Evaluating the link between periodontitis and oral squamous cell carcinoma through Wnt/β-catenin pathway: a critical review

Abstract

Oral Squamous Cell Carcinoma (OSCC), the main form of oral cancer, is a major health problem globally that affects 400,000 people every year. It has been postulated that periodontitis, a chronic inflammatory disease characterized by alveolar bone resorption, is an independent risk factor for OSCC. However, the mechanisms underlying this link are not fully elucidated. It has been demonstrated that the Wnt/β-catenin pathway is key to the transformation of oral potentially malignant disorders (OPMD) towards OSCC (i.e., leukoplakia), particularly in OPMD histologically diagnosed as oral dysplasia. Using a GEO database of oral carcinogenesis (GSE85195), the transcriptional modification of 19 Wnt ligands and 4 key regulatory proteins of β-catenin, including E-cadherin, APC, AXIN and GSK3B, during leukoplakia, and early and late stages OSCC, was determined. The transcriptional expression of these targets was also assessed in periodontitis (GEO database GSE223924). Together, it was found that Wnt ligands Wnt3, Wnt3a, Wnt5b and Wnt7b are concomitantly upregulated in periodontitis and oral carcinogenesis. With these results, and the information retrieved from the literature, this review discusses the potential role of the Wnt/β-catenin pathway as a molecular mechanism that could interlink periodontitis and OSCC.

Keywords: Wnt/β-catenin signaling; leukoplakia; oral squamous cell carcinoma (OSCC); periodontitis; transcriptional expression.

Figure 1

Transcriptomic analysis of Wnt ligands and components of β-catenin destruction complex in oral carcinogenesis. Transcriptomic datasets of 15 leukoplakia, 2 OSCC stage I, 22 OSCC stage II, 7 OSCC stage III and 3 OSCC stage IV samples were retrieved from the GEO database GSE85195. OSCC datasets were grouped as early stage (stages I and II) or late stage (stages II and IV). Only one normal oral mucosa was available in GSE85195. Raw transcriptomic data from the database were processed and normalized to Z-scores to standardize the data and allow direct comparison of expression levels. (A) Transcriptional Wnt ligand expression was organized in heat maps according to their expression patterns. (B) Z-scores of significantly upregulated Wnt ligands were graphed and arranged according to the Ward hierarchical clustering. One sample t-test was used for statistical analysis (*p < 0.05; **p < 0.01, ***p < 0.001, vs. the Z-score of each normal oral mucosa). Additionally, expression data for critical components of the Wnt signaling pathway, including (C) E-cadherin (CDH1), (D) APC, (E) GSK3B and (F) Axin1, were extracted and graphed using GraphPad Prism. One sample t-test was used for statistical analysis (**p < 0.01, ***p < 0.001, vs. the Z-score of each normal oral mucosa).

Figure 2

Transcriptomic analysis of Wnt ligands and components of β-catenin destruction complex in periodontitis. Transcriptomic datasets of 10 healthy controls and 10 periodontitis samples were retrieved from the GEO database GSE223924. Raw transcriptomic data from the database were processed and normalized to Z-scores to standardize the data and allow direct comparison of expression levels. (A) Transcriptional Wnt ligand expression was organized in heat maps according to their expression patterns. (B) Z-score of significantly upregulated Wnt ligands graphed and arranged according to the Ward hierarchical clustering. T-test was used for statistical analysis (*p < 0.05, vs. the Z-score of the corresponding healthy control). Additionally, expression data for critical components of the Wnt signaling pathway, including (C) E-cadherin (CDH1), (D) APC, (E) GSK3B and (F) Axin1, were graphed using GraphPad Prism. T-test was used for statistical analysis (*p < 0.05, vs. the Z-score of the corresponding healthy control).

Figure 3

Possible mechanisms by which periodontal pathogens may promote activation of the Wnt/β-catenin pathway during oral carcinogenesis. When the Wnt/β-catenin is “off”, β-catenin is targeted for proteasomal degradation by a complex composed by dishevelled segment polarity protein 1 (DVL1), AXIN, APC regulator of WNT signaling pathway (APC), casein kinase 1 alpha 1 (CSNK1A1/CK1α) and glycogen synthase kinase 3 beta (GSK3B/GSK3β). To promote β-catenin degradation, CK1α and GSK3B phosphorylate β-catenin at S45 and S33/S37/T41, respectively. β-catenin is also found forming a complex with E-Cadherin at the cell membrane. To activate the Wnt/β-catenin signaling pathway, extracellular Wnt ligands bind to the Frizzled (FDZ) receptor and the LDL receptor related protein (LRP) 5/6 co-receptor. With this, the destruction complex is drawn from the cytoplasm and bound to the receptor at the cell membrane, leading to upregulation of β-catenin. Stable β-catenin translocates to the nucleus as a co-transcriptional factor of TCF/LEF genes. Possible mechanisms by which periodontal pathogens may activate the Wnt/β-catenin pathway include increasing the levels of Wnt ligands at the extracellular medium, a gingipain-dependent proteolytic processing of β-catenin, and disrupting the β-catenin-E-cadherin complex at the cell membrane.