Huang Xiaoyan, Li Ailian, Xu Dianbo
Department of Gynecology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211112, China.
Biomedicines. 2025 Jun 30;13(7):1592. doi: 10.3390/biomedicines13071592.
: Endometrial cancer (EC) remains a major gynecologic malignancy with limited biomarkers for risk stratification. While killer cell lectin-like receptor G2 (KLRG2) exhibits oncogenic properties in other cancers, its clinical significance and mechanistic roles in EC are unknown. This study aims to systematically characterize KLRG2 expression in EC, evaluate its prognostic significance, decipher underlying molecular mechanisms, and explore its role in tumor immune microenvironment regulation. : We performed integrated multi-omics analyses using TCGA-UCEC (n = 552), GTEx, and GEO cohorts (GSE106191), complemented by qPCR validation (14 EC vs. 14 normal samples). Prognostic models were constructed via Cox regression and time-dependent ROC analysis. Epigenetic regulation was assessed through methylation profiling (UALCAN/MethSurv), and immune correlations were evaluated using TIMER/ESTIMATE algorithms. : KLRG2 was significantly overexpressed in EC tissues compared to normal endometrium ( < 0.001), validated by immunohistochemistry and qPCR. High KLRG2 expression independently predicted worse overall survival (HR = 3.08, 95% CI = 1.92-4.96) and progression-free interval (HR = 1.98, 95% CI = 1.37-2.87). Furthermore, elevated KLRG2 levels were significantly associated with advanced-stage disease ( < 0.001), deep myometrial invasion ( < 0.05), and high-grade histology ( < 0.001). Mechanistically, promoter hypomethylation was associated with KLRG2 overexpression ( < 0.001), while hypermethylation at three CpG sites (cg04915254, cg04520485, cg23104233) correlated with poor prognosis. Functional enrichment linked KLRG2 to cell cycle checkpoints and G Protein-Coupled Receptor signaling. Immune profiling revealed cytotoxic lymphocyte depletion (CD8+ T cells: Spearman's ρ = -0.247, < 0.001; NK CD56bright cells: Spearman's ρ = -0.276, < 0.001) and Th2 polarization (Spearman's ρ = 0.117, = 0.006). : This comprehensive EC study establishes KLRG2 as a dual diagnostic/prognostic biomarker and immunomodulatory target. These findings provide a rationale for developing KLRG2-directed therapies to counteract tumor-intrinsic proliferation and microenvironmental immune suppression. Future single-cell analyses are warranted to dissect KLRG2-mediated tumor-immune crosstalk.
子宫内膜癌（EC）仍然是一种主要的妇科恶性肿瘤，用于风险分层的生物标志物有限。虽然杀伤细胞凝集素样受体G2（KLRG2）在其他癌症中表现出致癌特性，但其在EC中的临床意义和机制作用尚不清楚。本研究旨在系统地表征KLRG2在EC中的表达，评估其预后意义，解读潜在的分子机制，并探索其在肿瘤免疫微环境调节中的作用。
我们使用TCGA-UCEC（n = 552）、GTEx和GEO队列（GSE106191）进行了综合多组学分析，并通过qPCR验证（14例EC与14例正常样本）进行补充。通过Cox回归和时间依赖性ROC分析构建预后模型。通过甲基化分析（UALCAN/MethSurv）评估表观遗传调控，并使用TIMER/ESTIMATE算法评估免疫相关性。
与正常子宫内膜相比，KLRG2在EC组织中显著过表达（<0.001），免疫组织化学和qPCR验证了这一点。高KLRG2表达独立预测较差的总生存期（HR = 3.08，95%CI = 1.92-4.96）和无进展生存期（HR = 1.98，95%CI = 1.37-2.87）。此外，KLRG2水平升高与晚期疾病（<0.001）、深肌层浸润（<0.05）和高级别组织学（<0.001）显著相关。从机制上讲，启动子低甲基化与KLRG2过表达相关（<0.001），而三个CpG位点（cg04915254、cg04520485、cg23104233）的高甲基化与预后不良相关。功能富集将KLRG2与细胞周期检查点和G蛋白偶联受体信号传导联系起来。免疫分析显示细胞毒性淋巴细胞减少（CD8+T细胞：Spearman's ρ = -0.247，<0.001；NK CD56bright细胞：Spearman's ρ = -0.276，<0.001）和Th2极化（Spearman's ρ = 0.117，= 0.006）。
这项全面的EC研究将KLRG2确立为一种双重诊断/预后生物标志物和免疫调节靶点。这些发现为开发针对KLRG2的疗法以对抗肿瘤内在增殖和微环境免疫抑制提供了理论依据。未来有必要进行单细胞分析以剖析KLRG2介导的肿瘤-免疫串扰。
