Departments of Pathology, the Fourth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, PR China.
Shijiazhuang Hospital of Traditional Chinese Medicine, No.233, zhongshan Road, Shijiazhuang, 050011, PR China.
Diagn Pathol. 2024 Aug 22;19(1):113. doi: 10.1186/s13000-024-01513-1.
CLDN is a core component of tight junctions (TJs). Abnormal expressions of CLDNs are commonly detected in various types of tumors. CLDNs are of interest as a potential therapeutic target. CLDNs are closely associated with most cancers of epithelial origin, especially when CLDN7 promotes cancer cell metastasis, such as in gastric, cervical, and ovarian cancers.Its expression and prognosis in breast cancer (BC) remain unknown.The purpose of this study was to investigate the expression pattern of CLDN7 and related immune factors in BC and shed light on a better therapeutic avenue for BC patients.
The cBioPortal, GEPIA, and TCGA databases were used to comprehensively assess the expression of CLDN7 in BC. The Kaplan-Meier Plotter (KMP) database was applied to examine the relationship among the CLDN7 overexpression (OE), prognosis, and overall survival (OS) of BC patients. Immunohistochemical staining was performed on 92 BC tissue samples and 20 benign breast tumors to verify the expression level of CLDN-7 protein and its correlation with clinicopathological features and prognosis. TIMER2.0 was used to analyze the correlation between the CLDN7 OE and immune gene activation using BC-related transcriptomic data. Enrichment analyses of CLDN7-related immune pathways were conducted using online databases. The risk of expression of CLDN7-related immune genes was assessed and differentially expressed (DE) genes were included in the construction of the risk prognosis nomogram.
Both database analysis and clinical sample validation results showed that CLDN7 was significantly overexpressed (OE) in BC, and the OE was correlated with poor DFS in BC patients (p < 0.05). TIMER2.0 analysis indicated that CLDN7 OE was negatively associated with the activation of B-cells, CD4 T-cells, and CD8 T-cells but positively with the M macrophages. Pathway enrichment analysis suggested that CLDN7-related immune factors were mostly involved in the NF-κB and T-cell receptor (TCR) signaling pathways. Univariate Cox regression was used to analyze the correlation between 52 CLDN7 related genes and OS, and 22 genes that are related to prognosis were identified. Prognostic genes were included in the prognostic nomogram of BC with a C-index of 0.76 to predict the 3-year and 5-year OS probabilities of BC individuals.
These findings provide evidence for the role of CLDN7-linked tumor immunity, suggesting that CLDN7 might be a potential immunotherapeutic target for BC, and its association with immune markers could shed light on the better prognosis of BC.
CLDN 是紧密连接 (TJ) 的核心组成部分。在各种类型的肿瘤中，通常会检测到 CLDNs 的异常表达。CLDNs 作为一种潜在的治疗靶点备受关注。CLDNs 与大多数上皮来源的癌症密切相关，尤其是当 CLDN7 促进癌细胞转移时，如胃癌、宫颈癌和卵巢癌。CLDN7 在乳腺癌 (BC) 中的表达和预后尚不清楚。本研究旨在探讨 CLDN7 的表达模式及其与 BC 相关的免疫因子，为 BC 患者提供更好的治疗途径。
使用 cBioPortal、GEPIA 和 TCGA 数据库全面评估 CLDN7 在 BC 中的表达。应用 Kaplan-Meier Plotter (KMP) 数据库研究 CLDN7 过表达 (OE) 与 BC 患者的预后和总生存期 (OS) 之间的关系。对 92 例 BC 组织样本和 20 例良性乳腺肿瘤进行免疫组织化学染色，验证 CLDN-7 蛋白的表达水平及其与临床病理特征和预后的关系。使用 BC 相关转录组数据，通过 TIMER2.0 分析 CLDN7 OE 与免疫基因激活的相关性。使用在线数据库对 CLDN7 相关免疫途径进行富集分析。评估 CLDN7 相关免疫基因的表达风险，并将差异表达 (DE) 基因纳入风险预后列线图的构建。
数据库分析和临床样本验证结果均表明，CLDN7 在 BC 中明显过表达 (OE)，OE 与 BC 患者的不良 DFS 相关 (p<0.05)。TIMER2.0 分析表明，CLDN7 OE 与 B 细胞、CD4 T 细胞和 CD8 T 细胞的激活呈负相关，而与 M 巨噬细胞呈正相关。通路富集分析表明，CLDN7 相关免疫因子主要参与 NF-κB 和 T 细胞受体 (TCR) 信号通路。单因素 Cox 回归分析 52 个 CLDN7 相关基因与 OS 的相关性，筛选出 22 个与预后相关的基因。将预后基因纳入 BC 的预后列线图，C 指数为 0.76，可预测 BC 个体的 3 年和 5 年 OS 概率。
这些发现为 CLDN7 与肿瘤免疫的关系提供了证据，提示 CLDN7 可能是 BC 的一种潜在免疫治疗靶点，其与免疫标志物的关联可为 BC 提供更好的预后。
