Oral keratinocyte-mediated inflammation and epithelial disruption: A narrative review on IRF6 signaling and oral carcinogenic risk

Abstract

The oral epithelium is a dynamic interface between host and environment, where keratinocytes not only serve as structural components but also actively modulate immune responses. Emerging research identifies IRF6 as a pivotal regulator of epithelial differentiation and immune signaling within chronic inflammatory contexts. This narrative review explores the role of IRF6 and its downstream effects in oral keratinocytes, particularly in relation to Toll-like receptor (TLR) activation, CCL5-mediated inflammation, hypoxic signaling, and the epithelial-mesenchymal transition (EMT). It proposes a mechanistic framework for understanding the progression from chronic inflammation to epithelial disruption and malignant transformation in oral mucosal disorders. Modulation of IRF6 signaling represents a promising therapeutic target for restoring epithelial integrity and halting disease progression in chronic inflammatory oral diseases. This model lays groundwork for future research integrating molecular biomarkers and immune modulation strategies in oral pathology.

Keywords

oral keratinocytes chronic inflammation epithelial-mesenchymal transition oral squamous cell carcinoma oral lichen planus

Introduction

Head and neck cancer (HNC) represents the sixth most common malignancy worldwide.^1,2 Among the various subtypes, oral squamous cell carcinoma (OSCC) accounts for most cases.² While tobacco smoking and excessive alcohol consumption remain the most prominent and well-established risk factors for OSCC,^1,3 a growing subset of patients, classified as non-smoking and non-drinking (NSND), develop the disease in the absence of these traditional exposures. In such cases, alternative etiological factors such as chronic trauma and dysbiosis of the oral microbiome have been proposed.⁴

The oral epithelium functions as a critical interface between the host and the external environment. Oral keratinocytes, the predominant cell type in this barrier, play a dual role: they provide a physical defense against external insults and contribute to immune surveillance. This immunological function is largely mediated by pattern recognition receptors, particularly Toll-like receptors (TLRs), which enable keratinocytes to detect microbial components and initiate immune responses.^5,6 Upon activation, TLRs orchestrate a finely balanced immune reaction by regulating the production of pro-inflammatory and anti-inflammatory mediators.⁷ Specifically, TLR activation induces the expression of cytokines, chemokines, and type I interferons (IFNs), which collectively guide the epithelial immune response.⁸

TLR signaling in oral keratinocytes occurs via two main adaptor-dependent pathways: Myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF).⁸ The MyD88-dependent pathway involves the recruitment of interleukin-1 receptor-associated kinase 1 (IRAK1), which subsequently activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and members of the interferon regulatory factor (IRF) family.⁹ Among these, IRF6 has emerged as a key transcriptional regulator at the intersection of epithelial biology and immune function. Beyond its established role in epithelial differentiation and proliferation, IRF6 has been implicated in the regulation of cell-cell junctions and the modulation of inflammatory responses.¹⁰

Previously, we proposed a model in which IRF6 by acting downstream of TLR2 and the MyD88–IRAK1 axis regulates the expression of inflammatory mediators in oral keratinocytes. Notably, IRF6 activation leads to the induction of CC chemokine ligand 5 (CCL5), a potent chemoattractant involved in T cell recruitment and activation; therefore, epithelial immune signaling can be directly linked to broader inflammatory processes.¹¹

This narrative review aims to synthesize current knowledge regarding the molecular mechanisms governing inflammation in the oral epithelium, with a particular focus on IRF6 signaling, CCL5 regulation, the impact of hypoxic microenvironments on epithelial behavior as well as oral keratinocyte biology and chronic inflammation-related carcinogenesis. To do so, literature included in this review was identified through structured searches in multiple databases (PubMed, Scopus, and Embase) up to June 2025, with additional references retrieved from key publications. Given the narrative nature of this review, a systematic evidence synthesis or meta-analysis was not performed; rather, studies that contributed to the proposed mechanistic framework linking IRF6 signaling to oral carcinogenic risk were critically selected. By integrating these key pathways, we propose a conceptual framework that connects keratinocyte function to chronic inflammation and oral disease progression. Understanding these molecular circuits may unveil novel therapeutic targets and offer translational insights into the pathogenesis of OSCC.

Oral epithelium

The oral mucosa consists of two layers: the stratified oral epithelium and the underlying connective tissue, which houses the vascular, lymphatic, and neural networks essential for epithelial support and regeneration.¹² The oral epithelium functions as a specialized barrier that protects the body from chemical, mechanical, and microbial insults encountered in the oral environment. This protection is mediated through both structural and immunological mechanisms.

Structurally, it forms a physical shield via stratification and intercellular junctions. Histologically, the oral epithelium is predominantly composed of keratinocytes that differentiate progressively as they migrate from the basal layer to the superficial surface. The basal layer contains proliferative, undifferentiated cells, while the suprabasal layers undergo morphological and biochemical transitions culminating in terminal differentiation. These layers are classically defined as the basal, spinous, granular (or intermediate), and superficial layers, with the degree of keratinization varying according to anatomical site and function.¹³ In regions such as the buccal mucosa, the epithelium is non-keratinized and stratified, tailored for flexibility and resilience.¹⁴ The thickness of this mucosa ranges from approximately 0.3 mm in the mandibular canine area to 6.7 mm in the maxillary tuberosity, reflecting site-specific functional adaptations.¹⁵ Notably, the oral epithelium exhibits a high turnover rate, which is essential for barrier renewal and microbial resistance.^12,16 In particular, the buccal mucosa demonstrates rapid regeneration, with a reported renewal cycle of 6–7 days—faster than the turnover of 5–11 days for keratinized sites like the gingiva on primate models.^17–19

The other key feature of the oral epithelium structure is the presence of cell junctions. Epithelial cells develop polarity through specialized cell-to-cell contact structures known as epithelial junctions. These junctional complexes consist of tight junctions, desmosomes and adherens junctions. Tight junctions serve as barriers to both paracellular and intramembrane diffusion, controlling the permeability of the epithelial layer by regulating the movement of lipids and proteins between the apical and basolateral membranes. Key proteins involved in the formation of tight junctions include the transmembrane proteins claudin and occludin, which localize within these structures and mediate the connection between the basolateral membranes of adjacent cells.^20,21

