衰老相关分泌表型分子在肝内胆管癌发生发展中的作用探究  

The Role of Senescence-associated Secretory Phenotype Molecules in Tumorigenesis and Progression of Intrahepatic Cholangiocarcinoma

作　　者：平荣宇 王虎强 马玟濠 原蒙蒙 杨冬 PING Rong-yu;WANG Hu-qiang;MA Wen-hao;YUAN Meng-meng;YANG Dong(State Key Laboratory of Medical Proteomics,National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,Beijing,102206,China;College of Life Sciences,Hebei University,Baoding,Hebei,071002,China)

机构地区：[1]军事科学院军事医学研究院生命组学研究所医学蛋白质组全国重点实验室国家蛋白质科学中心(北京),北京102206 [2]河北大学生命科学学院,河北保定071002

出　　处：《现代生物医学进展》2025年第5期801-811,832,共12页Progress in Modern Biomedicine

基　　金：国家自然科学基金面上项目(32270711)。

摘　　要：目的:探究衰老相关分泌表型(senescence-associated secretory phenotype,SASP)分子在肝内胆管癌发生发展中的作用。方法:利用蛋白质组数据进行肝内胆管癌分子分型并进行亚型间生存分析,对肿瘤相对于癌旁及其不同亚型之间的SASP差异蛋白进行GO(Gene ontology)功能富集分析;利用转录组数据通过ESTIMATE、xCell、TIDE评分对肿瘤不同亚型进行免疫浸润分析及免疫治疗反应预测;搜集整合驱动基因相关数据库,并与SASP差异蛋白进行交叠比较;采用Pearson相关系数筛选与SASP差异蛋白相关的lncRNA。结果:将116例肿瘤样本划分为3个亚型,生存曲线提示S3亚型预后较差,生存时间更短。S3亚型肿瘤纯度低,免疫细胞、基质细胞含量高但对免疫治疗的反应较差,存在细胞毒性T细胞功能失调、T细胞排斥。肿瘤相对于癌旁上调的SASP差异蛋白倾向于参与染色体区域的核酸代谢、对外界刺激的反应,下调的SASP蛋白倾向于参与线粒体区域的脂质代谢等过程。共筛选到5个SASP相关驱动基因,其中INSR、PIK3CA是S3恶性亚型特有的。共得到4个与肝内胆管癌SASP差异蛋白相关的lncRNA分子,生存曲线提示INAFM2为危险因素。结论:肝内胆管癌的SASP相关差异蛋白在肿瘤发生过程中倾向于在染色体区域发挥核酸代谢作用,在向恶性亚型转化的过程中倾向于在线粒体区域发挥脂质代谢调节及蛋白磷酸化作用。INAFM2有望成为肝内胆管癌诊断和治疗的新靶点。Objective:To investigate the role of senescence-associated secretory phenotype(SASP)molecules in tumorigenesis and progression of intrahepatic cholangiocarcinoma.Methods:We performed molecular typing of ICC using proteomic data and conducted survival analysis among subtypes.We obtained two classes of differential proteins,including the proteins differentially expressed between ICC tumors and the paired normal adjacent tissues,and the proteins highly expressed specifically in a subtype.The GO term over/under-representation analyses on the differential SASP proteins were performed based on the hypergeometric distribution model.Using transcriptomic data,we analyzed immune infiltration and predicted immune therapy response for different ICC subtypes through ESTIMATE,xCell,and TIDE scores.We collected and integrated driver gene databases and they were intersected with SASP differential genes.Pearson correlation coefficients were used to screen for lncRNAs and SASP differential genes.Results:One hundred and sixteen tumor samples were classified into three subtypes.Subtype 3 had a poorer prognosis and shorter survival time.Subtype 3 had low tissue purity,high content of immune and stromal cells,but responded poorly to immunotherapy because of cytotoxic T lymphocytes dysfunction and T cell exclusion.GO terms in which upregulated differential SASP proteins of tumour vs.normal adjacent tissue were enriched in nucleic acid metabolism and response to external stimulus in chromosomal region,while downregulated SASP proteins were enriched in processes such as lipid metabolism in mitochondrial regions.Five driver genes related to SASP were identified,with INSR and PIK3CA being specific to the malignant subtype 3.Four lncRNA molecules were identified to be highly correlated with SASP differential genes in ICC.Survival analysis indicated that INAFM2 is a risk factor.Conclusions:SASP differential genes in ICC tend to play a role in nucleic acid metabolism in chromosomal regions during tumorigenesis,and tend to regulate lipid metab

关 键 词：衰老相关分泌表型 肝内胆管癌 生物信息学 驱动基因 长链非编码RNA 

分 类 号：R3[医药卫生—基础医学] Q255[生物学—细胞生物学] R735.8R318.04