转录因子PU.1在人胶质瘤中的表达特征和功能

Expression and function of transcription factor PU.1 in human gliomas

目的:研究转录因子PU.1在人脑胶质瘤中的表达特征,分析PU.1与病人预后、肿瘤血管生成间的关系,为探索靶向调控肿瘤相关巨噬细胞以治疗脑胶质瘤提供实验基础。方法:收集4例非肿瘤人脑组织样本和23例人脑胶质瘤组织样本,其中WHO-Ⅱ级6例、WHO-Ⅲ级8例、WHO-Ⅳ级9例。对组织进行染色,观察PU.1与肿瘤相关巨噬细胞特征性分子Iba1的共定位情况,分析40倍视野下PU.1阳性细胞数量与胶质瘤病理分级、血管内皮细胞数量的关系。分析TCGA人脑胶质瘤组织中编码PU.1的基因SPI1的转录水平与胶质瘤病理分级、编码Iba1的基因AIF1的转录水平及病人生存时间的关系。结果:在人脑胶质瘤组织中,PU.1表达于肿瘤相关巨噬细胞中。非肿瘤组织每个视野中PU.1阳性细胞平均数量为(1.79±0.30)个,WHO-Ⅱ级脑胶质瘤为(18.56±2.01)个,WHO-Ⅲ级脑胶质瘤为(25.35±3.98)个,WHO-Ⅳ级脑胶质瘤为(31.40±2.74)个。PU.1阳性细胞多组CD31阳性细胞数量平均为(50.36±5.92)个,PU.1阳性细胞少组CD31阳性细胞数量平均为(33.29±3.73)个。对TCGA人脑胶质瘤数据库分析发现SPI1的转录水平与AIF1的转录水平线性相关,SPI1在WHO-Ⅳ级脑胶质瘤中的转录水平高于WHO-Ⅱ级和WHO-Ⅲ级脑胶质瘤,SPI1的转录水平与脑胶质瘤病人的预后有关,SPI1转录水平高的脑胶质瘤病人预后差。结论:PU.1是脑肿瘤相关巨噬细胞的特征性转录因子,PU.1的表达与胶质瘤病理分级相关,PU.1是潜在的预测脑胶质瘤病人预后的指标,PU.1可能具有调控肿瘤相关巨噬细胞促进脑胶质瘤血管生成的作用,进一步探索PU.1在脑胶质瘤血管生成中的作用将为发展脑肿瘤的创新治疗方案提供新思路。

Objective:To investigate the expression character of the transcription factor PU.1 in human gliomas and analyze its correlation with survival of patients and tumor vascularization.Methods:We collected 4 non-tumor human brain samples and 23 human glioma samples,including 6 in WHO-Ⅱgrade,8 in WHO-Ⅲgrade,and 9 in WHO-Ⅳgrade.We analyzed the expressing location of PU.1 and Iba1 with immunohistological methods and clarified the correlation between the number of PU.1 positive cells,glioma grades and the number of endothelial cells.With TCGA glioma data,we analyzed the correlation between the transcription levels of SPI1(the gene encoding PU.1)and glioma grades,as well as the correlation between the transcription levels of AIF1(the gene encoding Iba1)and the survival time of patients.Results:The expression of PU.1 colocalized with Iba1,the specific marker of tumor-associated macrophages.The number of PU.1 positive cells per field was 1.79±0.30 in non-tumor human brain tissue,18.56±2.01 in WHO-Ⅱgrade gliomas,25.35±3.98 in WHO-Ⅲgrade gliomas,and 31.40±2.74 in WHO-Ⅳgrade gliomas.Also,50.36±5.92 endothelial cells per field were counted in gliomas with more PU.1 positive cells,while 33.29±3.73 endothelial cells per field in gliomas with less PU.1 positive cells.By analyzing TCGA data,we found the transcription counts of SPI1 had a linear correlation to the transcription counts of AIF1 in human gliomas,and higher transcription counts of SPI1 predicted worse survival.Conclusion:PU.1 is a specific transcription factor for tumor-associated macrophages in human gliomas.The expression of PU.1 correlates with the grades of gliomas,and it is a potential molecular predictor for the survival of patients,which might play an important role in modulating tumor-associated macrophages to promote glioma-angiogenesis.Further exploration of the function of PU.1 on glioma-vascularization will give rise to new ideas for novel brain tumor treatment.