Desmosomes regulate permeability; however, this can be affected by factors such as hypoxia, medications, radiation, and bacterial dysbiosis.²² These junctions connect the lateral walls of keratinocytes, while hemidesmosomes anchor keratinocytes to the basement membrane.²³ Keratins play a fundamental role in these junctions. In fact, defects in keratin 5 (K5) and K14 lead to cytoskeletal loss in basal keratinocytes, causing epidermolysis bullosa simplex, a condition characterized by blistering lesions following minor trauma.²⁴ Desmosomes are also interconnected through desmosomal cadherins, including desmogleins and desmocollins, which facilitate strong intercellular adhesion.²⁵

Similarly, mature adherens junctions are established through calcium-dependent interactions between cadherin molecules on neighboring epithelial cells. E-cadherin, the primary adhesion protein in epithelial adherens junctions, serves as a membrane anchor for the actin cytoskeleton by interacting with P120-catenin, α-catenin, and β-catenin. This cadherin-catenin complex not only reinforces cell-cell adhesion but also plays a crucial role in the dynamic regulation of adherens junctions under various physiological conditions.²⁶

Immunologically, the oral epithelium regulates tolerance or activation in response to microbial antigens through signaling pathways and immune cell interactions.^5,27 These intercellular junctions strengthen the immune barrier that protects the oral epithelium from mechanical and chemical injuries by resisting both physiological and pathogenic mechanical stress. However, oral mucosal immunity relies not only on the physical properties of cell junctions but also on a network of signaling proteins produced by keratinocytes, which interact with the basement membrane and immune system cells, particularly antigen-presenting cells (APCs).^17,28

Toll-like receptors

Toll-like receptors (TLRs), members of the pattern recognition receptor family, are wide class of receptors involved in innate and adaptive immune responses.²⁹ TLRs bind numerous antigens by recognizing conserved pathogen-associated molecular patterns (PAMPs) or Damage-associated molecular patterns (DAMPS), to which the oral cavity is constantly exposed, and triggering inflammatory responses during tissue damage.^29,30 Once activated, TLRs coordinated expression of genes involved in specific signaling pathways in the regulation of innate and adaptive immunity and tissue repair and regeneration. To do so, TLRs are coupling in its cytoplasmatic domain to adaptor molecules including myeloid differentiation factor 88 (MyD88), TIR domain-containing protein (TIRAP), and TIR domain-containing adaptor inducing interferon-β-related adaptor molecule (TRAM). This potentially leads to the activation of two main pathways, the MyD88-dependent (used by all TLRs except TLR3) and the MyD88-independent TRAM/TRIF pathway (used by TLR3 and some signals of TLR4).³¹ TLR activation on epithelial cells has been shown to induce the production of several cytokines, chemokines, and antimicrobial peptides.³² Genetic disruption of TLRs and adaptor molecules of the TLR pathway has been associated with tumor development and progression in mice.³³ TLRs—particularly TLR2 and TLR4—have been widely studied in oral mucosal diseases.^34,35 However, TLR2 is of interest since it had been reported as tumoral suppressor, its lack led to increase cell proliferation and decreased apoptosis in a mouse model,³³ it plays a role in Treg expansion and their suppressive capacity,³⁶ and its expression increases in OSCC keratinocytes vs its healthy control.

Interferon regulatory factor 6 (IRF6)

IRF6 is a member of the Interferon Regulatory Factor (IRF) family that comprises nine transcription factors involved in various biological processes.^37,38 IRF6 has been extensively studied in the context of craniofacial formation defects.³⁷ If fact, mutations in IRF6 are known to cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome (PPS).^38,39 Patients with VWS are at higher risk of wound healing complications following surgical repair.⁴⁰

IRF6 is unique among IRF family members due to its epithelial-specific expression and its central role in regulating keratinocyte differentiation.^41–43 Unlike most IRFs, which are broadly expressed in immune cells, IRF6 is largely restricted to epithelial tissues. However, given its close genetic similarity to IRF5 and IRF7, evidence suggests that IRF6 may assume analogous functions to these factors within epithelial cells,⁴³ particularly in innate immune signaling. Beyond immunity, IRF6 controls epithelial cell cycle dynamics: its phosphorylation targets the protein for ubiquitination and proteasomal degradation.⁴⁴ Reduced IRF6 expression results in elevated Cyclin D3 levels, a key G1-phase marker, underscoring its role in cell cycle arrest. However, IRF6 alone is insufficient to fully regulate proliferation, as its stability depends on an inductive environment that prevents degradation.⁴⁵

These findings align with research in cancer cells, where IRF6 acts as a tumor suppressor.⁴⁶ IRF6 expression is downregulated in squamous cell carcinomas, where it is associated with invasive tumor cell behavior⁴⁷ and epithelial-mesenchymal transition (EMT) in breast cancer.⁴⁸ Restoring IRF6 expression halts cell cycle progression and proliferation.^41,49 IRF6 has also been implicated in the development of vulvar squamous cell carcinoma arising from vulvar lichen sclerosus⁵⁰ and as a prognostic marker for cervical neoplastic stages⁵¹ and gastric cancer, where it predicts poorer outcomes.⁵²

More recently, IRF6 has also been recognized for its role in innate immunity where it plays a role in TLR signaling, regulating the activation of type I interferons and contributing to NFκB signaling in response to pathogenic stimuli.⁵³ It also functions as a tumor suppressor studied in various cancers.^{41,46–48,50,51} Additionally, it contributes to immune responses through TLR signaling pathways in oral keratinocytes.^42,54 The interplay between TLR3 and IRF6 in wound healing suggests a functional connection regulated within keratinocytes.⁵⁵

Specifically, activation of IRF6 via the MyD88-IRAK1 pathway induces the production of CCL5, a chemokine dependent on TLR2 signaling in epithelial cell lines.^43,56 CCL5 plays a crucial role in T-cell activation and the production of other pro-inflammatory cytokines.⁴³ Notably, IRF6 mediates cytokine inflammatory responses in oral keratinocytes exposed to the periodontal pathogen Porphyromonas gingivalis, leading to enhanced differentiation of basal layer keratinocytes.⁵⁷ These findings highlight an innate immune role for IRF6, previously attributed solely to other IRF family members.

