人脑胶质母细胞瘤中NFKBIA多态性的分析研究

发布时间：2018-09-14 17:57

【摘要】：研究目的：在胶质母细胞瘤中已发现核因子κB（NF-κB）的过度激活，且与胶质母细胞瘤的发生、发展和浸润、复发、放射敏感性、化疗耐受以及胶质瘤细胞的免疫应答、凋亡等生物学行为关系密切，NF-κB的功能有赖于它的活化以及它所引起的相应基因的转录、表达。NF-κB抑制因子α（NFKBIA）能抑制NF-κB激活，从而抑制NF-κB在肿瘤中的生物学功能，在多种肿瘤中已发现NFKBIA的变异、多态性、单体型的这些转变导致NFKBIA蛋白丧失抑制NF-κB蛋白活化的能力，从而阻止肿瘤细胞凋亡。然而，尚未发现有胶质母细胞瘤中NFKBIA蛋白表达水平与基因型关系的报道，而胶质母细胞瘤中NFKBIA多态性仍未知。因此我们的研究目的为研究NFKBIA在胶质瘤中的多态性及是否存在基因型与蛋白表达、拷贝数的关系。为进一步阐明NFKBIA在胶质母细胞疾病发展中的作用、NFKKBIA多态性与预后关系以及针对NFKBIA稳定性的靶向治疗可能性奠定基础。研究方法：收集苏州大学附属第一医院自2009年到2011年收治的胶质瘤病人的组织标本，选取其中病理诊断为原发多形性胶质母细胞瘤、临床资料较完善的24例胶质母细胞瘤组织标本，首先，，应用PCR扩增及直接测序检测NFKBIA变异，再次，应用Western Blot检测NFKBIA蛋白表达，再进一步应用其实时定量PCR检测NFKBIA拷贝数变异及mRNA表达。结果：胶质母细胞瘤中存在NFKIBA基因单核苷酸多态性rs1957106（CC/CT/TT）；包括基因型CC、基因型CT、基因型TT三种形态。胶质母细胞瘤中NFKBIA蛋白水平在CT基因型和TT基因型中显著低于CC基因型；胶质母细胞瘤中NFKBIA蛋白水平和NFKBIA mRNA表达水平均显著低于非瘤组织；而且含有CT基因型和TT基因型的胶质母细胞瘤NFKBIA mRNA表达水平明显低于含有CC基因型的胶质母细胞瘤(CT和TT:0.31±0.11，CC:0.54±0.18，非瘤脑组织:0.78±0.12，P0.001)；含有CT基因型或TT基因型的10个胶质母细胞瘤中有7个的拷贝数显著低于含有CC基因型的肿瘤，而这些胶质母细胞瘤同时有低NFKBIA蛋白及低NFKBIA mRNA表达水平。结论：胶质母细胞瘤中NFKBIA单核苷酸多态性rs1957106基因型CT、基因型TT与胶质母细胞瘤中NFKBIA低蛋白表达、低拷贝数密切相关。
[Abstract]:Mutations, polymorphisms and haplotypes of NFKBIA have been found in a variety of tumors, resulting in the loss of the ability of NFKBIA protein to inhibit the activation of NF- 魏 B protein, thus preventing tumor cell apoptosis. In order to further elucidate the role of NFKBIA in the development of glioblastoma disease, the relationship between NFKKBIA polymorphism and prognosis and the possibility of targeted therapy for the stability of NFKBIA can be established. In 24 cases of glioblastoma with perfect clinical data, NFKBIA mutation was detected by PCR amplification and direct sequencing, and NFKBIA protein expression was detected by Western Blot. Results: single nucleotide polymorphism rs1957106 (CC/CT/TT) of NFKIBA gene was found in glioblastoma, including CC, genotype CT, genotype TT. The level of NFKBIA protein in glioblastoma was significantly lower than that in CT genotype and TT genotype, and the level of NFKBIA protein and NFKBIA mRNA expression in glioblastoma was significantly lower than that in non-tumor tissue. Conclusion: NFKBIA single nucleotide polymorphism rs1957106 genotype CT, genotype TT in glioblastoma is closely related to the low protein expression and low copy number of NFKBIA in glioblastoma.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R739.41

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