泛癌整合分析miR-200家族靶标肿瘤基因异质性的研究

Pan-cancer integration study on miR-200 family members targeted heterogeneity in different tumors

目的探讨miR-200家族对不同肿瘤预后的影响及其靶标基因调控异质性的机制。方法从癌症基因图谱(the Cancer Genome Atlas,TCGA)下载泛癌研究项目(PanCanAtlas)中21种不同组织病理学恶性实体瘤样本的转录组数据和临床表型,并分析miR-200家族与肿瘤预后的关系。进一步选择生存风险评估结果互相矛盾的5种肿瘤进行miR-200家族靶标基因的WGCNA聚类分析。收集膀胱癌组织标本,采用免疫组织化学法和荧光定量PCR验证肿瘤组织中与miR-200家族表达显著相关的靶标基因的表达,并分析其对患者生存的影响。结果miR-200家族高表达是膀胱癌和胃腺癌预后的保护因素(HR=0.55~0.68,P=0.0001~0.0340;HR=0.61~0.72,P=0.0055~0.0170),是肝细胞癌和胸腺瘤预后的不利因素(HR=1.46~1.65,P=0.0061~0.0120;HR=7.44~13.04,P=0.0002~0.0210);miR-141和miR-429对肾乳头状细胞癌生存的影响相反。基因聚类分析显示,miR-200家族靶标TIMP2基因表达可延长膀胱癌患者生存时间,miR-141负调控肾乳头状细胞癌EPHA2基因而延长患者生存时间。膀胱癌组织的TIMP2蛋白与miR-200家族表达呈负相关,miR-200家族高表达患者预后较好。结论miR-200家族对不同肿瘤预后的影响存在异质性,可能是miR-200家族靶标分子在不同肿瘤的表达存在差异,导致miR-200家族调控生物学功能的异质性。

Objective To investigate the effect of miR-200 family members on the prognosis of different tumors and the mechanism of target gene regulation heterogeneity.Methods The transcriptome data and clinical phenotypes of 21 different histopathological malignant solid tumor samples from the PanCanAtlas were downloaded from the Cancer Genome Atlas(TCGA),and the relationship between miR-200 family members and tumor prognosis were analyzed.Five tumors with contradictory survival risk assessment results were further selected for WGCNA cluster analysis of miR-200 family target genes.The expression of target genes significantly related to miR-200 family expression in bladder cancer tissues was verified by immunohistochemistry and fluorescent quantitative PCR,and their effects on patient survival were analyzed.Results The high expression of miR-200 family was a protective factor for the prognosis of bladder cancer and gastric adeno-carcinoma(HR=0.55~0.68,P=0.0001~0.0340;HR=0.61~0.72,P=0.0055~0.0170),and a negative factor for the prognosis of liver cancer and thymoma(HR=1.46~1.65,P=0.0061~0.0120;HR=7.44~13.04,P=0.0002~0.0210),while miR-141 and miR-429 had opposite effects on the survival of renal papillary cell carcinoma.Furter clustering of miR-200 family target gens showed that the expression of TIMP2 gene increased the survival time of bladder cancer patients,and miR-141 prolonged the survival of the patients with renal papillary cell carcinoma by negatively regulated EPHA2 gene. TIMP2 protein expression in bladder cancer was negatively correlated with miR-200 family expression and patients with high expression had better prognosis. Conclusion miR-200 family had different effects on the prognosis of different tumors,and the heterogeneity of miR-200 family targeted molecules results to the heterogeneity of biological function of miR-200 family in cancers.