C-C motif chemokine ligand 5 (CCL5)

CCL5, also known as RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted), is part of the C-C motif chemokine family, which also includes CCL3 (macrophage inflammatory protein-1α, MIP-1α) and CCL4 (MIP-1β).⁵⁸ This chemokine plays a crucial role in immune responses by acting as a potent chemoattractant for various immune cells and modulating inflammatory pathways.⁵⁹

The primary receptor for CCL5 is C-C chemokine receptor type 5 (CCR5). However, it can also interact with CCR1, CCR3, CCR4, CD44, and GPCR-independent pathways.⁶⁰ Notably, dipeptidyl peptidase IV (DPPIV/CD26) enzymatically modifies CCL5 by removing the first two amino acids from its N-terminus, which enhances its affinity for CCR5 while diminishing its binding to CCR1 and CCR3.^61,62 Additionally, this post-translational modification has been shown to influence Ca²⁺ release, further affecting intracellular signaling pathways.⁶³ These enzymatic alterations may contribute to the specificity of CCL5’s function in different immune contexts, potentially fine-tuning immune cell recruitment and activation.

CCL5 is a target gene regulated by NFκB and is produced by a variety of cell types, including T lymphocytes, macrophages, platelets, synovial fibroblasts, tubular epithelial cells, and tumor cells.⁵⁹ Due to the widespread expression of its receptors, CCL5 exerts a broad immunological influence by recruiting monocytes, mast cells, dendritic cells, natural killer (NK) cells, eosinophils, basophils, CD4+ and CD8+ T cells, and B cells to sites of inflammation or infection.⁶⁴

Given its strong chemoattractant properties, CCL5 is implicated in various inflammatory diseases, autoimmune disorders, and cancer progression.⁵⁸ In chronic inflammatory conditions, elevated levels of CCL5 contribute to sustained immune cell infiltration, amplifying tissue damage and disease pathology.⁵⁹ Additionally, in the tumor microenvironment, CCL5 has been associated with tumor growth, immune evasion, and metastasis, making it a potential target for therapeutic intervention.⁵⁸

IRF6 as a regulator of epithelial differentiation and EMT in chronic inflammation

This review underscores the pivotal role of oral keratinocytes in regulating inflammatory responses within the oral mucosa. The differentiation status of these cells directly influences the integrity of epithelial junctions, the magnitude of inflammatory responses, and the expression of key regulatory molecules such as IRF6, NFκB, and CCL5.

In addition to its established role in epithelial morphogenesis, IRF6 has been identified as a regulator of immune responses in keratinocytes. It promotes terminal differentiation, suppresses proliferation, and negatively regulates p63 by repressing pro-proliferative genes while upregulating differentiation markers (e.g. Transglutaminase 1 (TGM1), Involucrin (IVL), and Keratin 13 (KRT13)).^42,46,65,66 IRF6 has also been implicated in tumor suppression through its interaction with factors such as Maspin and by modulating epithelial differentiation pathways.^48,49 Notably, Ke et al.⁶⁷ demonstrated that IRF6 regulates EMT-related genes, including Transforming Growth Factor Beta-3 (TGFβ3) and snail family transcriptional repressor 2 (SNAI2), during palatal development, highlighting its broader role in epithelial plasticity.

EMT, characterized by the loss of apicobasal polarity, decreased E-cadherin expression, and acquisition of mesenchymal markers like vimentin and fibronectin^68,69 occurs during embryonic development, wound repair, and cancer progression.⁶⁹ Previous findings support the role of IRF6 in regulating EMT in oral keratinocytes.⁶⁷ Girousi et al.⁷⁰ showed that IRF6-deficient keratinocytes exhibited disorganized colony architecture, reduced E-cadherin at junctions, delayed migration, and impaired stratification in both 2D and 3D models. These alterations suggest increased epithelial reactivity and permeability, conditions that can promote chronic inflammation.^42,71 Moreover, irf6 knockout keratinocytes demonstrated significantly impaired calcium-induced differentiation, with reduced expression of those markers previously mentioned, TGM1, IVL, and KRT13,⁷⁰ suggesting a potential shift toward EMT. As expected, this calcium-induced differentiation response was absent in IRF6-ablated keratinocytes. However, although partial rescue was achieved by ectopic IRF6 expression, low levels of exogenous IRF6 were insufficient to restore IVL and TGM1 expression, suggesting that a threshold level of IRF6 is required for full functional activity.⁷⁰ These findings emphasize IRF6’s critical function in maintaining epithelial stability and suggest that its dysregulation may drive inflammation-associated epithelial remodeling and predispose tissues to malignant transformation.

Chronic inflammation and hypoxia: The dual role of CCL5 in oral carcinogenesis

Chronic inflammation and cancer are closely linked.^72,73 The interaction between IRF6 and TLR2 signaling provides new insights into the mechanisms by which oral keratinocytes regulate immune responses. In epithelial cells, stimulation with Lipopolysaccharide (LPS) and Fibroblast Stimulating Lipopeptide 1 (FSL-1) activated CCL5 expression, a process directly influenced by the phosphorylation status of IRF6.⁴³ Simultaneously, TLR activation also triggers NFκB signaling, supporting the role of oral keratinocytes as key coordinators of the inflammatory response. The interplay between IRF6, CCL5, and NFκB reveals a tightly coordinated regulatory mechanism that amplifies and sustains inflammation within the oral mucosa.

NFκB plays a central role by establishing a positive feedback loop that amplifies inflammatory signaling. It regulates the transcription of numerous genes involved in inflammation, including pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNFα), chemokines (IL-8, MIP-1α, MCP-1, CCL5), adhesion molecules (ICAM, VCAM, E-selectin), inducible enzymes (COX-2, iNOS), and EMT-related transcription factors such as Snail.^74,75 Taking together, these responses contribute to tissue remodeling, hypoxia, and the potential activation of EMT, linking chronic inflammation to disease progression and possibly malignant transformation.^75,76 Inflammatory mediators such as soluble factors, oxidative stress or hypoxia can foster the acquisition of EMT-like features in cancer cells and reduce the susceptibility of carcinoma cells to lymphocytes, natural killer cells, lymphokine activated killer.⁶⁹

Hypoxia is a hallmark of both physiological and pathological conditions. Tissues exposed to the external environment—such as those in the upper airway—naturally experience fluctuating oxygen levels. In pathological contexts, however, hypoxia tends to become more severe, particularly in inflamed tissues where edema, vasculitis, and the recruitment of oxygen-consuming immune cells exacerbate oxygen deprivation.⁷⁷ The transcription factor hypoxia-inducible factor 1-alpha (HIF-1α) is the principal regulator of cellular adaptation to hypoxia. It activates a broad range of genes involved in survival, metabolism, and inflammation.⁷⁸ Members of the HIF transcription factor family are essential for cancer cell adaptation to hypoxic environments, as their activation leads to the reprogramming of metabolic pathways, protein synthesis, and cell cycle progression.⁷⁶

