Table3_Transcriptomic and Metabolomic Profiling in Helicobacter pylori–Induced Gastric Cancer Identified Prognosis- and Immunotherapy-Relevant Gene Signatures.DOCX

Background: Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer (GC). However, how HP infection influences the metabolism and further regulates the progression of GC remains unknown.
Methods: We comprehensively evaluated the metabolic pattern of HP-positive (HP+) GC samples using transcriptomic data and correlated these patterns with tumor microenvironment (TME)–infiltrating characteristics. The metabolic score was constructed to quantify metabolic patterns of individual tumors using principal component analysis (PCA) algorithms. The expression alterations of key metabolism-related genes (MRGs) and downstream metabolites were validated by PCR and untargeted metabolomics analysis.
Results: Two distinct metabolic patterns and differential metabolic scores were identified in HP+ GC, which had various biological pathways in common and were associated with clinical outcomes. TME-infiltrating profiles under both patterns were highly consistent with the immunophenotype. Furthermore, the analysis indicated that a low metabolic score was correlated with an increased EMT subtype, immunosuppression status, and worse survival. Importantly, we identified that the expression of five MRGs, GSS, GMPPA, OGDH, SGPP2, and PIK3CA, was remarkably correlated with HP infection, patient survival, and therapy response. Furthermore, the carbohydrate metabolism and citric acid may be downstream regulators of the function of metabolic genes in HP-induced GC.
Conclusion: Our findings suggest that there is cross talk between metabolism and immune promotion during HP infection. MRG-specific transcriptional alterations may serve as predictive biomarkers of survival outcomes and potential targets for treatment of patients with HP-induced GC.

背景：慢性幽门螺杆菌（Helicobacter pylori, HP）感染被认为是非贲门型胃癌（non-cardia gastric cancer, GC）的主要致病因素。然而，幽门螺杆菌感染如何影响代谢进程，并进一步调控胃癌进展的具体机制仍未明确。方法：本研究利用转录组数据，全面评估了HP阳性（HP+）胃癌样本的代谢模式，并将该模式与肿瘤微环境（tumor microenvironment, TME）浸润特征进行关联分析。通过主成分分析（principal component analysis, PCA）算法构建代谢评分，以量化单个肿瘤的代谢特征。本研究采用聚合酶链式反应（PCR）与非靶向代谢组学分析，验证了关键代谢相关基因（metabolism-related genes, MRGs）的表达变化及下游代谢物的改变。结果：本研究在HP阳性胃癌样本中鉴定出两种截然不同的代谢模式及差异的代谢评分，二者共享多条生物学通路，且与临床结局密切相关。两种代谢模式下的肿瘤微环境浸润特征均与免疫表型高度契合。进一步分析显示，低代谢评分与上皮间质转化（Epithelial-Mesenchymal Transition, EMT）亚型占比升高、免疫抑制状态及不良生存结局显著相关。尤为关键的是，本研究发现GSS、GMPPA、OGDH、SGPP2及PIK3CA这5个代谢相关基因（MRGs）的表达水平，与HP感染、患者生存情况及治疗反应显著相关。此外，糖代谢与柠檬酸或可作为HP诱导胃癌中代谢基因功能的下游调控因子。结论：本研究结果表明，在HP感染过程中，代谢通路与免疫激活之间存在交叉串扰。代谢相关基因特异性的转录改变，可作为HP诱导胃癌患者生存结局的预测生物标志物，同时也可为该类患者的治疗提供潜在靶点。