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Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by activating the neutrophil chemotaxis in the tumour microenvironment

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Abstract

Background

We aimed to determine the significance of Porphyromonas gingivalis (P. gingivalis) in promoting tumour progression in the tumour microenvironment (TME) of oral squamous cell carcinoma (OSCC).

Methods

The Gene Expression Omnibus (GEO) was used to screen out the differentially expressed genes from the two datasets of GEO138206 and GSE87539. Immunohistochemistry and immunofluorescence analysis of samples, cell biological behaviour experiments, and tumour-bearing animal experiments were used to verify the results in vivo and in vitro. The mechanism was revealed at the molecular level, and rescue experiments were carried out by using inhibitors and lentiviruses.

Results

CXCL2 was selected by bioinformatics analysis and was found to be related to a poor prognosis in OSCC patients. Samples with P. gingivalis infection in the TME of OSCC had the strongest cell invasion and proliferation and the largest tumour volume in tumour-bearing animal experiments and exhibited JAK1/STAT3 signalling pathway activation and epithelial-mesenchymal transition (EMT). The expression of P. gingivalis, CXCL2 and TANs were independent risk factors for poor prognosis in OSCC patients. A CXCL2/CXCR2 signalling axis inhibitor significantly decreased the invasion and proliferation ability of cells and the tumour volume in mice. When lentivirus was used to block the CXCL2/CXCR2 signalling axis, the activity of the JAK1/STAT3 signalling pathway was decreased, and the phenotype of EMT was reversed.

Conclusion

Porphyromonas gingivalis promotes OSCC progression by recruiting TANs via activation of the CXCL2/CXCR2 axis in the TME of OSCC.

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Availability of data and materials

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

GEO:

Gene Expression Omnibus

OSCC:

Oral squamous cell carcinoma

TANs:

Tumour—associated neutrophils

P. gingivalis :

Porphyromonas gingivalis

References

  1. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR (2020) Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6:92–113. https://doi.org/10.1038/s41572-020-00224-3

    Article  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA: Cancer J Clin 71:7–33. https://doi.org/10.3322/caac.21654

    Article  PubMed  Google Scholar 

  3. Liu J, Jiang X, Zou A, Mai Z, Huang Z, Sun L, Zhao J (2021) circIGHG-induced epithelial-to-mesenchymal transition promotes oral squamous cell carcinoma progression via miR-142-5p/IGF2BP3 signaling. Can Res 81:344–355. https://doi.org/10.1158/0008-5472.Can-20-0554

    Article  CAS  Google Scholar 

  4. Amieva M, Peek RM Jr (2016) Pathobiology of helicobacter pylori-induced gastric cancer. Gastroenterology 150:64–78. https://doi.org/10.1053/j.gastro.2015.09.004

    Article  CAS  PubMed  Google Scholar 

  5. Inaba H, Sugita H, Kuboniwa M, Iwai S, Hamada M, Noda T, Morisaki I, Lamont RJ, Amano A (2014) Porphyromonas gingivalis promotes invasion of oral squamous cell carcinoma through induction of proMMP9 and its activation. Cell Microbiol 16:131–145. https://doi.org/10.1111/cmi.12211

    Article  CAS  PubMed  Google Scholar 

  6. Liu XB, Gao ZY, Sun CT, Wen H, Gao B, Li SB, Tong Q (2019) The potential role of P. gingivalis in gastrointestinal cancer: a mini review. Infect Agents Cancer 14:23. https://doi.org/10.1186/s13027-019-0239-4

    Article  Google Scholar 

  7. Irfan M, Delgado RZR, Frias-Lopez J (2020) The oral microbiome and cancer. Front Immunol 11:591088. https://doi.org/10.3389/fimmu.2020.591088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65:S140–S146. https://doi.org/10.1111/j.1753-4887.2007.tb00352.x

    Article  PubMed  Google Scholar 

  9. Kraus RF, Gruber MA (2021) Neutrophils-from bone marrow to first-line defense of the innate immune system. Front Immunol 12:767175. https://doi.org/10.3389/fimmu.2021.767175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Giese MA, Hind LE, Huttenlocher A (2019) Neutrophil plasticity in the tumor microenvironment. Blood 133:2159–2167. https://doi.org/10.1182/blood-2018-11-844548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sahingur SE, Yeudall WA (2015) Chemokine function in periodontal disease and oral cavity cancer. Front Immunol 6:214. https://doi.org/10.3389/fimmu.2015.00214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vashishta A, Jimenez-Flores E, Klaes CK, Tian S, Miralda I, Lamont RJ, Uriarte SM (2019) Putative Periodontal Pathogens, Filifactor Alocis and Peptoanaerobacter Stomatis, induce differential cytokine and chemokine production by human neutrophils. Pathogens (Basel, Switzerland). https://doi.org/10.3390/pathogens8020059

