by targeting their target genes for degradation and/or translational repression. Several microRNAs have recently been shown to be definitely linked to glioblastoma, like miR-181 and miR-21. Recently, increasing evidences suggest microRNAs could entry into nucleus and target to promoter regions of genes, resulting in gene overexpressions or inhibitions. However, no studies comprehensively analyze the nuclear microRNA expression patterns involved in glioblastoma pathogenesis. Moreover, the roles and functions of these nuclear microRNAs in the glioblastoma formation are still unclear. The overall specific aims are to better characterize the nuclear microRNA expression changes and their physiological functions during glioblastoma development. We will use the high-throughput sequencing analysis (NGS) to comprehensively investigate the nuclear microRNA profiles in different tumorigenic glioblastoma cell lines compared with primary astrocyte. We will also find the cytokines which could regulate nuclear microRNA levels and import mechanisms. Next, after overexpressing nuclear microRNAs, we will try to explore the nuclear microRNAs-mediated gene networks by NGS. We will also identify the novel direct target genes which could be targeted and regulated in the promoter regions by nuclear microRNAs. Then, we will investigate the relationship among the unknown nuclear microRNA expressions, target gene effects and glioblastoma pathogenesis. Finally, the synergistic effects with the temozolomide and unknown nuclear microRNAs combined therapy will also be tested in vivo and in xenograft animal model. The clinical significance of nuclear microRNAs and target genes will also be investigated by TCGA database analysis and clinical tumor samples. The present proposal is an innovative study in researching nuclear microRNA regulations and their functions in glioblastoma development. The results will not only provide a better insight to the role of nuclear microRNA in tumorigenesis but also new directions for clinical application in glioblastoma multiforme therapy. It will also provide a strategy for development of new chemotherapeutic combination of microRNAs and temozolomide clinically. We expect this new way can raise the survival rate of the patients with brain tumor.
|Effective start/end date||8/1/15 → 7/31/16|
- Glioblastoma multiforme
- Nuclear microRNAs
- next generation sequencing