Dai Yonggang, Wang Hongya, Wang Wei, Zhuang Xuewei
Department of Clinical Laboratoryaboratory, Shandong Provincial Third Hospital, Shandong University, No.11 Middle Wuyingshan Road, Tianqiao District, Jinan City, 250031, Shandong Province, People's Republic of China.
Department of Clinical Microbiology Laboratory, Shandong Second Provincial General Hospital, No. 4 Duanxing West Road, Huaiyin District, Jinan City, 250031, Shandong Province, People's Republic of China.
Sci Rep. 2025 Aug 13;15(1):29768. doi: 10.1038/s41598-025-15082-w.
Cell death modalities play crucial roles in cancer evolution and therapeutic responses. Among various mechanisms, necrosis by sodium overload (NECSO) is a newly recognized process initiated by disruptions in Na homeostasis, manifesting through osmotic stress, energy depletion, and immunogenic damage. The TRPM4 gene, which encodes a calcium-activated and sodium-selective ion channel, has surfaced as a significant regulator connecting ionic metabolism with oncogenic pathways. Given these insights, our study aims to comprehensively analyze the expression and implications of TRPM4 across diverse cancer types to elucidate its potential as a biomarker and therapeutic target. We conducted a systematic investigation of TRPM4 across 33 cancer types defined by the Cancer Genome Atlas (TCGA), integrating transcriptomic, proteomic, epigenetic, and clinical datasets from TCGA, GTEx, and Human Protein Atlas (HPA). We employed differential expression analyses, receiver operating characteristic (ROC) curves, and survival analyses, alongside mutation and methylation assessments. Furthermore, we explored TRPM4's immunological aspects through immune infiltration analyses. Our analyses revealed significant TRPM4 overexpression in several tumors, such as bladder (BLCA), cholangiocarcinoma (CHOL), and ovarian cancer (OV), whilst being downregulated in others like kidney clear cell carcinoma (KIRC) and lung adenocarcinoma (LUAD). Notably, TRPM4 expression correlated with overall survival, disease-specific survival, and progression-free interval, highlighting its prognostic value. Furthermore, promoter methylation and mutation patterns elucidated the mechanisms underlying TRPM4 dysregulation, and immune infiltration analyses suggested its involvement in tumor immune evasion. This investigation highlights TRPM4's dual role in mediating sodium-induced cell death and modulating the tumor microenvironment, proposing it as a potential biomarker for cancer diagnosis and prognosis, though its association with demographic and pathological characteristics appears limited and tumor-type specific. Given its import in various malignancies and potential therapeutic implications through ion channel-focused strategies, TRPM4 warrants further exploration as a target for precision oncology.
细胞死亡方式在癌症演变和治疗反应中起着关键作用。在各种机制中，钠超载诱导的坏死（NECSO）是一种新认识的过程，由钠稳态破坏引发，通过渗透应激、能量耗竭和免疫原性损伤表现出来。TRPM4基因编码一种钙激活的钠选择性离子通道，已成为连接离子代谢与致癌途径的重要调节因子。基于这些见解，我们的研究旨在全面分析TRPM4在多种癌症类型中的表达及意义，以阐明其作为生物标志物和治疗靶点的潜力。我们对癌症基因组图谱（TCGA）定义的33种癌症类型进行了TRPM4的系统研究，整合了来自TCGA、GTEx和人类蛋白质图谱（HPA）的转录组学、蛋白质组学、表观遗传学和临床数据集。我们采用了差异表达分析、受试者工作特征（ROC）曲线分析和生存分析，以及突变和甲基化评估。此外，我们通过免疫浸润分析探索了TRPM4的免疫学方面。我们的分析显示，TRPM4在几种肿瘤中显著过表达，如膀胱癌（BLCA）、胆管癌（CHOL）和卵巢癌（OV），而在其他肿瘤如肾透明细胞癌（KIRC）和肺腺癌（LUAD）中则下调。值得注意的是，TRPM4表达与总生存期、疾病特异性生存期和无进展生存期相关，突出了其预后价值。此外，启动子甲基化和突变模式阐明了TRPM4失调的潜在机制，免疫浸润分析表明其参与肿瘤免疫逃逸。这项研究突出了TRPM4在介导钠诱导的细胞死亡和调节肿瘤微环境中的双重作用，提出它作为癌症诊断和预后的潜在生物标志物，尽管其与人口统计学和病理特征的关联似乎有限且具有肿瘤类型特异性。鉴于其在各种恶性肿瘤中的重要性以及通过聚焦离子通道策略的潜在治疗意义，TRPM4作为精准肿瘤学的靶点值得进一步探索。
