Neisseria sicca and Corynebacterium matruchotii inhibited oral squamous cell carcinomas by regulating genome stability

ABSTRACT

Periodontitis is a risk factor for the development of oral squamous cell carcinomas (OSCC). Both DNA damage response (DDR) and activation of inflammasomes induced by the microbiome might play important roles in the development of tumors, in relation to genome stability of tumor cells. Herein, we explored whether periodontitis negative-associated bacteria (Neisseria sicca and Corynebacterium matruchotii, namely called ‘PNB’), which were highly abundant in healthy populations, could inhibit OSCC by promoting genome stability. Firstly, a murine SCC-7 tumor-bearing model that colonized with PNB was designed and used in this study. Then, cyclin D1 was detected by immunohistochemistry. Levels of DDR, NLRP3 inflammasomes and pro-inflammatory cytokines in tumors were detected by RT-qPCR or Western blot. Immune cells in spleens were detected by immunohistochemistry or immunofluorescence. Finally, the anti-cancer activity of PNB was assessed in vitro using CCK-8 assays and flow cystometry. Compared with the control, PNB decreased tumor weights from 0.77 ± 0.26 g to 0.42 ± 0.15 g and downregulated the expression of Cyclin D1. PNB activated the DDR by up-regulating γ-H2AX, p-ATR, and p-CHK1. PNB activated NLRP3 inflammasome-mediated pyroptosis via increases of NLRP3, gasdermin D, and mRNA levels of apoptosis-associated speck-like protein, Caspase-1. PNB suppressed the inflammatory response by down-regulating mRNA levels of NF-κΒ and IL-6 in tumors as well as the populations of CD4+ T cells and CD206+ immune cells in spleens. PNB inhibited proliferation and promoted cell death of HSC-3 cells. In conclusion, Neisseria sicca and Corynebacterium matruchotii showed a ‘probiotic bacterial’ potential to inhibit OSCC by regulating genome stability.

GRAPHICAL ABSTRACT

KEYWORDS:

• Periodontal negative-associated bacteria
• OSCC
• DNA damage response
• inflammasomes
• Anti-cancer

Acknowledgements

We would like to thank Prof. Qianming Chen for kindly providing tumor cell lines. We would also thank Pengfei Guo, Xu Pu and Haonan Zou for providing the assistance with the animal experiments.

Disclosure statement

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was approved by the Ethics Committee of West China Hospital of Stomatology, Sichuan University (WCCSIRB-D-2016-052).

Authors’ contributions

[Xin Shen] Methodology, data curation, data analysis and interpretation, statistical analysis, writing – original draft, and writing – review and editing. [Bo Zhang] Data curation and data analysis and interpretation. [Xiaoyu Hu] Data curation. [Jia Li] Data curation. [Miaomiao Wu] Data curation. [Caixia Yan] Data curation. [Yutao Yang] Data curation. [Yan Li] Conceptualization, funding acquisition, methodology, supervision, and writing –review and editing.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81771085, 81991500, 81991502), the Key Projects of Sichuan Provincial Department of Science and Technology (grant number 2020YFSY0008) and the Open Project Fund for Key Laboratory of Guangdong Science and Technology Department (grant number KF2019120101).