乳腺癌患者CLDN4在免疫细胞浸润和癌细胞干性调节中的作用研究及药物靶点预测  

Study of the role of CLDN4 in the regulation of immune cell infiltration and cancer cell stemness in patients with breast cancer and prediction of drug targets

作　　者：林加曼 王美文 李乐桐 王强 LIN Jiaman;WANG Meiwen;LI Letong;WANG Qiang(Department of Public Health,Baotou Medical College,Inner Mongolia University of Science&Technology,Baotou Inner Mongolia 014040,China;Chinese PLA Center for Disease Control and Prevention,Beijing 100071,China)

机构地区：[1]内蒙古科技大学包头医学院公共卫生学院,内蒙古包头014000 [2]中国人民解放军疾病预防控制中心,北京100071

出　　处：《天津药学》2025年第3期343-349,357,共8页Tianjin Pharmacy

基　　金：国家自然科学基金项目(81472478)。

摘　　要：目的探讨CLDN4异常表达与乳腺癌发生的相关性及其在肿瘤微环境和免疫调节中的作用,为乳腺癌靶向药物研发提供靶点。方法选用TIMER数据库(TIMER)、生物医学数据分析盒子(SangerBox)、GENT2、人类蛋白质图谱数据库(HPA)、UALCAN、Kaplan-Meier Plotter、TCGA mplab和cBioPortal数据库分析CLDN4的表达、突变和甲基化水平以及对临床预后的影响。采用人类癌症转移数据库(HCMDB)、肿瘤免疫单细胞中心(TISCH2)、SangerBox、scTIME Portal和癌症单细胞状态图谱(CancerSEA)数据库评估CLDN4表达与肿瘤微环境和免疫反应的相关性。结果与正常乳腺组织相比,乳腺癌组织中CLDN4 mRNA的表达水平更高(P<0.05);CLDN4在乳腺癌患者中的表达水平与其分子分型、肿瘤分期和淋巴结转移状态显著相关(P<0.05);在不同临床病理特征下,乳腺癌患者的CLDN4启动子甲基化水平均显著低于健康样本(P<0.05),表明CLDN4启动子甲基化水平与乳腺癌患者的临床病理特征呈负相关。进一步分析CLDN4表达与肿瘤转移相关性,结果显示乳腺癌转移患者较未转移患者CLDN4表达显著上调(P<0.05);在原发性肿瘤中,CLDN4与基质细胞和免疫细胞浸润水平呈负相关,并显著抑制4个免疫细胞和7个免疫检查点基因;在转移性肿瘤中,CLDN4主要在恶性细胞中表达,并与缺氧和转移密切相关。此外,通过SangerBox网站研究发现CLDN4的表达与预估、免疫和基质评分呈负相关(P<0.05)。结论CLDN4可以抑制免疫细胞功能并调节乳腺癌细胞干性特征,表明CLDN4可作为乳腺癌治疗的靶向药物的潜在靶点。Objective To explore the correlation between aberrant CLDN4 expression and breast carcinogenesis and its role in tumor microenvironment and immune regulation,and to provide targets for breast cancer targeted drug development.Methods TIMER,Biomedical Data Analysis Box(SangerBox),GENT2,Human Protein Atlas(HPA),UALCAN,Kaplan-Meier Plotter,TCGA mplab and cBioPortal databases were selected to analyze the expression,mutation,and methylation levels of CLDN4,and the impact on clinical prognosis.The Human Cancer Metastasis Database(HCMDB),Tumor Immunity Single Cell Center(TISCH),Biomedical Data Analysis Box(SangerBox),scTIME Portal,and CancerSEA databases were used to assess the correlation of CLDN4 expression with the tumor microenvironment and immune response.Results Promoter hypomethylation and upregulation of CLDN4 expression were significantly associated with breast cancer clinicopathology and low survival(P<0.05).In primary tumors,CLDN4 expression was upregulated in stromal and immune cells and significantly suppressed four immune cells and seven immune checkpoint genes.In addition,CLDN4 expression was negatively correlated with ESTIMATE,immune and stromal scores(P<0.05).In metastatic tumors,CLDN4was predominantly expressed in malignant cells and was strongly associated with hypoxia and metastasis.The expression level of CLDN4 mRNA was higher in breast cancer tissues compared with normal breast tissues(P<0.05);The expression level of CLDN4 in breast cancer patients was significantly correlated with their molecular typing,tumor stage,and lymph node metastatic status(P<0.05);and the methylation level of CLDN4 promoter in breast cancer patients was significantly lower than that of healthy samples under different clinicopathological features(P<0.05),indicating that the methylation level of CLDN4 promoter was negatively correlated with the clinicopathological characteristics of breast cancer patients.Further analysis of the correlation between CLDN4 expression and tumor metastasis showed that CLDN4 expression was signifi

关 键 词：乳腺癌 CLDN4 肿瘤微环境 免疫检查点 

分 类 号：R737.9[医药卫生—肿瘤]