Integrative analysis identifies the intratumoral Fusobacterium nucleatum as a driver of cervical cancer malignancy.

Abstract

Background: Fusobacterium nucleatum (F. nucleatum) is an oral commensal bacterium that acts as a pathobiont with pro-tumorigenic activity in various gastrointestinal cancers. However, its functional role, invasive capacity, and mechanistic contributions in cervical cancer remain largely unexplored.

Methods: We identified F. nucleatum in cervical cancer tissues using bioinformatics and clinical 16S rRNA sequencing. Its spatial localization and intracellular presence were confirmed by fluorescence in situ hybridization (FISH) and transmission electron microscopy (TEM), respectively. Functional validation included in vitro assays for proliferation, migration, and apoptosis in cervical cancer cell lines, with bacterial invasion visualized by confocal microscopy, and in vivo tumor growth assessment in a xenograft model. The underlying mechanism involving high mobility group box 1 (HMGB1) and the NF-κB pathway was analyzed by western blot, qPCR, immunofluorescence, and ELISA.

Results: F. nucleatum was enriched in cervical cancer and correlated with poor patient survival. It invaded cervical cancer cells, promoted proliferation, migration, and invasion, suppressed apoptosis in vitro, and accelerated tumor growth in vivo. Mechanistically, infection triggered HMGB1 upregulation and specific activation of the canonical NF-κB pathway (via IκBα degradation, p65 phosphorylation/nuclear translocation), leading to selective secretion of IL-6/IL-8.

Conclusion: Our study suggests that F. nucleatum is associated with cervical cancer malignancy, potentially acting through upregulation of HMGB1 and activation of the canonical NF-κB signaling pathway, thereby contributing to an altered tumor microenvironment. These findings reveal a previously unrecognized microbial-driven oncogenic mechanism in cervical cancer and highlight its potential as a prognostic marker and a therapeutic target.

Clinical trial number: Not applicable in our manuscript.