The transition from chronic inflammation to malignancy is a complex process that involves multiple factors. Within the oral cavity, one of these key factors is microbial dysbiosis. Olsen and Yilmaz⁷⁹ reported an association between periodontitis and increased risk of oral, gastrointestinal, and pancreatic cancers, suggesting that chronic inflammation and dysbiosis are significant drivers of orodigestive carcinogenesis. Porphyromonas gingivalis, a key pathogen in periodontal disease, has been specifically linked to gingival squamous cell carcinoma.⁸⁰ Interestingly, LPS of P. gingivalis—previously shown to induce IRF6-mediated differentiation—also triggers CCL5 expression.⁵⁷ These reports provide evidence to link microbial stimuli to inflammatory signaling and epithelial transformation.

Of the highlighted chemokines previously, CCL5 is of interest since it plays a key role in immune responses by acting as a potent chemoattractant for various immune cells and by modulating inflammatory signaling pathways.^58,59 IRF6 was found to influence the regulation of CCL5,⁴³ a notable finding given CCL5’s established function in T cell recruitment and its involvement in sustaining chronic inflammation.⁶⁴ This regulatory relationship suggests that IRF6 may be involved in suppressing inflammation-induced EMT, particularly under chronic inflammatory conditions or in the early stages of tumorigenesis. However, the role of CCL5 remains complex and context dependent. While CCL5 can act as an immune-protective factor in certain settings, its overexpression has also been associated with poor prognosis in others. Notably, CCL5 expression is often enhanced under hypoxic conditions,⁵⁸ which are common in inflamed or tumorigenic tissues. Therefore, the function of CCL5 appears to vary depending on the microenvironment and disease stage. A deeper understanding of this dual role will be essential for improving the diagnosis and treatment of oral potentially malignant disorders (OPMDs) and for preventing the malignant transformation of chronic inflammatory conditions.

The ability of cells to adapt their metabolic activity under hypoxic conditions helps explain the activation of distinct signaling pathways in both physiological and pathological contexts. For example, CCL5 has been identified as an immune-protective factor contributing to immune surveillance in solid tumors.⁸¹ However, overexpression of the CCR5/CCL5 axis has also been linked to poor clinical outcomes in OSCC, including regional lymph node metastasis and decreased overall survival.⁸²

The CCL5/CCR5 axis also contributes to the stabilization and accumulation of HIF-1α, although this effect is highly dependent on the oxygen levels present in the microenvironment.⁵⁹ Under conditions, HIF-1α is hydroxylated by prolyl hydroxylases (PHDs) and subsequently ubiquitinated by the von Hippel-Lindau (VHL) protein, leading to its proteasomal degradation. In contrast, under hypoxic conditions, reduced oxygen availability inhibits PHD activity, resulting in HIF-1α stabilization and accumulation.⁸³ Once stabilized, HIF-1α forms a transcriptional complex that binds to hypoxia response elements (HREs) in the promoters of target genes. This complex activates the expression of genes involved in metabolic reprogramming (e.g. GLUT1), angiogenesis (e.g. VEGF), and regulation of the inflammatory profile.^59,83

This mechanism is particularly relevant in oral submucous fibrosis (OSF), another OPMD characterized by persistent hypoxia and epithelial atrophy. OSF has been described as an “overhealing wound,” in which vascular collapse and excessive fibrotic remodeling generate a chronically hypoxic microenvironment that drives malignant potential.^84,85 The resulting epithelial atrophy and loss of barrier function render the mucosa more vulnerable to physical and chemical insults, further increasing susceptibility to malignant transformation.⁸⁴

A translational framework for chronic inflammation-driven epithelial disruption in oral mucosa

Building on the findings presented in this review and the current scientific literature, we propose a model wherein the oral mucosa, under physiological and normoxic conditions, maintains a highly regulated keratinocyte differentiation program. This culminates in the terminal differentiation of keratinocytes, marked by nuclear loss in the stratum corneum (Figure 1(a)). In this state, the epithelium forms an effective physical and immunological barrier, reinforced by strong intercellular junctions and elevated E-cadherin expression (Figure 1(b)).

Figure 1.

Schematic histological and cellular structure of a healthy, immunocompetent and normoxic conditions in oral epithelium. The figure illustrates a hypothetical architecture and schematic representation of oral keratinocyte immune signaling under normoxic conditions. (a) Healthy oral epithelium, characterized by a well-organized stratified squamous structure, strong cell-cell adhesion, and complete differentiation of keratinocytes that ends in nuclear loss in the outmost layer in most oral mucosa. (b) This diagram illustrates the innate immune response of oral keratinocytes under normal oxygen levels (Normoxia). Upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), Toll-like receptor 2 (TLR2) activates downstream signaling through MyD88 and IRAK1. This leads to the activation of transcription factors IRF6 and NFκB. Phosphorylated IRF6 translocate to the nucleus, where it regulates the expression of differentiation markers (TGM1, IVL, KRT13) and suppresses the proliferation-associated gene p63. Concurrently, IRF6 enhanced by NFκB induces the transcription of pro-inflammatory cytokines and chemokines such as CCL5, IL-1, IL-2, IL-6, IL-8, TNFα, and MIP-1α, which recruit immune cells to the site of inflammation. Under normoxic conditions, HIF-1α is hydroxylated by prolyl hydroxylase domain proteins (PHDs) and targeted for degradation by the von Hippel–Lindau (VHL) complex, thereby preventing hypoxia-associated responses.

Well-differentiated keratinocytes also exhibit immunocompetence. Upon exposure to microbial or danger-associated signals such as LPS or FSL-1, TLR2 is activated, triggering the MyD88–IRAK1 signaling cascade. This leads to the phosphorylation of IRF6 and parallel activation of NFκB. Both transcription factors translocate into the nucleus, where they induce the expression of inflammatory mediators such as CCL5. IRF6 activation simultaneously represses the proliferative marker p63 and promotes the expression of differentiation-associated genes including TGM1, Involucrin, Keratin 13, TGFβ3, and SNAI2, thereby maintaining epithelial integrity (Figure 1(b)).

