FRAT1对胶质瘤干细胞的调控作用及机制研究

The cancer stem cell (CSC) hypothesis suggests that glioma is driven by a subpopulation of glioma stem cells (GSCs) which also contributes to their resistance to therapy. Therefore, it is important for both research on cancer and clinical practice to further explore the intrinsic molecular basis beneath the tumorigenicity of GSCs. FRAT1 is a core component of the Wnt/β-catenin pathway, FRAT1 has been identified as a proto-oncogene involved in tumorigenesis. Previous studies have shown that FRAT1 is strikingly overexpressed in several human cancers including esophageal cancer, cervical cancer, breast cancer, ovarian cancer, and so on. We found that FRAT1 was highly expressed in most subtypes of gliomas and the expression levels of FRAT1 were significantly positively correlated with increasing WHO grades. The results also suggested that FRAT1 protein expression was positively correlated with tumor proliferation. Furthermore, RNAi targeting FRAT1 can suppress proliferation and invasion of human brain glioma cells in vitro and in vivo. Our previous study found that FRAT1 and stem cell marker CD133 showed co-expression in GSCs. Moreover, FRAT1 mRNA and protein were highly expressed in GSCs. On the basis of precedent researches, this study will investigate the expression of FRAT1 in GSCs, explore the FRAT1 effect on biological features of GSCs and possible molecular mechanism. The findings of the present study will provide a deeper understanding of the function of FRAT1 and the machanisms of tumorigenicity of glioma. Meanwhile, the results will help us to establish FRAT1 interventions for gene therapy of glioma.

胶质瘤干细胞因其极强的致瘤特性和对放化疗的抵抗性，被视为胶质瘤的根源和潜在的治疗靶点。FRAT1是Wnt/β-catenin信号转导通路的重要成员，研究表明它是一个在肿瘤增殖和侵袭中有着重要作用的基因。本课题组前期研究显示，FRAT1在脑胶质瘤中高表达，其表达水平随胶质瘤病理级别的升高而增高；下调FRAT1表达能够抑制脑胶质瘤细胞的增殖和侵袭。我们还发现FRAT1在胶质瘤干细胞中高表达且与CD133在胶质瘤干细胞中存在共定位现象。本研究将在前期工作的基础上，分析FRAT1在胶质瘤干细胞中的表达，系统探讨FRAT1对胶质瘤干细胞的生物学特性的影响，进而研究FRAT1影响胶质瘤干细胞的可能分子机制。从而为全面理解FRAT1这一癌基因的功能及胶质瘤的形成机制提供依据，同时建立针对FRAT1的胶质瘤干细胞干预措施，为胶质瘤的临床治疗提供新的思路。

脑胶质瘤是中枢神经系统最常见的恶性肿瘤，尽管目前其治疗方法在不断地改善，但疗效仍未得到显著提高。因此，发现脑胶质瘤具有诊断和治疗意义的分子靶点对于改善其恶性生物学行为从而攻克这一疾病有着重要的科学意义和临床应用价值。FRAT1是Wnt/β-catenin信号转导通路的重要成员，它在多种恶性肿瘤中高表达，并参与其恶性行为，是一个在肿瘤的增殖和侵袭中有着重要作用的基因。我们在前期研究中发现FRAT1在脑胶质瘤中高表达，其表达水平随胶质瘤病理级别的升高而增高。. 本项目在课题组前期研究的基础上对FRAT1基因对胶质瘤干细胞生物学特性的影响及分子机制进行研究，能够按照计划任务书进行，得到以下重要结果：1、FRAT1过表达与脑胶质瘤细胞的增殖、侵袭、病理性血管新生、胶质母细胞瘤患者不良预后成显著正相关。2、对胶质瘤细胞U251进行FRAT1 RNAi后，U251细胞体内、体外的增殖、侵袭能力均明显受到抑制。3、全基因组芯片及生物信息学分析证实，FRAT1通过调控CCND1、CDC42、IL8、FAS基因的表达在胶质瘤细胞U251中发挥作用。. 本课题组在国家自然科学基金青年基金的资助下截至目前共发表学术论文20篇，其中SCI论文5篇；课题组负责人郭庚博士获得中国博士后科学基金资助；本课题研究成果《FRAT1基因对人脑胶质细胞瘤生物学特性的影响及临床应用》经山西省科学技术厅鉴定为国际先进水平并获山西省科技进步三等奖；共培养1名博士研究生、3名硕士研究生顺利毕业。. 本项目经费使用合理，严格按照计划任务书中的经费预算执行。研究立题新颖、设计合理、结论可靠、成果颇丰。FRAT1有望成为脑胶质细胞瘤基因治疗的靶点，从而对攻克脑胶质瘤具有一定的科学意义和临床应用价值。