    Article  PubMed  Google Scholar 

  13. Chen Y, Shao Z, Jiang E et al (2020) CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. J Cell Physiol 235:5995–6009. https://doi.org/10.1002/jcp.29525

    Article  CAS  PubMed  Google Scholar 

  14. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I (2015) Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metas 32:353–368. https://doi.org/10.1007/s10585-015-9714-5

    Article  CAS  Google Scholar 

  15. Acharyya S, Oskarsson T, Vanharanta S et al (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150:165–178. https://doi.org/10.1016/j.cell.2012.04.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14:736–746. https://doi.org/10.1038/nrc3818

    Article  CAS  PubMed  Google Scholar 

  17. Wang J, Lv X, Guo X et al (2021) Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells. Oncogenesis 10:8. https://doi.org/10.1038/s41389-020-00292-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Geng F, Liu J, Guo Y, Li C, Wang H, Wang H, Zhao H, Pan Y (2017) Persistent exposure to Porphyromonas gingivalis promotes proliferative and invasion capabilities, and tumorigenic properties of human immortalized oral epithelial cells. Front Cell Infect Microbiol 7:57. https://doi.org/10.3389/fcimb.2017.00057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qiu X, Lei Z, Wang Z, Xu Y, Liu C, Li P, Wu H, Gong Z (2019) Knockdown of LncRNA RHPN1-AS1 inhibits cell migration, invasion and proliferation in head and neck squamous cell carcinoma. J Cancer 10:4000–4008. https://doi.org/10.7150/jca.29029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guo ZC, Jumatai S, Jing SL, Hu LL, Jia XY, Gong ZC (2021) Bioinformatics and immunohistochemistry analyses of expression levels and clinical significance of CXCL2 and TANs in an oral squamous cell carcinoma tumor microenvironment of Porphyromonas gingivalis infection. Oncol Lett 21:189. https://doi.org/10.3892/ol.2021.12450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schmid MC, Khan SQ, Kaneda MM et al (2018) Integrin CD11b activation drives anti-tumor innate immunity. Nat Commun 9:5379. https://doi.org/10.1038/s41467-018-07387-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xue Y, Du HD, Tang D et al (2019) Correlation between the NLRP3 inflammasome and the prognosis of patients with LSCC. Front Oncol 9:588. https://doi.org/10.3389/fonc.2019.00588

    Article  PubMed  PubMed Central  Google Scholar 

  23. Vyhnalova T, Danek Z, Gachova D, Linhartova PB (2021) The role of the oral microbiota in the etiopathogenesis of oral squamous cell carcinoma. Microorganisms. https://doi.org/10.3390/microorganisms9081549

    Article  PubMed  PubMed Central  Google Scholar 

  24. Whitmore SE, Lamont RJ (2014) Oral bacteria and cancer. PLoS Pathog 10:e1003933. https://doi.org/10.1371/journal.ppat.1003933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Damgaard C, Kantarci A, Holmstrup P, Hasturk H, Nielsen CH, Van Dyke TE (2017) Porphyromonas gingivalis-induced production of reactive oxygen species, tumor necrosis factor-α, interleukin-6, CXCL8 and CCL2 by neutrophils from localized aggressive periodontitis and healthy donors: modulating actions of red blood cells and resolvin E1. J Periodontal Res 52:246–254. https://doi.org/10.1111/jre.12388

    Article  CAS  PubMed  Google Scholar 

  26. Kamarajan P, Ateia I, Shin JM, Fenno JC, Le C, Zhan L, Chang A, Darveau R, Kapila YL (2020) Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin. PLoS Pathog 16:e1008881. https://doi.org/10.1371/journal.ppat.1008881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ibáñez L, de Mendoza I, MaritxalarMendia X, García de la Fuente AM, Quindós Andrés G, Aguirre Urizar JM (2020) Role of Porphyromonas gingivalis in oral squamous cell carcinoma development: a systematic review. J Periodontal Res 55:13–22. https://doi.org/10.1111/jre.12691

    Article  Google Scholar 

  28. Harusato A, Viennois E, Etienne-Mesmin L et al (2019) Early-life microbiota exposure restricts myeloid-derived suppressor cell-driven colonic tumorigenesis. Cancer Immunol Res 7:544–551. https://doi.org/10.1158/2326-6066.Cir-18-0444

    Article  PubMed  PubMed Central  Google Scholar 

  29. Glogauer JE, Sun CX, Bradley G, Magalhaes MA (2015) Neutrophils increase oral squamous cell carcinoma invasion through an invadopodia-dependent pathway. Cancer Immunol Res 3:1218–1226. https://doi.org/10.1158/2326-6066.Cir-15-0017