Under the persistent inflammatory stimuli present in oral lichen planus (OLP) and other potentially malignant disorders (OPMDs), sustained CCL5 expression and immune cell infiltration can lead to reduced IRF6 expression (Figure 2(a)). This may result from epigenetic modifications or a compensatory tissue repair response. The downregulation of IRF6 contributes to decreased E-cadherin and other differentiation-related proteins, weakening epithelial cohesion and barrier function (Figure 2(b) and (e)). Poorly differentiated keratinocytes at the epithelial surface may exhibit heightened reactivity, further amplifying inflammation (Figure 2(b)).

Figure 2.

Schematic representation of the histological progression from chronic inflammation to carcinogenesis and oral keratinocyte inflammatory signaling under hypoxic conditions in oral epithelium. The figure illustrates a hypothetical explanation and the sequential changes in oral epithelial architecture associated with chronic inflammation and the potential progression toward squamous cell carcinoma. (a) Low IRF6 levels disrupts keratinocyte differentiation, leading to weaker epithelial structure, irregular nuclei retention in the superficial layers, and compromised barrier function that perhaps generates a more reactive keratinocyte reaction and differentiation affectation. (b) Inflammation can appear and become chronic by persistent exposure to harmful stimuli (e.g. tobacco, alcohol, and trauma followed by dysbiosis of a microbiome more productor of lactate) that perpetuates inflammation. (c) Inflammatory infiltrated accumulate, junctional integrity is lost and keratinocytes become reactive, promoting a hypoxic environment. In the healing process, persistent inflammation and hypoxia induce activation of EMT pathways. This process is marked by the loss of epithelial markers, acquisition of mesenchymal traits, and increased motility and invasiveness of keratinocytes. (d) Finally, the sum of the following events: disrupted differentiation, chronic inflammation and EMT results in neoplastic transformation characterized by uncontrolled proliferation, abnormal architecture, and immune cell infiltration. (e) This diagram illustrates the dysregulated inflammatory response of oral keratinocytes under hypoxic conditions. In environments where oxygen levels are diminished such as in chronic inflammation and are exacerbated by local conditions, key signaling pathways shift in response to cellular stress. Stimulation of TLR2 by PAMPs or DAMPs continues to activate MyD88 and IRAK1, triggering NFκB signaling. This results in the upregulation of inflammatory mediators including IL-1, IL-2, IL-6, IL-8, TNFα, and chemokines such as CCL5. Simultaneously, IRF6 is degraded via ubiquitination and proteasomal targeting, leading to reduced differentiation signals (e.g. KRT13, IVL, TGM1), release of p63-mediated proliferative programs, in combination with the expression of EMT-related markers such as VCAM, iNOS, COX-2, and E-selectin that contributes to epithelial disruption. The loss of IRF6 weakens epithelial integrity, decrease levels of E cadherin and contributes to a proinflammatory and protumorigenic state. HIF-1α accumulates due to reduced oxygen-dependent hydroxylation by PHDs and evasion of degradation by the VHL complex. Stabilized HIF-1α translocates to the nucleus, where it binds HREs, upregulating genes like GLUT1, VEGF, and IGF2. These adaptations promote angiogenesis, metabolic reprogramming, and shift toward an immune-regulatory phenotype, including Treg recruitment. This cascade fosters a microenvironment conducive to immune evasion, EMT, and potentially malignant transformation, linking unresolved chronic inflammation to cancer progression.

Chronic inflammation also fosters a hypoxic and acidic microenvironment (Figure 2(b)), exacerbated by external factors such as tobacco smoking, alcohol consumption, trauma, and microbial dysbiosis (Figure 2(b)). These conditions support the growth of lactate-producing bacteria, contributing to tissue acidification and perpetuation of inflammation. Hypoxia also promotes proteasomal degradation of IRF6, further reducing its regulatory influence on p63 and epithelial differentiation. Simultaneously, pro-inflammatory and adhesion molecules such as ICAM, VCAM, COX-2, iNOS, and E-selectin become upregulated, driving further epithelial damage (Figure 2(e)).

In parallel, reduced oxygen availability inhibits the activity of prolyl hydroxylases, resulting in the stabilization of hypoxia-inducible factor 1α (HIF-1α). Stabilized HIF-1α translocates into the nucleus, where it binds hypoxia-responsive elements (HREs) and activates the transcription of genes involved in metabolic reprogramming (e.g. GLUT1), angiogenesis (e.g. VEGF), and immune regulation. These changes contribute to the induction of EMT (Figure 2(c)), characterized by the loss of apicobasal polarity, downregulation of epithelial markers, and increased keratinocyte invasiveness, ultimately promoting malignant transformation and progression to OSCC (Figure 2(d)).

Taken together, this model elucidates the molecular and cellular mechanisms through which chronic inflammation disrupts keratinocyte homeostasis and promotes epithelial remodeling. By focusing on the TLR2-IRF6-CCL5 axis and the impact of hypoxia, this framework highlights potential therapeutic targets to restore epithelial integrity and immune balance in OPMDs.

Future studies should focus on validating this model using patient-derived tissues, assessing dynamic IRF6 and CCL5 expression profiles, and evaluating therapeutic interventions such as IRF6 supplementation or CCL5/CCR5 antagonism (e.g. Maraviroc). These insights may contribute to early diagnosis, better prognostication, and prevention of malignant transformation in chronic inflammatory oral diseases.

Future perspectives

This review has outlined a mechanistic framework in which chronic inflammation, hypoxia, and epithelial plasticity converge to destabilize oral keratinocyte homeostasis. The TLR2–IRF6–CCL5 axis, together with hypoxia-induced stabilization of HIF-1α, emerges as a central pathway linking persistent inflammatory signaling to impaired differentiation, EMT, and malignant progression. While this framework provides a valuable lens for understanding the molecular underpinnings of oral carcinogenesis, it also underscores broader clinical implications where knowledge remains incomplete. One example is OSF, an OPMD characterized by progressive fibrosis, vascular collapse, and epithelial atrophy. OSF has been described as an “overhealing wound,” where recurrent trauma and chronic irritation lock the mucosa in a cycle of perpetual repair.⁸⁴ Hypoxia is an obligatory feature of this process, driving both fibrotic remodeling and malignant risk. More recently, hypoxia-driven epigenetic modifications, such as DNA methylation, histone alterations, and microRNA dysregulation, were shown to sustain myofibroblast activation and accelerate disease progression.⁸⁵ Gene–gene crosstalk, including PTEN with TGF-β and NFκB, further reinforce fibrosis and carcinogenic risk. Within the model proposed here, OSF exemplifies how hypoxia reduces IRF6 activity while amplifying CCL5 expression, fostering a pro-inflammatory, EMT-prone epithelial state. Therefore, OSF is not only a fibrotic disorder but also a clinically relevant model for studying inflammation- and hypoxia-driven carcinogenesis.

