剪接蛋白SRSF1在恶性胶质瘤发生发展中的作用及机制研究

项目名称： 剪接蛋白SRSF1在恶性胶质瘤发生发展中的作用及机制研究

项目编号： No.81502166

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周雪霞

作者单位： 天津医科大学

项目金额： 20万元

中文摘要： 恶性胶质瘤是最常见的高致死性颅内原发性肿瘤，基因的异常选择性剪接与恶性胶质瘤发展密切相关。我们的前期工作发现：①剪接蛋白SRSF1 mRNA在胶质瘤中表达显著增加，且其高表达的患者生存期更短；②敲低胶质母细胞瘤细胞系中SRSF1表达，可抑制细胞增殖和存活；③SRSF1可调控S6K1基因的选择性剪接。据此提出选择性剪接异常在恶性胶质瘤发生、发展中起重要作用的研究设想。在本研究中，我们将利用一系列生物学技术，在分子、细胞、动物水平，深入研究SRSF1在恶性胶质瘤发生、发展中的作用及分子机制，全面探索其调控的下游靶基因剪接事件及其生物学功能。我们的研究将从剪接调控水平上探讨恶性胶质瘤发病机理，最终为恶性胶质瘤的治疗提供可能的新方法和新靶点。

中文关键词： 胶质瘤；选择性剪接；富含丝氨酸/精氨酸的剪接蛋白1；肿瘤发生

英文摘要： Malignant glioma is the most common and highly lethal type of primary brain cancer. Aberrant alternative splicing may be a significant but yet under-explored contributor to the heterogeneous pathological characteristics of malignant gliomas. Our previous results showed that a splicing factor, serine-arginine rich splicing factor 1 (SRSF1) was upregulated in a human glioma microarray. And there is a highly significant correlation between elevated SRSF1 expression and short overall survival of patients. In addition, knockdown of SRSF1 in glioblastoma (GBM) cell lines resulted in proliferation and survival inhibition in vitro. We further found that SRSF1 could modulate alternative splicing of ribosomal S6 kinase 1 gene (S6K1). According to these resluts, we propose the hypothesis that aberrant alternative splicing play an important role in malignant glioma tumorigenesis. In this project, we aim to explore the function and molecular mechanisms of SRSF1 in the tumorigenesis of malignant glioma, by using molecular, cellular biology techniques and animal models, including fully identifying its downstream splicing targets and their relevant roles in the pathogenesis and progression of malignant glioma. Taken together, this project will enrich our knowledge of glioma pathogenesis at the splicing regulation level and provides novel strategies and potential therapeutic targets for malignant glioma treatment.

英文关键词： glioma;alternative splicing;SRSF1;tumorigenesis