Fusobacteria modulate oral carcinogenesis and promote cancer progression

Abstract

Background: Evidence suggest periodontal bacterial infection can contribute to oral cancer initiation and progression. Aim: To investigate the effects of periodontal bacteria on oral cancer cell behavior using a cell-based system and a mouse carcinogenesis model. Methods: Oral cancer cell lines were polyinfected with four periodontal bacteria. Cytokine levels and relative changes in oncogene mRNA expression were determined post-infection. Oral tumours in mice induced by 4-nitroquinoline-1-oxide (4NQO) were compared with and without administrating periodontal bacteria. Results: Polyinfected oral cancer cells had upregulated MMP1, MMP9, and IL-8. The expression of cell survival markers MYC, JAK1, and STAT3 and epithelial-mesenchymal transition markers ZEB1 and TGF-β were also significantly elevated. Monoinfections showed F. nucleatum alone had comparable or greater effects than the four bacteria together. Fusobacterial culture supernatant, primarily LPS, was sufficient to induce IL-8 secretion, demonstrating that direct contact of live Fusobacteria with cancer cells might not be required to exert changes in cancer cell behaviour. In the 4NQO-induced oral tumour model, mice infected with bacteria developed significantly larger and more numerous lesions compared to those not infected. Conclusion: This study demonstrated that Fusobacteria could potentially enhance cancer cell invasiveness, survival, and EMT when presented in the oral tumour microenvironment. Abbreviations: 4NQO, 4-nitroquinoline-1-oxide; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; IL-8, interleukin-8; JAK1, Janus kinase 1; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; OSCCs, oral squamous cell carcinomas; PK, proteinase K; PMB, Polymyxin B; qRT-PCR, quantitative real-time polymerase chain reaction; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor beta; ZEB1, zinc finger E-Box binding homeobox 1

Keywords

• 4nqo
• oral cancer
• periodontal bacteria
• inflammation
• fusobacterium nucleatum