# The Link between Periodontal Disease and Oral Cancer--A Certainty or a Never-Ending Dilemma?
## 4 Periodontal Disease and Oral Cancer
### The Link between Periodontal Disease and Oral Cancer-Current Vision
gingivalis_, which has more mobility and invasion skills than other oral bacteria, might potentially disseminate across the area and speed up the in-situ carcinogenesis process. With the passage of food and water, _P. gingivalis_ can easily move from the mouth cavity to other parts of the oro-digestive tract. A clinical study has validated a link between oral bacteria and squamous cell carcinoma, finding that greater levels of _P. gingivalis_ were linked to a higher incidence of squamous cell carcinoma [110]. When comparing squamous cell cancer tissues to the adjacent or normal tissues, the intensity of positive immunohistochemistry staining for _P. gingivalis_ was substantially higher in the squamous cell carcinoma tissues, indicating a probable link between _P. gingivalis_ and squamous cell carcinoma patients who had greater median serum levels of _P. gingivalis_ immunoglobulin G (Ig G) and IgA than the controls [111, 112]. _P. gingivalis_ penetrates the oral mucosa by targeting Grainyhead-like 2 (GRHL2), an epithelium specific transcription factor, according to a recent study [113]. Later, GRHL2 damages the epithelial barrier by inhibiting the production of tight junction proteins, resulting in greater periodontal tissue loss. Furthermore, _P. gingivalis_ stimulates the production of cytokines like interleukin-6 (IL-6), which activate tumor-promoting transcription factors like STAT1. _P. gingivalis_ can also create a microenvironment by targeting the cluster of differentiation 274 (CD274) and programmed cell death 1 ligand 2 (PDCD1 LG2) through STAT1 activation [114]. _P. gingivalis_ also causes the proenzyme matrix metalloproteinase 9 (proMMP9) to be expressed, and then the active form of the salivary matrix metalloproteinase 9 (MMP-9) to be produced. MMP-9 is thought to play a major role in the defacement of the tumor microenvironment, which supports cancer cell invasion and metastasis [102]. C-reactive protein (CRP) levels in the blood are linked to _P. gingivalis_ (CRP). CRP opsonizes _P. gingivalis_ for complement-binding and activates the complement, according to studies [115]. The link between high levels of CRP in the blood and an elevated risk of epithelial malignancies has been established [116]. Table 1 shows the mechanisms by which _P. gingivalis_ may promote oral cancer. Researchers demonstrated through studies that relied on bacterial cultures and biochemical analysis that Gram-negative anaerbes (_Fusobacterium_ spp., _Prevotella_ spp., etc.) were present more frequently on the tumor surface of OSCC [73]. \begin{table}
\begin{tabular}{c c} \hline \hline  & **Mechanisms** \\ \cline{2-3}  & \multicolumn{2}{c}{Alveolar bone loss is accelerated via IL-17A} \\ _P. gingivalis_ promoting oral cancer & Activation of immunologic and inflammatory reactions via IL-1, IL-6, IL-8, TNF-\(\alpha\) \\  & Creating favorable microenvironment via PDCD1 LG2 \\  & Degradation of tumor microenvironment via MMP9 \\  & \multicolumn{2}{c}{Osponization of bacteria for complement-binding and activation of complement (CRP)} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Possible mechanism for _P. gingivalis_ promoting oral cancer. Other studies have reported that _F. nuclatum, Pseudomonas aeruginosa (P. aeruginosa)_[117], and _Fusobacterium periodonticum (F. periodonticum)_ are associated with OSCC development [107].