间皮素介导高级别浆液性卵巢癌铂化疗耐药并作为化疗敏感性的预测指标  

Mesothelin mediates platinum resistance in high-grade serous ovarian cancer and serves as a predictive marker for chemotherapy sensitivity

作　　者：钟彧婧 王艺颖 刘海鸥 陆佳琦 ZHONG Yu-jing;WANG Yi-ying;LIU Hai-ou;LU Jia-qi(Department of Gynecology,Obstetrics and Gynecology Hospital,Fudan University,Shanghai 200090,China)

机构地区：[1]复旦大学附属妇产科医院妇科,上海200090

出　　处：《复旦学报（医学版）》2024年第6期873-881,共9页Fudan University Journal of Medical Sciences

基　　金：上海市科委科技创新医学创新研究项目(23Y11909500)。

摘　　要：目的探究间皮素(mesothelin,MSLN)在高级别浆液性卵巢癌(high-gradeserousovariancancer,HGSOC)化疗耐药中的可能机制。方法基于卵巢癌公共数据库进行Meta分析,评估MSLN表达水平与卵巢癌患者总体生存率(overall survival,OS)的关系;通过通路富集分析探索MSLN调控的关键信号通路及其在化疗耐药中的潜在作用;利用TCGA-HGSOC数据库探究MSLN介导化疗耐药相关的基因组特征;通过Msln敲低小鼠ID8卵巢癌细胞构建腹腔转移瘤模型,验证MSLN在卵巢癌化疗耐药中的生物学功能。结果MSLN高表达与患者不良预后相关(HR:1.42,95%CI:1.16~1.74);差异基因及通路富集分析表明MSLN高表达上调耐药相关基因及药物代谢、DNA结合信号通路。基因组关联分析显示MSLN高表达与染色体不稳定基因组特征CX3、CX11和CX13评分负相关;体内实验发现Msln敲低可增强顺铂抑瘤作用。结论MSLN高表达可能是HGSOC患者不良预后和化疗耐药的潜在生物标志物。Objective To elucidate the potential mechanisms by which mesothelin(MSLN)contributes to chemotherapy resistance in high-grade serous ovarian cancer(HGSOC).Methods A Meta-analysis utilizing public ovarian cancer databases was performed to evaluate the correlation between MSLN expression levels and overall survival(OS)in ovarian cancer patients.Pathway enrichment analysis was employed to identify key signaling pathways regulated by MSLN and their roles in chemotherapy resistance.Additionally,the TCGA-HGSOC database was analyzed to examine genomic features associated with MSLN-mediated chemotherapy resistance.To validate the biological function of MSLN in chemotherapy resistance,an intraperitoneal metastasis model was established using MSLN-knockdown ID8 ovarian cancer cells in mice.Results Elevated MSLN expression was significantly associated with poor patient prognosis(HR:1.42,95%CI:1.16-1.74).Differential gene expression and pathway enrichment analyses revealed that high MSLN expression upregulates resistance-associated genes and pathways involved in drug metabolism and DNA-binding signaling.Genomic association analysis showed a negative correlation between high MSLN expression and chromosomal instability features,specifically CX3,CX11,and CX13 scores.In vivo studies demonstrated that MSLN knockdown enhanced the tumorsuppressive effects of cisplatin.Conclusion High MSLN expression represents a potential biomarker for poor prognosis and chemotherapy resistance in HGSOC patients,suggesting MSLN as a promising target for therapeutic intervention.

关 键 词：间皮素(MSLN) 高级别浆液性卵巢癌(HGSOC) 顺铂 化疗耐药 

分 类 号：R730.1[医药卫生—肿瘤]