Chen Yuhang, Zhang Fenglin, Dai Suoyi, Zhao Jiangang, Cai Wenxun, Zhang Ke, Liao Xinghe, Chen Lianyu
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
BMC Cancer. 2025 May 21;25(1):913. doi: 10.1186/s12885-025-14319-1.
The metabolism of lactate and lactylation of proteins are believed to influence tumor development through their effects on the tumor microenvironment and immune escape mechanisms. Nevertheless, its significance in pancreatic ductal adenocarcinoma (PDAC) has yet to be fully understood. This investigation sought to assess the predictive value and treatment implications of lactate-related genes (LRGs) in PDAC.
We analyzed PDAC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), identifying LRGs. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, we delineated lactate subtypes and extracted differentially expressed genes. Functional enrichment and gene set enrichment analysis (GSEA) analyses were conducted to explore pathways. A lactate-linked risk signature was constructed using Lasso-Cox regression, and its prognostic value was validated. In vitro experiments were executed to examine the function of MCU in PDAC cells. In vitro experiments were conducted to detect the malignant potential of MCU in PDAC cells and its effect on lactic acid metabolism.
Two lactate subtypes were identified, with distinct gene expression profiles and clinical outcomes. The risk signature, comprising four LRGs, predicted survival with significant accuracy. In vitro, MCU knockdown reduced cell proliferation, migration, invasion, and stemness, confirming its role in PDAC malignancy. At the same time, it can also inhibit lactate production and glycolysis processes.
Our investigation underscores the importance of LRGs in PDAC, providing a novel prognostic signature and therapeutic target.
乳酸代谢和蛋白质乳酸化被认为通过影响肿瘤微环境和免疫逃逸机制来影响肿瘤发展。然而，其在胰腺导管腺癌（PDAC）中的意义尚未完全明确。本研究旨在评估乳酸相关基因（LRG）在PDAC中的预测价值及对治疗的启示。
我们分析了来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的PDAC数据，鉴定出LRG。使用加权基因共表达网络分析（WGCNA）和一致性聚类，我们划分了乳酸亚型并提取了差异表达基因。进行功能富集和基因集富集分析（GSEA）以探索相关通路。使用套索-考克斯回归构建乳酸相关风险特征，并验证其预后价值。开展体外实验以检测MCU在PDAC细胞中的功能。进行体外实验以检测MCU在PDAC细胞中的恶性潜能及其对乳酸代谢的影响。
鉴定出两种乳酸亚型，具有不同的基因表达谱和临床结局。由四个LRG组成的风险特征能显著准确地预测生存情况。在体外，敲低MCU可降低细胞增殖、迁移、侵袭和干性，证实其在PDAC恶性进展中的作用。同时，它还能抑制乳酸生成和糖酵解过程。
我们的研究强调了LRG在PDAC中的重要性，提供了一种新的预后特征和治疗靶点。