    Article  CAS  PubMed  Google Scholar 

  30. Lakschevitz FS, Aboodi GM, Glogauer M (2013) Oral neutrophils display a site-specific phenotype characterized by expression of T-cell receptors. J Periodontol 84:1493–1503. https://doi.org/10.1902/jop.2012.120477

    Article  CAS  PubMed  Google Scholar 

  31. El-Bayoumy K, Christensen ND, Hu J et al (2020) An Integrated approach for preventing oral cavity and oropharyngeal cancers: two etiologies with distinct and shared mechanisms of carcinogenesis. Cancer Prev Res (Philadelphia, PA) 13:649–660. https://doi.org/10.1158/1940-6207.Capr-20-0096

    Article  CAS  Google Scholar 

  32. Zhang Q, Wang J, Yao X et al (2021) Programmed cell death 10 mediated CXCL2-CXCR2 signaling in regulating tumor-associated microglia/macrophages recruitment in glioblastoma. Front Immunol 12:637053. https://doi.org/10.3389/fimmu.2021.637053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin T, Zhang E, Mai PP, Zhang YZ, Chen X, Peng LS (2021) CXCL2/10/12/14 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma. Biosci Rep. https://doi.org/10.1042/bsr20204312

  34. Grépin R, Guyot M, Giuliano S et al (2014) The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma. Can Res 74:873–883. https://doi.org/10.1158/0008-5472.Can-13-1267

    Article  Google Scholar 

  35. Wei ZW, Xia GK, Wu Y et al (2015) CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer. Cancer Lett 359:335–343. https://doi.org/10.1016/j.canlet.2015.01.033

    Article  CAS  PubMed  Google Scholar 

  36. Susek KH, Karvouni M, Alici E, Lundqvist A (2018) The Role of CXC Chemokine Receptors 1–4 on immune cells in the tumor microenvironment. Front Immunol 9:2159. https://doi.org/10.3389/fimmu.2018.02159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chapman RW, Minnicozzi M, Celly CS et al (2007) A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation. J Pharmacol Exp Ther 322:486–493. https://doi.org/10.1124/jpet.106.119040

    Article  CAS  PubMed  Google Scholar 

  38. Lee J, Roberts JS, Atanasova KR, Chowdhury N, Han K, Yilmaz Ö (2017) Human primary epithelial cells acquire an epithelial-mesenchymal-transition phenotype during long-term infection by the oral opportunistic pathogen, Porphyromonas gingivalis. Front Cell Infect Microbiol 7:493. https://doi.org/10.3389/fcimb.2017.00493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, Tsai M, Sadeh J, Magnussen H (2010) SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J 35:564–570. https://doi.org/10.1183/09031936.00048509

    Article  CAS  PubMed  Google Scholar 

  40. Guo Z, Jing S-l, Jumatai S et al (2022) Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by activating the neutrophil chemotaxis in the tumor microenvironment, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-1663147/v1

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Acknowledgements

Not applicable.

Funding

This study was supported by 1. National Natural Science Foundation of China, (Project Number: 82160189); 2. The project of Tianshan Innovation Team of Xinjiang Uygur Autonomous Region, (Project Number: 202110755).

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Authors and Affiliations

  1. Oncological Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Institute of Stomatology, No.137, Li Yu Shan South Road, Urumqi, 830054, Xinjiang, People’s Republic of China

    Zhi-chen Guo, Sakendeke Jumatai & Zhong-cheng Gong

  2. Department of Ophthalmology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

    Si-li Jing

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Contributions

ZCGo conceived and designed the study. ZCGu conducted the experiments. SJ and SLJ performed the statistical analysis. ZCGu wrote the manuscript. ZCGu reviewed and edited the manuscript. All authors agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhong-cheng Gong.

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The authors declare no potential conflict of interests.

Ethics approval and consent to participate

Written informed consent was obtained from all OSCC patients. All clinical experiments were approved by the institutional ethical review board of XinJiang Medical University (Approval No. IACUC20180411-13). All animal researches adhere to the ARRIVE guidelines (https://arriveguidelines.org/arrive-guidelines), and were approved by the Ethics Committee of The First Affiliated Hospital of XinJiang Medical University.

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A preprint has previously been published [40].

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Guo, Zc., Jing, Sl., Jumatai, S. et al. Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by activating the neutrophil chemotaxis in the tumour microenvironment. Cancer Immunol Immunother 72, 1523–1539 (2023). https://doi.org/10.1007/s00262-022-03348-5

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