Another key aspect highlighted in this review is the link between IRF6 and microbial signaling. We focused on the capacity of IRF6 to induce CCL5 expression, a relationship that becomes particularly pronounced following TLR2 stimulation, a pathway engaged by specific microbial ligands. This emphasizes the role of pathogens and their metabolites in promoting oral carcinogenesis. Indeed, recent human studies have identified distinct microbiome profiles associated with oral cancer.^86,87 Dysbiotic microbial communities, particularly in an atrophic and hypoxic epithelium, may compromise barrier integrity, heightening susceptibility to malignant transformation.

From a translational standpoint, the concept of field cancerization across the aerodigestive tract is also relevant. Clinical evidence indicates a two-way relationship between head and neck cancers and esophageal carcinoma, with patients affected by one malignancy at higher risk of developing a second primary tumor in contiguous mucosa.⁸⁸ This suggests that dysregulated epithelial signaling—potentially involving IRF6 instability and sustained CCL5 expression—may not be restricted to the oral cavity but reflect a broader vulnerability across mucosal fields. Such insights highlight the importance of developing integrated surveillance strategies for patients with oral cancer and OPMDs, extending beyond the primary lesion to adjacent mucosal sites.

Despite these advances, important uncertainties and limitations remain. Most investigations of IRF6 in keratinocyte biology and cancer have relied on in vitro models, with limited validation in patient-derived tissues. Interestingly, IRF6 has also been recently associated with ovarian cancer development and progression,⁸⁹ reinforcing IRF6 broader relevance in oncogenesis. However, its specific role in oral cancer remains unclear. The dynamic regulation of IRF6 phosphorylation, its degradation under hypoxic conditions, and its interaction with CCL5 in human OPMDs and OSCC require systematic study. Moreover, while modulation of IRF6 activity appears promising as a therapeutic strategy, it is unlikely to be sufficient on its own. Effective interventions will likely need combinatorial approaches targeting IRF6 alongside hypoxia signaling, microbial dysbiosis, and chronic inflammation.

Moving forward, advancing this framework will require closer collaboration between researchers and clinicians. Studies using patient-derived tissues are essential to validate the IRF6–CCL5–TLR2 axis and clarify its clinical relevance in oral cancer. Only by integrating molecular insights with real-world clinical data can we determine whether targeting this pathway offers tangible benefits for diagnosis, prognosis, and therapy in chronic inflammatory oral diseases.

Conclusion

Oral keratinocytes are increasingly recognized as active regulators of immune responses and epithelial integrity, particularly under chronic inflammatory conditions. This review proposes a mechanistic model in which IRF6 functions as a central mediator linking epithelial differentiation, immune signaling, and inflammation resolution in the oral mucosa. Through its regulation of p63 and downstream effectors like CCL5, IRF6 maintains a homeostatic balance between epithelial renewal and immune activation.

Chronic inflammation is a key contributor to epithelial dysfunction and malignant transformation in the oral cavity. This review proposes a model in which oral keratinocytes act not only as structural components but also as active regulators of immune signaling, primarily through the TLR2–IRF6–CCL5 axis. Under homeostatic conditions, IRF6 supports terminal differentiation and immune balance. However, in the presence of sustained inflammation, hypoxia, and environmental stressors, IRF6 expression is diminished, leading to impaired epithelial integrity, exaggerated inflammatory responses, and activation of EMT-associated pathways.

By integrating molecular pathways of inflammation, differentiation, and hypoxic adaptation, the proposed model offers a conceptual framework for understanding disease progression in oral potentially malignant disorders (OPMDs). It also points toward novel therapeutic targets, including IRF6 stabilization and CCR5/CCL5 pathway modulation, with potential to prevent malignant transformation.

Further research using patient-derived tissues and in vivo models is warranted to validate this model and explore its translational applications. These efforts may ultimately contribute to improved diagnostic, prognostic, and therapeutic strategies for managing chronic inflammatory oral diseases and reducing oral cancer risk.

Footnotes

Author contributions

Y.A.O-O: Conceptualization, Writing—original draft. M.T.P-S: Conceptualization, Writing—review & editing.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Yuliana Andrea Osorio-Osorno

Monica Tatiana Parada-Sanchez

References

Sarode

Maniyar

Sarode

, et al. (2020) Epidemiologic aspects of oral cancer. Disease-a-Month 66(12): 100988.

Chamoli

Gosavi

Shirwadkar

, et al. (2021) Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics. Oral Oncology 121: 105451.

Bugshan

Farooq

(2020) Oral squamous cell carcinoma: Metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis. F1000Research 9: 229.

Tran

Maddineni

Arnaud

, et al. (2023) Oral cavity cancer in young, non-smoking, and non-drinking patients: A contemporary review. Critical Reviews in Oncology/Hematology 190: 104112.

Wang

Tang

Pang

, et al. (2019) The maintenance of an oral epithelial barrier. Life Sciences 227: 129–136.

Goto

Kiyono

(2012) Epithelial barrier: An interface for the cross-communication between gut flora and immune system. Immunological Reviews 245(1): 147–163.

Joosten

LAB

Abdollahi-Roodsaz

Dinarello

, et al. (2016) Toll-like receptors and chronic inflammation in rheumatic diseases: New developments. Nature Reviews Rheumatology 12: 344–357.

Shaik-Dasthagirisaheb

Huang

Weinberg

, et al. (2015) Aging and contribution of MyD88 and TRIF to expression of TLR pathway-associated genes following stimulation with Porphyromonas gingivalis. Journal of Periodontal Research 50(1): 89–102.

Saikh

(2021) MyD88 and beyond: A perspective on MyD88-targeted therapeutic approach for modulation of host immunity. Immunologic Research 69(2): 117–128.

10.

Antiguas

DeMali

Dunnwald

(2022) IRF6 regulates the delivery of E-cadherin to the plasma membrane. Journal of Investigative Dermatology 142(2): 314–322.

