STAT3通过上调miR-182-5p表达促进脑胶质瘤发生和侵袭的分子机制研究

Glioma accounts for about 46% of intracranial tumors. Malignant glioma becomes a common cause of death in cancer patients. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) leads to the tumorigenesis and invasiveness of glioma. However, it is unknown whether STAT3 can directly regulate miRNA expression to promote glioma tumorigenesis and invasiveness. Based on our recent data analysis, miR-182-5p may be as a target of STAT3. To test this hypothesis, the project intends to use a variety of glioma cell lines to verify whether abnormal activation or decreased expression of STAT3 affects the expression of miR-182-5p. Bioinformatics analysis by using prediction software such as TargetScan predict some potential target genes of miR-182-5p and will identify a candidate target gene of miR-182-5p by using luciferase reporter assays etc. Moreover, we will evaluate whether the role of STAT3 in promoting gliomagenesis depends on the STAT3/miR-182-5p/candidate target gene axis by in vitro and in vivo analysis. We also propose to determine the expression correlation analysis of STAT3/miR-182-5p/candidate target gene by using mouse intracranial tumor model and the tissues of glioma patients. If this project application are completed, not only will we understand the mechanisms for the tumorigenesis and invasiveness of glioma, but also will we learn whether miR-182-5p can serve as a potential therapeutic target. Our study will have potentially high translational impact and may lead to the validation of molecular targets that can be used in designing effective strategies to control glioma in clinics.

脑胶质细胞瘤（脑胶质瘤）约占颅内肿瘤的46%。其中恶性胶质瘤成为肿瘤患者常见的致死原因。信号转导及转录活化因子3(STAT3)过度活化导致脑胶质瘤的发生和侵袭，然而尚不清楚STAT3是否可以直接调节miRNA表达以促进脑胶质瘤发生和侵袭。前期，通过文献检索进行数据分析发现miR-182-5p可能作为STAT3调节靶点。本项目拟采用不同脑胶质瘤细胞株验证STAT3异常活化和表达降低是否导致miR-182-5p表达变化，同时利用TargetScan等软件对miR-182-5p的靶基因预测并采用荧光素酶报告基因等方法进行验证。体内体外实验分析STAT3/miR-182-5p/靶基因对STAT3促进脑胶质瘤发生和侵袭的影响。利用小鼠脑内肿瘤模型和脑胶质瘤病人组织对三者之间表达相关性分析。本研究对阐明胶质瘤发生和侵袭机制有重要意义，为开发以针对miR-182-5p为靶点的抗脑胶质瘤药物提供理论依据。

恶性胶质瘤是一种致命的癌症。STAT3异常活化导致胶质瘤的发生。STAT3诱导蛋白编码基因转录已被广泛研究;然而，我们对STAT3调控的miRNA基因转录在胶质瘤发生中的作用知之甚少。在本研究中，我们发现STAT3的异常激活或表达减少分别促进或抑制miR-182-5p的表达。同时利用TargetScan等软件对miR-182-5p的靶基因预测并采用荧光素酶报告基因等方法证实了PCDH8可能是miR-182-5p下游的关键靶基因之一。体内体外实验分析了STAT3/miR-182-5p/PCDH8对STAT3促进脑胶质瘤发生和侵袭的影响。利用小鼠脑内肿瘤模型和脑胶质瘤病人组织对三者之间的表达关系进行了相关性分析。本研究对阐明胶质瘤发生和侵袭机制有重要意义，为开发以针对miR-182-5p为靶点的抗脑胶质瘤药物提供理论依据。