目的:研究人胰岛素样生长因子2 mRNA结合蛋白2(insulin like growth factor 2 mRNA binding protein 2,IGF2BP2)在膀胱癌中的表达水平及其与膀胱癌免疫表型的相关性,并进一步评估IGF2BP2对膀胱癌分子分型的预测价值.方法:基于生物信息学分析肿瘤患者的高通量RNA测序数据,明确IGF2BP2在癌和癌旁组织中的表达水平.采用单样本基因集富集分析(single-sample gene set enrichment analysis,ssGSEA)算法评估不同肿瘤患者的免疫细胞浸润以及12种不同分子分型的膀胱癌的特征通路富集得分.采用受试者工作特征(receiver operating characteristic curve,ROC)曲线评估IGF2BP2预测膀胱癌分子分型的准确性.采用微环境细胞群计数(microenvironment cell populations-counter,MCP-counter)算法评估膀胱癌患者的免疫细胞浸润水平.从IMvigor210CoreBiologies包中获取膀胱癌患者的RNA测序数据以及临床病理特征数据,分析IGF2BP2与膀胱癌患者免疫表型的相关性.结果:IGF2BP2在膀胱癌组织中表达水平显著高于癌旁组织.在膀胱癌中,IGF2BP2表达水平与CD8+T细胞、NK细胞和巨噬细胞等肿瘤浸润免疫细胞的浸润水平呈显著正相关.此外,IGF2BP2 与肿瘤突变负荷(tumor mutation burden,TMB)和微卫星不稳定性(microsatellite instability,MSI)以及程序性细胞死亡1(programmed cell death 1,PD-1)等免疫检查点的表达水平也具有较高的相关性.IGF2BP2高表达患者的GZMA、GZMB、PRF1等抗肿瘤免疫细胞效应分子表达量显著增高,但同时HAVCR2、CTLA-4及LAG3等免疫抑制性基因的表达也显著升高.IGF2BP2高表达的患者更倾向于形成炎症性肿瘤微环境,ROC曲线则提示IGF2BP2高表达患者的分子亚型多为基底亚型,更适合使用免疫治疗.结论:IGF2BP2在膀胱癌中高表达,高表达IGF2BP2的肿瘤具有较高的免疫原性,其免疫分型通常为炎症型.此外,IGF2BP2表达水平也可以准确地预测膀胱癌的分子分型.
Value of IGF2BP2 in predicting bladder cancer molecular subtypes and its correlation with the inflammatory tumor microenvironment
Objective:To investigate the expression levels of insulin like growth factor 2 mRNA binding pro-tein 2(IGF2BP2)in bladder cancer and its correlation with the immune phenotype of bladder cancer,and further e-valuate the predictive value of IGF2BP2 in molecular subtyping of bladder cancer.Methods:Based on bioinformat-ics analysis of high-throughput RNA sequencing data from tumor patients,we determined the expression levels of IGF2BP2 in cancer and adjacent tissues.The single-sample gene set enrichment analysis(ssGSEA)algorithm was used to evaluate the immune cell infiltration in different tumor patients and the enrichment scores of 12 different molecular subtypes related pathways of bladder cancer.Receiver operating characteristic(ROC)curves were used to evaluate the accuracy of IGF2BP2 in predicting molecular subtypes of bladder cancer.The microenvironment cell populations-counter(MCP-counter)algorithm was used to evaluate the immune cell infiltration level in bladder cancer patients.RNA sequencing data and clinical pathological data of bladder cancer patients were obtained from the IMvigor210CoreBiologies package to analyze the correlation between IGF2BP2 and the immune phenotype of bladder cancer patients.Results:The expression level of IGF2BP2 is higher in bladder cancer tissues than in adja-cent tumor tissues.In bladder cancer,the expression level of IGF2BP2 is significantly positively correlated with the infiltration level of CD8+T cells,NK cells and macrophages.In addition,IGF2BP2 had a high correlation with the expression levels of tumor mutation burden(TMB),microsatellite instability(MSI),programmed cell death 1(PD-1)and other immune checkpoint molecules.The expressions of anti-tumor cell effectors such as GZMA,GZMB,PRF1 were higher in patients with high expression of IGF2BP2,but the expressions of immune suppres-sive genes such as HAVCR2,CTLA-4 and LAG3 also significantly increased.Patients with bladder cancer who had a high expression of IGF2BP2 tended to form an inflammatory tumor microenvironment.ROC curves revealed that high IGF2BP2 expression indicated a basal subtype of bladder cancer,representing better response to immu-notherapy.Conclusion:IGF2BP2 is highly expressed in bladder cancer.Tumors with high expression of IGF2BP2 have high immunogenicity,and their immune subtype is usually inflammatory.In addition,the expression level of IGF2BP2 can accurately predict the molecular subtype of bladder cancer.
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