11.

Osorio-Osorno

Parada-Sanchez

Arango

, et al. (2020) Oral lichen planus: A chronic inflammatory model to study the regulation of the Toll-like receptor signaling in oral keratinocytes. Journal of Oral Biosciences 62(2): 115–122.

12.

Groeger

Meyle

(2015) Epithelial barrier and oral bacterial infection. Periodontology 2000 69(1): 46–67.

13.

Dale

Salonen

Jones

(1990) New approaches and concepts in the study of differentiation of oral epithelia. Critical Reviews in Oral Biology and Medicine 1(3): 167–190.

14.

Silverman

(1967) Ultrastructure studies of oral mucosa. I. Comparison of normal and hyperkeratotic human buccal epithelium. Journal of Dental Research 46(6): 1433–1443.

15.

Chen

Ahmad

, et al. (2015) Biomechanics of oral mucosa. Journal of the Royal Society, Interface 12(109): 20150325.

16.

Evans

(2017) Treating scars on the oral mucosa. Facial Plastic Surgery Clinics of North America 25(1): 89–97.

17.

Casariego

Pérez

(2017) Knowledge of oral mucosa as a tarjet organ to induce pharma-immunotherapy. Archivos de alergia e inmunología clinica 48: 9–20.

18.

Kirschner

Rühl

(1969) Radioautographic studies with 3H-thymidine on the regeneration of epithelial attachments. Deutsche zahnarztliche Zeitschrift 24(9): 816–824.

19.

Polimeni

Xiropaidis

Wikesjö

(2006) Biology and principles of periodontal wound healing/regeneration. Periodontology 2000 41(24): 30–47.

20.

Shin

Fogg

Margolis

(2006) Tight junctions and cell polarity. Annual Review of Cell and Developmental Biology 22(1): 207–235.

21.

Itoh

Bissell

(2003) The organization of tight junctions in epithelia: Implications for mammary gland biology and breast tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 8(4): 449–462.

22.

Baumgart

Dignass

(2002) Intestinal barrier function. Current Opinion in Clinical Nutrition and Metabolic Care 5(6): 685–694.

23.

Presland

Jurevic

(2002) Making sense of the epithelial barrier: What molecular biology and genetics tell us about the functions of oral mucosal and epidermal tissues. Journal of Dental Education 66(4): 564–574.

24.

Lloyd

Cheng

, et al. (1995) The basal keratin network of stratified squamous epithelia: Defining K15 function in the absence of K14. Journal of Cell Biology 129(5): 1329–1344.

25.

Harrison

Brasch

Lasso

, et al. (2016) Structural basis of adhesive binding by desmocollins and desmogleins. Proceedings of the National Academy of Sciences 113(26): 7160–7165.

26.

Harris

TJC

Tepass

(2010) Adherens junctions: From molecules to morphogenesis. Nature Reviews Molecular Cell Biology 11(7): 502–514.

27.

Novak

Haberstok

Bieber

, et al. (2008) The immune privilege of the oral mucosa. Trends in Molecular Medicine 14(5): 191–198.

28.

Muthukuru

Jotwani

Cutler

(2005) Oral mucosal endotoxin tolerance induction in chronic periodontitis. Infection and Immunity 73(2): 687–694.

29.

Stanimirovic

Zeljic

Jankovic

, et al. (2013) TLR2, TLR3, TLR4 and CD14 gene polymorphisms associated with oral lichen planus risk. European Journal of Oral Sciences 121(5): 421–426.

30.

Amin

Yussif

Ahmed

(2020) The effect of smoking on clinical presentation and expression of TLR-2 and CD34 in Oral lichen Planus patients: Clinical and immunohistochemical study. BMC Oral Health 20(1): 129.

31.

Rich

Hussaini

Parachuru

VPB

, et al. (2014) Toll-like receptors and cancer, particularly oral squamous cell carcinoma. Frontiers in Immunology 5: 464.

32.

Ritter

Mennerich

Weith

, et al. (2005) Characterization of Toll-like receptors in primary lung epithelial cells: Strong impact of the TLR3 ligand poly(I:C) on the regulation of Toll-like receptors, adaptor proteins and inflammatory response. Journal of Inflammation 2(1): 16.

33.

Lowe

Crother

Rabizadeh

, et al. (2010) Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One 5(9): e13027.

34.

Janardhanam

Prakasam

Swaminathan

, et al. (2012) Differential expression of TLR-2 and TLR-4 in the epithelial cells in oral lichen planus. Archives of Oral Biology 57(5): 495–502.

35.

Zeng

Yang

Chen

, et al. (2018) Porphyromonas gingivalis ipopolysaccharide induces over production of CC chemokine ligand 2 via Toll-like receptor-4 in oral lichen planus. Journal of Oral Pathology & Medicine 47(2): 166–172.

36.

Sutmuller

RPM

(2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. Journal of Clinical Investigation 116(2): 485–494.

37.

Parada-Sanchez

Chu

Cox

, et al. (2017) Disrupted IRF6-NME1/2 complexes as a cause of cleft lip/palate. Journal of Dental Research 96(11): 1330–1338.

38.

Kondo

Schutte

Richardson

, et al. (2011) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics 32(2): 285–289.

39.

Bezerra

da Silva

HPV

Bortolin

, et al. (2020) IRF6 polymorphisms in Brazilian patients with non-syndromic cleft lip with or without palate. Brazilian Journal of Otorhinolaryngology 86(6): 696–702.

40.

Jones

Canady

Brookes

, et al. (2011) Wound complications following cleft repair in children with Van der Woude Syndrome. The Journal of Craniofacial Surgery 21(5): 1350–1353.

41.

Zengin

Ekinci

Kucukkose

, et al. (2015) IRF6 is involved in the regulation of cell proliferation and transformation in MCF10A cells downstream of notch signaling. PLoS One 10(7): 1–15.

42.

Richardson

Dixon

Malhotra

, et al. (2006) Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nature Genetics 38(11): 1329–1334.

43.

Kwa

Nguyen

Huynh

, et al. (2014) Interferon regulatory factor 6 differentially regulates toll-like receptor 2-dependent chemokine gene expression in epithelial cells. Journal of Biological Chemistry 289(28): 19758–19768.

44.

Bailey

Abbott

Margaryan

, et al. (2008) Interferon regulatory factor 6 promotes cell cycle arrest and is regulated by the proteasome in a cell cycle-dependent manner. Molecular and Cellular Biology 28(7): 2235–2243.

