Oshi Masanori, Rog Colin, Yan Li, Endo Itaru, Takabe Kazuaki
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Front Med (Lausanne). 2025 Aug 26;12:1588604. doi: 10.3389/fmed.2025.1588604. eCollection 2025.
Adenosine Triphosphate (ATP) is mainly generated by oxidative phosphorylation in non-malignant cells, whereas malignant cells rely predominantly on glycolysis for energy production, known as the "Warburg effect." This study used the gene set variation analysis (GSVA) algorithm to evaluate glycolysis signaling in hepatocellular carcinoma (HCC), and investigated its relationship with tumor aggressiveness and patient prognosis.
Enhanced level of glycolysis signaling was measured using the "Hallmark-GLYCOLYSIS" gene set in the MSigDB, applied via GSVA across multiple independent HCC cohorts.
There was no significant difference in glycolysis signaling between HCC and other liver diseases in two cohorts. However, enhanced glycolysis signaling linked to gene sets associated with cell proliferation and cancer-promoting pathways, such as unfolded protein response, epithelial mesenchymal transition, and apoptosis, consistently in both cohorts. HCC with high glycolysis signaling score showed increased homologous recombination deficiency ( = 0.004), intratumor heterogeneity ( = 0.005), and mutation burden ( = 0.022). No consistent associations with glycolysis were observed with immune cells infiltration nor cytolytic activity, except for Th1 cells. Clinically, high glycolysis signaling correlated with advanced tumor stage and significantly worse survival outcomes, serving as an independent prognostic biomarker [hazard ratio (HR) = 6.78 and < 0.001 in OS, HR = 6.56 and = 0.027 in DSS].
Elevated glycolysis signaling is linked to enhanced malignant pathways, genomic instability, and worse clinical outcomes in HCC, indicating its potential as a prognostic biomarker.
三磷酸腺苷（ATP）主要由非恶性细胞中的氧化磷酸化产生，而恶性细胞主要依靠糖酵解来产生能量，即所谓的“瓦伯格效应”。本研究使用基因集变异分析（GSVA）算法评估肝细胞癌（HCC）中的糖酵解信号，并研究其与肿瘤侵袭性和患者预后的关系。
使用MSigDB中的“Hallmark-GLYCOLYSIS”基因集测量糖酵解信号增强水平，并通过GSVA应用于多个独立的HCC队列。
在两个队列中，HCC与其他肝病之间的糖酵解信号无显著差异。然而，在两个队列中，糖酵解信号增强均与细胞增殖和癌症促进途径相关的基因集有关，如未折叠蛋白反应、上皮间质转化和凋亡。糖酵解信号得分高的HCC显示同源重组缺陷增加（P = 0.004）、肿瘤内异质性增加（P = 0.005）和突变负担增加（P = 0.022）。除Th1细胞外，未观察到糖酵解与免疫细胞浸润或细胞溶解活性之间存在一致关联。临床上，高糖酵解信号与肿瘤晚期相关，生存结果显著更差，可作为独立的预后生物标志物[总生存期（OS）中的风险比（HR）= 6.78，P < 0.001；疾病特异性生存期（DSS）中的HR = 6.56，P = 0.027]。
糖酵解信号升高与HCC中恶性途径增强、基因组不稳定和更差的临床结果相关，表明其作为预后生物标志物的潜力。
