Ye Wanchun, Zhang Xiaolei, Tang Zhongjie, Hu Yufeng, Zheng Yuanliang, Yuan Yuping
The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, The Second Affiliated Hospital of Shanghai University, Wenzhou, China.
Department of Clinical Laboratory, Jinan Fourth People's Hospital, Jinan, China.
BMC Gastroenterol. 2025 Apr 15;25(1):256. doi: 10.1186/s12876-025-03878-z.
Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide, with limited therapeutic options and a poor prognosis, particularly in advanced stages. Glycometabolism, a hallmark of cancer, plays a critical role in tumor progression, immune evasion, and response to therapy. However, the specific roles of glycometabolism-related genes and their prognostic and therapeutic implications in GC remain inadequately understood.
Transcriptomic and clinical data from GC patients were retrieved from TCGA and GEO databases. Glycometabolism-related genes were identified and analyzed using machine learning algorithms to construct a prognostic model. Functional assays, immune profiling, and pathway enrichment analyses were performed to explore the roles of these genes in tumor progression, immune-modulatory effects, and drug resistance. PLOD2, the gene with the highest prognostic significance, was further investigated to uncover its underlying regulatory mechanisms, roles in immune modulation, and contribution to therapeutic resistance.
A glycometabolism-related prognostic model consisting of four genes (PLOD2, CHSY3, SLC2A3 and SLC5A1) was developed and validated, effectively stratifying GC patients into high- and low-risk subgroups with distinct survival outcomes. Among these, PLOD2 emerged as the most significant gene, exhibiting strong associations with tumor progression and poor survival. Functional analyses revealed that PLOD2 promotes glycolysis and tumor progression through activation of the PI3K/AKT/mTOR pathway. Immune profiling revealed that PLOD2 overexpression is associated with an immunosuppressive tumor microenvironment, characterized by increased M2 macrophage infiltration and reduced immune activity. Moreover, treatment with rapamycin, an mTOR inhibitor, significantly suppressed PLOD2-mediated proliferation and anchorage-independent growth in GC cells, highlighting the central role of the PI3K/AKT/mTOR pathway in PLOD2-driven oncogenic behaviors.
This study identifies PLOD2 as a key prognostic biomarker and therapeutic target in gastric cancer. As a central component in a glycometabolism-related model, PLOD2 promotes glycolysis, tumor progression, and immune evasion via the PI3K/AKT/mTOR pathway. The model effectively stratifies patient risk, offering both prognostic utility and therapeutic insight. Targeting PLOD2-mediated pathways may represent a promising strategy for precision therapy and improved clinical outcomes in gastric cancer.
胃癌（GC）是全球癌症相关死亡的主要原因之一，治疗选择有限且预后较差，尤其是在晚期。糖代谢作为癌症的一个标志，在肿瘤进展、免疫逃逸和治疗反应中起着关键作用。然而，糖代谢相关基因在胃癌中的具体作用及其预后和治疗意义仍未得到充分了解。
从TCGA和GEO数据库中检索胃癌患者的转录组和临床数据。使用机器学习算法识别和分析糖代谢相关基因，以构建预后模型。进行功能分析、免疫图谱分析和通路富集分析，以探索这些基因在肿瘤进展、免疫调节作用和耐药性中的作用。对预后意义最高的基因PLOD2进行进一步研究，以揭示其潜在的调控机制、在免疫调节中的作用以及对治疗耐药性的影响。
开发并验证了一个由四个基因（PLOD2、CHSY3、SLC2A3和SLC5A1）组成的糖代谢相关预后模型，该模型有效地将胃癌患者分为具有不同生存结果的高风险和低风险亚组。其中，PLOD2是最显著的基因，与肿瘤进展和不良生存密切相关。功能分析表明，PLOD2通过激活PI3K/AKT/mTOR通路促进糖酵解和肿瘤进展。免疫图谱分析显示，PLOD2过表达与免疫抑制性肿瘤微环境相关，其特征是M2巨噬细胞浸润增加和免疫活性降低。此外，使用mTOR抑制剂雷帕霉素治疗可显著抑制PLOD2介导的胃癌细胞增殖和非锚定依赖性生长，突出了PI3K/AKT/mTOR通路在PLOD2驱动的致癌行为中的核心作用。
本研究确定PLOD2为胃癌的关键预后生物标志物和治疗靶点。作为糖代谢相关模型的核心组成部分，PLOD2通过PI3K/AKT/mTOR通路促进糖酵解、肿瘤进展和免疫逃逸。该模型有效地对患者风险进行分层，具有预后价值和治疗指导意义。靶向PLOD2介导的通路可能是胃癌精准治疗和改善临床结局的一种有前景的策略。
