Introduction

The oral epithelium, the layer of cells lining the mouth, is a crucial component of the body's first line of defense against environmental threats and pathogens. Its integrity and function are maintained by various cellular structures, among which adherens junctions (AJs) are fundamental. AJs play a critical role in cell-cell adhesion, tissue integrity, and cellular signaling. This article delves into the role of AJs in oral epithelial health, exploring their involvement in various oral diseases and highlighting potential future research directions that could pave the way for novel therapeutic approaches.  

Adherens Junctions (AJs)

Adherens junctions (AJs) are fundamental cell-cell adhesion structures, typically located at apical areas of cell-cell contact in polarized differentiated epithelia, between tight junctions (TJs), which lie more apically, and desmosomes, found more basolaterally. The crosstalk between AJs and TJs is essential for forming the epithelial barrier. In stratified epithelial tissues, such as those lining the oral mucosa, TJs are present at the stratum granulosum, where the barrier is established. However, AJs and desmosomes are interspersed throughout cell-cell contact in the underlying stratified epithelium layers, playing critical roles in tissue organization, stratification, and mechanical stability. AJs are abundant throughout most oral mucosal epithelium, gingival epithelium, and sulcular epithelium, with fewer AJs and desmosomes in the junctional epithelium.

AJ Composition

The core composition of the AJ includes classical cadherin and catenin protein families. E-cadherin, a transmembrane glycoprotein, is the cornerstone AJ molecule in epithelial tissues, with stratified epithelia also containing P-cadherin at their basal layers. E-cadherin has five extracellular domains forming calcium-dependent interactions with cadherin molecules of the same (cis) and adjacent cells (trans), both critical for establishing cell-cell adhesions. Intracellularly, E-cadherin binds to p120 catenin (p120) through its juxtamembrane domain and to β-catenin through its catenin-binding domain. P120 regulates AJ complex stability and turnover, while β-catenin binds to α-catenin, establishing connections with the actin cytoskeleton.

Fig. 1 Schematic representation of the basic structural components of the adherens junctions (Niessen C. M. 2007).

AJ Structural and Signaling Roles

The cross-talk of AJs with the actin cytoskeleton is critical for establishing and maintaining cell and tissue architecture, regulating epithelial cell linkage and dynamics, and responding to mechanical stresses. During stratified epithelia development, tensile actin cables form apically, followed by an expansion of actin fibers throughout the epidermal sheet, enabling cell movement and further formation of cell-cell junctions, eventually generating a stratified tissue.

Beyond their structural role, AJs have numerous signaling functions in normal physiological conditions and diseases such as cancer. A well-studied phenomenon with tumorigenesis implications is "cadherin switching" during the Epithelial-to-Mesenchymal Transition (EMT), marked by E-cadherin downregulation and replacement by mesenchymal cadherins, promoting cell migration and metastasis. AJ components can also influence cell behavior and promote disease through their disruption or even presence. For example, β-catenin acts as a transcriptional activator of the Wnt signaling pathway upon AJ disruption, maintaining the proliferation of keratinocyte stem cells in stratified epithelia but promoting tumorigenesis in aberrant conditions. Similarly, AJ disruption through α-catenin loss can promote cell growth and proliferation via Hedgehog and Hippo pathways. P120 functions as a signaling regulator, with phosphorylation destabilizing AJs and promoting cell growth, while its nuclear translocation upon disruption acts as a tumor promoter.

Adherens Junctions in Dental Enamel Development

Dental enamel, the hard outer layer of the tooth, is formed by ameloblasts-specialized cells that secrete enamel matrix proteins. The differentiation of ameloblasts and enamel formation are processes heavily reliant on AJs. Research has shown that Rho-associated coiled-coil-containing protein kinase (ROCK) plays a pivotal role in ameloblast differentiation and enamel production by regulating AJ function. ROCK inhibition impairs ameloblast polarization and the formation of actin and E-cadherin structures, which are essential for proper enamel development.

Integral membrane proteins such as E-cadherin and N-cadherin, along with associated proteins like α-catenin, β-catenin, p120, vinculin, actin, and myosin, are crucial for ameloblast function. For instance, matrix metalloproteinase 20 (MMP20) is an essential protein that cleaves extracellular domains of E- and N-cadherin, facilitating ameloblast organization during enamel formation. Additionally, p120 knockout models show defective enamel development due to impaired attachment and detachment of ameloblasts during the secretory stage of enamel formation. Mutations in nectin-1 and nectin-3, integral AJ proteins, also result in enamel defects, underscoring the importance of AJs in enamel maintenance.

Adherens Junctions and Oral Cancer

Oral cancers, particularly oral squamous cell carcinoma (OSCC), present a significant clinical challenge due to their aggressive nature and poor prognosis. AJs play a crucial role in OSCC pathogenesis through epithelial-to-mesenchymal transition (EMT), a process involving the downregulation of E-cadherin and the upregulation of mesenchymal cadherins like N-cadherin. This transition leads to a loss of strong cell-cell adhesion and increased cell motility, which contributes to cancer progression and metastasis.

Adherens Junctions and Oral Melanoma

Oral melanoma is a rare and aggressive form of oral cancer, often occurring in the maxillary anterior gingiva. Despite its rarity, understanding the role of AJs in oral melanoma is crucial for developing effective treatments. Research on canine oral melanocytic tumors suggests that the absence of E-cadherin is associated with unfavorable clinical outcomes. However, the role of E-cadherin in human oral melanoma remains largely unexplored, highlighting a need for further investigation in this area.

Conclusion

Adherens junctions are vital for maintaining the health and integrity of the oral epithelium. Their role in enamel development, oral cancers, and oral melanoma underscores their importance in oral health. Despite substantial research, many aspects of AJ function and dysregulation remain to be explored. The study of AJs offers a promising avenue for oral disease research, with the potential to lead to new prognostic, diagnostic, and therapeutic advancements in oral health.