Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients

Abstract

BACKGROUND

An increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined.

AIM

To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer.

METHODS

Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival.

RESULTS

RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori).

CONCLUSION

F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.

Keywords: Fusobacterium nucleatum; Helicobacter pylori; Gastric cancer; Survival; Interferon; Mobility

Core Tip: Fusobacterium nucleatum (F. nucleatum) is frequently enriched in the gastric cancer-associated microbiota. Here, we showed that F. nucleatum solicits a rapid but transient interferon response from gastric cancer cells. In addition, F. nucleatum leads to deregulation of the genes functioning in regulation of actin filament dynamics, likely changing cell mobility. In a patient cohort receiving gastrectomy, combined infection of F. nucleatum and Helicobacter pylori infection incurs poorer survival, indicating these two pathogens act synergistically to promote invasiveness of gastric cancer. Our finding suggests that F. nucleatum is a biomarker as treatment outcome predicator.