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Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells.

ABSTRACT: Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo. To the best of our knowledge, this study is the first to demonstrate the direct effect of exposure to P. gingivalis on the tumorigenic behavior of pancreatic cancer cell lines. Our findings shed light on potential mechanisms underlying the pancreatic cancer-periodontitis link.

SUBMITTER: Gnanasekaran J

PROVIDER: S-EPMC7465784 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells.

Gnanasekaran JebaMercy J Binder Gallimidi Adi A Saba Elias E Pandi Karthikeyan K Eli Berchoer Luba L Hermano Esther E Angabo Sarah S Makkawi Hasna A HA Khashan Arin A Daoud Alaa A Elkin Michael M Nussbaum Gabriel G

Cancers 20200818 8

Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingiv ...[more]

PMID: 32824786

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Project description:Recent epidemiological studies revealed a significant association between oral squamous cell carcinoma (OSCC) and Porphyromonas gingivalis, a major pathogen of periodontal disease. As a keystone pathogen of periodontitis, P. gingivalis is known not only to damage local periodontal tissues, but also to evade the host immune system and eventually affect systemic health. However, its role in OSCC has yet to be defined. To explore the underlying effect of chronic P. gingivalis infection on OSCC and to identify relevant biomarkers as promising targets for therapy and prevention, we established a novel model by exposing human immortalized oral epithelial cells (HIOECs) to P. gingivalis at a low multiplicity of infection (MOI) for 5-23 weeks. The P. gingivalis infected HIOECs were monitored for tumor biological alteration by proliferation, wound healing, transwell invasion, and gelatin zymography assays. Microarray and proteomic analyses were performed on HIOECs infected with P. gingivalis for 15 weeks, and some selected data were validated by quantitative real-time PCR and (or) western blot on cells infected for 15 and 23 weeks. Persistent exposure to P. gingivalis caused cell morphological changes, increased proliferation ability with higher S phase fraction in the cell cycle, and promoted cell migratory and invasive properties. In combining results of bioinformatics analyses and validation assays, tumor-related genes such as NNMT, FLI1, GAS6, lncRNA CCAT1, PDCD1LG2, and CD274 may be considered as the key regulators in tumor-like transformation in response to long-time exposure of P. gingivalis. In addition, some useful clinical biomarkers and novel proteins were also presented. In conclusion, P. gingivalis could promote tumorigenic properties of HIOECs, indicating that chronic P. gingivalis infection may be considered as a potential risk factor for oral cancer. The key regulators detected from the present model might be used in monitoring the development of OSCC with chronic periodontal infection.

Project description:Studies are showing that the stress hormone cortisol can reach high levels in the gingival sulcus and induce shifts in the metatranscriptome of the oral microbiome. Interestingly, it has also been shown that cortisol can influence expression levels of Type IX Secretion System (T9SS) genes involved in gliding motility in bacteria belonging to the phylum Bacteroidota. The objective of this study was to determine if cortisol impacts gene expression and surface translocation of Porphyromonas gingivalis strain W50. To conduct these experiments, P. gingivalis was stabbed to the bottom of soft agar plates containing varying cortisol concentrations (0 μM, 0.13 μM, 1.3 μM, and 13 μM), and surface translocation on the subsurface was observed after 48 h of incubation. The results show that when grown with certain nutrients, i.e., in rich medium with the addition of sheep blood, lactate, or pyruvate, cortisol promotes migration of P. gingivalis in a concentration-dependent manner. To begin to examine the underlying mechanisms, quantitative PCR was used to evaluate differential expression of genes when P. gingivalis was exposed to cortisol. In particular, we focused on differential expression of T9SS-associated genes, including mfa5, since it was previously shown that Mfa5 is required for cell movement and cell-to-cell interactions. The data show that mfa5 is significantly up-regulated in the presence of cortisol. Moreover, an mfa5 deletion mutant showed less surface translocation compared to the wild-type P. gingivalis in the presence of cortisol, and the defects of the mfa5 deletion mutant were restored by complementation. Overall, cortisol can stimulate P. gingivalis surface translocation and this coincides with higher expression levels of T9SS-associated genes, which are known to be essential to gliding motility. Our findings support a high possibility that the stress hormone cortisol from the host can promote surface translocation and potentially virulence of P. gingivalis.

Project description:BACKGROUND Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy, characterized by high recurrence rate resulting in poor prognosis. Porphyromonas gingivalis, most closely correlated with chronic periodontitis, is increasingly thought to play a significant role in OSCC development via influencing tumor-associated macrophages. However, its specific function remains unclear. In this study, we attempted to explore the mechanism of action of P. gingivalis in the recurrence of OSCC by bioinformatics analysis, to lay a foundation for subsequent basic experiments. MATERIAL AND METHODS The P. gingivalis-infected macrophage microarray dataset (GSE24897) and the OSCC advanced relapse patient microarray dataset (GSE87593) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially-expressed genes (DEGs) were screened using R system, and the intersected DEGs were analyzed for functional enrichment, and protein-protein interaction (PPI) networks were constructed. The expression of significant DEG in GSE24897 microarray was assessed to determine its effect on macrophage immune infiltration in pan-cancer by applying the TIMER 2.0 repository. To detect the expression of DOK3 in OSCC specimens, immunohistochemical (ICH) assay was used. RESULTS A total of 106 co-expressed DEGs were upregulated and 131 were downregulation. The biological processes were mainly enriched in DNA-templated transcription terms, the cellular component enrichment was mainly enriched in the nucleus terms, and the molecular function enrichment was mainly enriched in protein-binding function terms. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the DEGs were mainly enriched in the MAPK signaling pathway. Overall analysis of the PPI network showed a significant aggregation, with the top 10 hub co-expressed genes (CASP3, FYN, HNRNPA2B1, NR3C1, RELA, REL, POLR2F, RAN, RHOA, and STAT5B). DOK3 is significantly upregulated in P. gingivalis-infected macrophages, which is associated with macrophage infiltration and differentiation. There was more positive DOK3 staining in the group with P. gingivalis infection. CONCLUSIONS P. gingivalis can affect the recurrence of OSCC by increasing the expression of DOK3 in TAMs, which may be involved in activation of signaling pathways such as TNF and MAPK.

Dataset Information

Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells.

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Intracellular <i>Porphyromonas gingivalis</i> Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells.

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