Carneiro Klezzer de Oliveira, Araújo Taíssa Maíra Thomaz, Da Silva Mourão Ronald Matheus, Casseb Samir Mansour Moraes, Demachki Samia, Moreira Fabiano Cordeiro, Dos Santos Ândrea Kely Campos Ribeiro, Ishak Geraldo, Da Costa Daniel de Souza Avelar, Magalhães Leandro, Vidal Amanda Ferreira, Burbano Rommel Mario Rodriguez, de Assumpção Paulo Pimentel
Oncology Research Center, Federal University of Pará, Belém, Brazil.
Biological Sciences Institute, Federal University of Pará, Belém, Brazil.
Front Oncol. 2025 Mar 5;15:1530430. doi: 10.3389/fonc.2025.1530430. eCollection 2025.
Gastric cancer (GC), which has low survival rates and high mortality, is a major concern, particularly in Asia and South America, with over one million annual cases. Epstein-Barr virus (EBV) is recognized as a carcinogen that may trigger gastric carcinogenesis by infecting the stomach epithelium via reactivated B cells, with growing evidence linking it to GC. This study investigates the transcriptional and microbial profiles of EBV-infected versus EBV-non-infected GC patients.
Using Illumina NextSeq, cDNA libraries were sequenced, and reads were aligned to the human genome and analyzed with DESeq2. Kegg and differential analyses revealed key genes and pathways. Gene sensitivity and specificity were assessed using ROC curves (p < 0.05, AUC > 0.8). Non-aligned reads were used for microbiome analysis with Kraken2 for bacterial identification. Microbial analysis included LDA score, Alpha and Beta diversity metrics, with significance set at p ≤ 0.05. Spearman's correlation between differentially expressed genes (DEGs) and bacteria were also examined.
The data revealed a gene expression pattern in EBV-positive gastric cancer, highlighting immune response, inflammation, and cell proliferation genes (e.g., , , , ). ROC analysis identified genes with high specificity and sensitivity for discriminating EBV+ gastric cancer, including , , and that play pivotal roles in immune response, inflammation, and cancer. Functional enrichment pointed to cytokine-cytokine receptor interactions, antigen processing, and Th17 immune response, emphasizing the role of the tumor microenvironment, shaped by inflammation and immunomodulation, in EBV-associated GC. Microbial analysis revealed changes in the gastric microbiota in EBV+ samples, with a significant reduction in bacterial taxa. The genera and were more abundant in EBV+ GC, while more abundant bacteria in EBV- GC included , and . Spearman's correlation showed a strong link between DE bacterial genera and DEGs involved in processes like cell differentiation, cytokine production, digestion, and cell death.
These findings suggest a complex interaction between the host (EBV+ GC) and the microbiota, possibly influencing cancer progression, and offering potential therapeutic targets such as microbiota modulation or gene regulation. Comparing with EBV- samples further highlights the specific impact of EBV and the microbiota on gastric cancer pathogenesis.
胃癌（GC）生存率低、死亡率高，是一个主要问题，尤其是在亚洲和南美洲，每年有超过100万病例。爱泼斯坦-巴尔病毒（EBV）被认为是一种致癌物，它可能通过重新激活的B细胞感染胃上皮细胞，从而引发胃癌发生，越来越多的证据将其与胃癌联系起来。本研究调查了EBV感染与未感染的胃癌患者的转录组和微生物组特征。
使用Illumina NextSeq对cDNA文库进行测序，将读数与人类基因组比对，并使用DESeq2进行分析。KEGG和差异分析揭示了关键基因和途径。使用ROC曲线评估基因的敏感性和特异性（p < 0.05，AUC > 0.8）。未比对的读数用于微生物组分析，使用Kraken2进行细菌鉴定。微生物分析包括LDA评分、Alpha和Beta多样性指标，显著性设定为p ≤ 0.05。还检查了差异表达基因（DEG）与细菌之间的Spearman相关性。
数据揭示了EBV阳性胃癌中的基因表达模式，突出了免疫反应、炎症和细胞增殖基因（例如， ， ， ）。ROC分析确定了对鉴别EBV + 胃癌具有高特异性和敏感性的基因，包括 ， ， 和 ，它们在免疫反应、炎症和癌症中起关键作用。功能富集指向细胞因子-细胞因子受体相互作用、抗原加工和Th17免疫反应，强调了由炎症和免疫调节塑造的肿瘤微环境在EBV相关胃癌中的作用。微生物分析揭示了EBV + 样本中胃微生物群的变化，细菌分类群显著减少。 属和 属在EBV + 胃癌中更为丰富，而EBV - 胃癌中更丰富的细菌包括 属、 属和 属。Spearman相关性显示，DE细菌属与参与细胞分化、细胞因子产生、消化和细胞死亡等过程的DEG之间存在密切联系。
这些发现表明宿主（EBV + 胃癌）与微生物群之间存在复杂的相互作用，可能影响癌症进展，并提供了潜在的治疗靶点，如微生物群调节或基因调控。与EBV - 样本比较进一步突出了EBV和微生物群对胃癌发病机制的特定影响。
