Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by stimulating the release of neutrophil extracellular traps in the tumor immune microenvironment

Zhi-Chen Guo; Si-Li Jing; Xin-Yu Jia; Sadam Ahmed Elayah; Lin-Yang Xie; Hao Cui; Jun-Bo Tu; Si-Jia Na

doi:10.1007/s00011-023-01822-z

Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by stimulating the release of neutrophil extracellular traps in the tumor immune microenvironment

Inflamm Res. 2024 May;73(5):693-705. doi: 10.1007/s00011-023-01822-z. Epub 2023 Dec 27.

Authors

Zhi-Chen Guo^#^{1

2

3}, Si-Li Jing^#⁴, Xin-Yu Jia^#^{1

2

3}, Sadam Ahmed Elayah⁵, Lin-Yang Xie^{1

2

3}, Hao Cui^{1

2

3}, Jun-Bo Tu^{6

7

8}, Si-Jia Na^{9

10

11}

Affiliations

¹ Key Laboratory of Shanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China.
² Laboratory Center of Stomatology, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China.
³ Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China.
⁴ Shannxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, China.
⁵ Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Jiblah University for Medical and Health Sciences, Ibb, Yemen.
⁶ Key Laboratory of Shanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. tujunbo@mail.xjtu.edu.cn.
⁷ Laboratory Center of Stomatology, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. tujunbo@mail.xjtu.edu.cn.
⁸ Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. tujunbo@mail.xjtu.edu.cn.
⁹ Key Laboratory of Shanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. sijiana@xjtu.edu.cn.
¹⁰ Laboratory Center of Stomatology, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. sijiana@xjtu.edu.cn.
¹¹ Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, China. sijiana@xjtu.edu.cn.

^# Contributed equally.

PMID: 38150024
DOI: 10.1007/s00011-023-01822-z

Abstract

Background: The aim of this study was to investigate the impact of Porphyromonas gingivalis (P. gingivalis) on the progression of oral squamous cell carcinoma (OSCC) through neutrophil extracellular traps (NETs) in the tumor immune microenvironment.

Methods: The expression of NETs-related markers was identified through immunohistochemistry, immunofluorescence, and Western blotting in different clinical stages of OSCC samples. The relationship between NETs-related markers and clinicopathological characteristics in 180 samples was analyzed using immunohistochemistry data. Furthermore, the ability to predict the prognosis of OSCC patients was determined by ROC curve analysis and survival analysis. The effect of P. gingivalis on the release of NETs was identified through immunofluorescence and immunohistochemistry, both in vitro and in vivo. CAL27 and SCC25 cell lines were subjected to NETs stimulation to elucidate the influence of NETs on various cellular processes, including cell proliferation, migration, invasion, and metastasis in vitro. Furthermore, the impact of NETs on the growth and metastatic potential of OSCC was assessed using in vivo models involving tumor-bearing mice and tumor metastasis mouse models.

Results: Immunochemistry analysis revealed a significant correlation between the NETs-related markers and clinical stage, living status as well as TN stage. P. gingivalis has demonstrated its ability to effectively induce the release of NETs both in vivo and in vitro. NETs have the potential to facilitate cell migration, invasion, and colony formation. Moreover, in vivo experiments have demonstrated that NETs play a pivotal role in promoting tumor metastasis.

Conclusion: High expression of NETs-related markers demonstrates a strong correlation with the progression of OSCC. Inhibition of the NETs release process stimulated by P. gingivalis and targeted NETs could potentially open up a novel avenue in the field of immunotherapy for patients afflicted with OSCC.

Keywords: Porphyromonas gingivalis; Inflammation; Neutrophil extracellular traps; Oral squamous cell carcinoma; Tumor immune microenvironment.

MeSH terms

Aged
Animals
Bacteroidaceae Infections / immunology
Bacteroidaceae Infections / microbiology
Carcinoma, Squamous Cell* / immunology
Carcinoma, Squamous Cell* / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease Progression
Extracellular Traps* / immunology
Extracellular Traps* / metabolism
Female
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Mouth Neoplasms* / immunology
Mouth Neoplasms* / microbiology
Mouth Neoplasms* / pathology
Neutrophils / immunology
Porphyromonas gingivalis* / immunology
Tumor Microenvironment* / immunology

Grants and funding

2020SF-182/Key Research and Development Projects of Shaanxi Province