Periodontal Pathogens Promote Oral Squamous Cell Carcinoma by Regulating ATR and NLRP3 Inflammasome

Abstract

Periodontitis is closely related to oral cancer, but the molecular mechanism of periodontal pathogens involved in the occurrence and development of oral cancer is still inconclusive. Here, we demonstrate that, in vitro, the cell proliferation ability and S phase cells of the periodontitis group (colonized by Porphyromonas gingivalis and Fusobacterium nucleatum, P+) significantly increased, but the G1 cells were obviously reduced. The animal models with an in situ oral squamous cell carcinoma (OSCC) and periodontitis-associated bacteria treatment were constructed, and micro-CT showed that the alveolar bone resorption of mice in the P+ group (75.3 ± 4.0 μm) increased by about 53% compared with that in the control group (48.8 ± 1.3 μm). The tumor mass and tumor growth rate in the P+ group were all higher than those in the blank control group. Hematoxylin–eosin (H&E) staining of isolated tumor tissues showed that large-scale flaky necrosis was found in the tumor tissue of the P+ group, with lots of damaged vascular profile and cell debris. Immunohistochemistry (IHC) of isolated tumor tissues showed that the expression of Ki67 and the positive rate of cyclin D1 were significantly higher in tumor tissues of the P+ group. The qRT-PCR results of the expression of inflammatory cytokines in oral cancer showed that periodontitis-associated bacteria significantly upregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-18, apoptosis-associated speck-like protein containing a CARD (ASC) (up to six times), and caspase-1 (up to four times), but it downregulated nuclear factor (NF)-κB, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and IL-1β (less than 0.5 times). In addition, the volume of spleen tissue and the number of CD4+ T cells, CD8+ T cells, and CD206+ macrophages in the P+ group increased significantly. IHC and Western blotting in tumor tissues showed that expression levels of γ-H2AX, p-ATR, RPA32, CHK1, and RAD51 were upregulated, and the phosphorylation level of CHK1 (p-chk1) was downregulated. Together, we identify that the periodontitis-related bacteria could promote tumor growth and proliferation, initiate the overexpressed NLRP3, and activate upstream signal molecules of ATR-CHK1. It is expected to develop a new molecular mechanism between periodontitis-related bacteria and OSCC.

The Microbiome in Pancreatic Cancer-Implications for Diagnosis and Precision Bacteriophage Therapy for This Low Survival Disease

“…In pancreatic cancer, Porphyromonas gingivalis is the most studied, and data have shown in murine models that they are able to promote progression of pancreatic cancer ( Chen et al., 2020 ; Gnanasekaran et al., 2020 ; Hiraki et al., 2020 ). Other experimental data have shown that the P. gingivalis may invade and promote proliferation of other cancer types including oral squamous cell carcinoma ( Inaba et al., 2014 ; Geng et al., 2017 ; Chang et al., 2019 ; Hoppe et al., 2019 ; Yao et al., 2021 ), endothelial cancer ( Crooks et al., 2021 ), colorectal carcinoma ( Mu et al., 2020 ; Wang et al., 2021 ), oesophageal squamous cell carcinoma ( Meng et al., 2019 ; Liang et al., 2020 ; Chen et al., 2021 ), and head and neck cancer ( Utispan et al., 2018 ). Further, P. gingivalis has been shown to promote chemotherapy resistance to paclitaxel in oral squamous cell carcinoma ( Song et al., 2019 ).…”

U-Shaped Relationship of Rare Earth Element Lanthanum and Oral Cancer Risk: A Propensity Score-Based Study in the Southeast of China

“…The possible mechanisms mainly include the following: disruption of intracellular calcium homeostasis ( 37 ), formation of reactive oxygen species ( 35 ) as well as the disruption of physiological functions like the glutamate-glutamine cycle ( 38 ) or various signaling pathways such as the PI3K/Akt and NF-κB signaling pathway ( 12 , 36 ). Soluble La (III) species have the ability to activate NLRP3 inflammasome, and the latter was regarded as a key mediator of inflammation in promoting the development of oral cancer ( 21 – 23 ). These findings provide new insight into the action mechanism of La on cancer.…”

“…Other studies, however, showed that La has carcinogenic potential when its concentration fluctuates in colorectal and hepatic cancer cells ( 20 ). Of note, a recent study revealed that soluble La (III) species were found to cause NLRP3 inflammasome activation, which has been proved to be a mechanism for promoting oral cancer ( 21 – 23 ). However, most of those researches were restricted to cell or animal experiments.…”

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

“…These patients showed a higher probability of 32.8% for poorly differentiated OSCC than patients of good oral health at 11.5%. A very recent study by Yao et al [ 214 ] from 2021 developed a new mechanism connecting periodontopathogenic bacteria ( P. gingivalis and F. nucleatum ) and OSCC, by showing that these bacterial species upregulate NLRP3 expression and drive inflammasome activation. It was examined that this pathway can level up tumor growth and tumor proliferation.…”