Neutrophil Transcriptional Deregulation by the Periodontal Pathogen Fusobacterium nucleatum in Gastric Cancer: A Bioinformatic Study

Abstract

Background. Infection with the periodontal pathogen Fusobacterium nucleatum (F. nucleatum) has been associated with gastric cancer. The present study is aimed at uncovering the putative biological mechanisms underlying effects of F. nucleatum–mediated neutrophil transcriptional deregulation in gastric cancer. Materials and Methods. A gene expression dataset pertaining to F. nucleatum-infected human neutrophils was utilized to identify differentially expressed genes (DEGs) using the GEO2R tool. Candidate genes associated with gastric cancer were sourced from the “Candidate Cancer Gene Database” (CCGD). Overlapping genes among these were identified as link genes. Functional profiling of the link genes was performed using “g:Profiler” tool to identify enriched Gene Ontology (GO) terms, pathways, miRNAs, transcription factors, and human phenotype ontology terms. Protein-protein interaction (PPI) network was constructed for the link genes using the “STRING” tool, hub nodes were identified as key candidate genes, and functionally enriched terms were determined. Results. The gene expression dataset GEO20151 was downloaded, and 589 DEGs were identified through differential analysis. 886 candidate gastric cancer genes were identified in the CGGD database. Among these, 36 overlapping genes were identified as the link genes. Enriched GO terms included molecular function “enzyme building,” biological process “protein folding,’” cellular components related to membrane-bound organelles, transcription factors ER71 and Sp1, miRNAs miR580 and miR155, and several human phenotype ontology terms including squamous epithelium of esophagus. The PPI network contained 36 nodes and 53 edges, where the top nodes included PH4 and CANX, and functional terms related to intracellular membrane trafficking were enriched. Conclusion. F nucleatum-induced neutrophil transcriptional activation may be implicated in gastric cancer via several candidate genes including DNAJB1, EHD1, IER2, CANX, and PH4B. Functional analysis revealed membrane-bound organelle dysfunction, intracellular trafficking, transcription factors ER71 and Sp1, and miRNAs miR580 and miR155 as other candidate mechanisms, which should be investigated in experimental studies.

Identification of consensus head and neck cancer-associated microbiota signatures: a meta-analysis of 16S rRNA and The Cancer Microbiome Atlas datasets

“…21, [135][136][137] Furthermore, Fusobacterium can chemoattract neutrophils via release of SCFA and can also modulate neutrophils and endothelial cell functions in vitro. [138][139][140][141][142] Interestingly, we observed that patients with low levels of Fusobacterium within the tumour tissue had shorter overall survival, consistent to previous reports in HNSC. 45,60,143 In contrast, opposite findings have been reported for colorectal, gastric and oesophageal cancers, suggesting that Fusobacterium may have a different role in HNSC.…”

Global status and trends of gastric cancer and gastric microbiota research: a bibliometric analysis

“…A bioinformatic analysis suggested that neutrophil transcriptional activation induced by F. nucleatum may be implicated in the occurrence of GC through several candidate genes, including DNAJB1, EHD1, IER2, CANX, and PH4B. Functional analysis showed that membrane-bound organelle dysfunction, intracellular trafficking, transcription factors ER71 and Sp1, and miR580 and miR155 were other candidate mechanisms ( Zhou et al, 2022 ). The metabolic function analysis showed that F. nucleatum -positive GC tissues were significantly enriched in the biosynthesis of lysine, peptidoglycan, and tRNA metabolic functions ( Nie et al, 2021 ).…”

Fusobacterium nucleatum in tumors: from tumorigenesis to tumor metastasis and tumor resistance

“… 68 Another study proposed that F. nucleatum -induced transcriptional activation in neutrophils might be linked to gastric carcinogenesis through various candidate genes, with suggested functional mechanisms including organelle dysfunction and intracellular transport dysregulation. 69 Intriguingly, the impact of F. nucleatum appears to differ among GC subtypes, with F. nucleatum -positive patients displaying a poorer prognosis in the context of Lauren diffuse GC, while no substantial difference was noted in intestinal GC patients. This observation hints at the prospect that F. nucleatum may exert disparate modes of action within the domain of Lauren diffuse GC, 67 although further research is required to elucidate the precise mechanisms involved.…”