45.

Biggs

Rhea

Schutte

, et al. (2012) Interferon regulatory factor 6 is necessary, but not sufficient, for keratinocyte differentiation. Journal of Investigative Dermatology 132(1): 50–58.

46.

Restivo

Nguyen

Dziunycz

, et al. (2011) IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. The EMBO Journal 30: 4571–4585.

47.

Botti

Spallone

Moretti

, et al. (2011) Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas. Proceedings of the National Academy of Sciences of the United States of America 108(33): 13710–13715.

48.

Bailey

Khalkhali-Ellis

Kondo

, et al. (2005) Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: Identification of novel serpin partnership. The Journal of Biological Chemistry 48(Suppl. 2): 1–6.

49.

Bailey

Hendrix

MJC

(2008) IRF6 in development and disease: A mediator of quiescence and differentiation. Cell Cycle 7(13): 1925–1930.

50.

Rotondo

Borghi

Selvatici

, et al. (2016) Hypermethylation-induced inactivation of the IRF6 gene as a possible early event in progression of vulvar squamous cell carcinoma associated with lichen sclerosus. JAMA Dermatology 152(8): 928–933.

51.

Ainouze

Rochefort

Parroche

, et al. (2018) Human papillomavirus type 16 antagonizes IRF6 regulation of IL-1β. PLoS Pathogens 14(8): e1007158.

52.

Cheng

Wang

, et al. (2019) IRF6 is directly regulated by ZEB1 and ELF3, and predicts a favorable prognosis in gastric cancer. Frontiers in Oncology 9: 1–12.

53.

Parada Sanchez

(2012) Dissecting the Role of the Major Cleft Gene, IRF6, in Primary Palatal Epithelia. Seattle: University of Washington.

54.

Kwa

Scholz

Reynolds

(2016) RIPK4 activates an IRF6-mediated proinflammatory cytokine response in keratinocytes. Cytokine 83: 19–26.

55.

Ramnath

Tunny

Hohenhaus

, et al. (2015) TLR3 drives IRF6-dependent IL-23p19 expression and p19/EBI3 heterodimer formation in keratinocytes. Immunology and Cell Biology 93(9): 771–779.

56.

Huynh

Scholz

, et al. (2016) IRF6 regulates the expression of IL-36γ by human oral epithelial cells in response to Porphyromonas gingivalis. The Journal of Immunology 196(5): 2230–2238.

57.

Huynh

Scholz

, et al. (2017) Interferon regulatory factor 6 promotes keratinocyte differentiation in response to Porphyromonas gingivalis. Infection and Immunity 85(5): e00858-16.

58.

Aldinucci

Borghese

Casagrande

(2020) The ccl5/ccr5 axis in cancer progression. Cancers 12: 1–30.

59.

Zeng

Lan

Wei

, et al. (2022) CCL5/CCR5 axis in human diseases and related treatments. Genes & Diseases 9(1): 12–27.

60.

Roscic-Mrkic

Fischer

Leemann

, et al. (2003) RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement. Blood 102(4): 1169–1177.

61.

Chitadze

Wehkamp

Janssen

, et al. (2021) The serine protease CD26/DPP4 in non-transformed and malignant T cells. Cancers (Basel) 13(23): 5947.

62.

Proudfoot

AEI

Buser

Borlat

, et al. (1999) Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. Journal of Biological Chemistry 274(45): 32478–32485.

63.

Proost

De Meester

Schols

, et al. (1998) Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Journal of Biological Chemistry 273(13): 7222–7227.

64.

Marques

Guabiraba

Russo

, et al. (2013) Targeting CCL5 in inflammation. Expert Opinion on Therapeutic Targets 17(12): 1439–1460.

65.

Thomason

Zhou

Kouwenhoven

, et al. (2010) Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice. Journal of Clinical Investigation 120(5): 1561–1569.

66.

Moretti

Marinari

Lo Iacono

, et al. (2010) A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias. Journal of Clinical Investigation 120(5): 1570–1577.

67.

Xiao

Chen

, et al. (2015) IRF6 is the mediator of TGFβ3 during regulation of the epithelial mesenchymal transition and palatal fusion. Scientific Reports 5: 12791.

68.

González-González

Ortiz-Sarabia

Molina-Frechero

, et al. (2021) Epithelial-mesenchymal transition associated with head and neck squamous cell carcinomas: A review. Cancers 13(12): 3027.

69.

Ribatti

Tamma

Annese

(2020) Epithelial-mesenchymal transition in cancer: A historical overview. Translational Oncology 13(6): 100773.

70.

Girousi

Muerner

Parisi

, et al. (2021) Lack of IRF6 disrupts human epithelial homeostasis by altering colony morphology, migration pattern, and differentiation potential of keratinocytes. Frontiers in Cell and Developmental Biology 9: 718066.

71.

Ingraham

Kinoshita

Kondo

, et al. (2006) Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nature Genetics 38(11): 1335–1340.

72.

Singh

Baby

Rajguru

, et al. (2019) Inflammation and cancer. Annals of African Medicine 18(3): 121.

73.

Fernandes

Inchakalody

Bedhiafi

, et al. (2024) Chronic inflammation and cancer; the two sides of a coin. Life Sciences 338: 122390.

74.

Blackwell

Christman

(1997) The role of nuclear factor-κ B in cytokine gene regulation. American Journal of Respiratory Cell and Molecular Biology 17(1): 3–9.

75.

López-Nouoa

Nieto

(2009) Inflammation and EMT: An alliance towards organ fibrosis and cancer progression. EMBO Molecular Medicine 1: 303–314.

76.

Chen

Han

, et al. (2023) Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy 8(1): 70.

77.

Shen

Ojo

Ding

, et al. (2024) HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nature Communications 15(1): 9394.

78.

Semenza

(2003) Targeting HIF-1 for cancer therapy. Nature Reviews Cancer 3: 721–732.

79.

Olsen

Yilmaz

(2019) Possible role of Porphyromonas gingivalis in orodigestive cancers. Journal of Oral Microbiology 11(1): 1563410.

80.

Katz

Onate

Pauley

, et al. (2011) Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. International Journal of Oral Science 3(4): 209–215.

81.

Dangaj

Bruand

Grimm

, et al. (2019) Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell 35(6): 885–900.e10.

82.

González-Arriagada

Coletta

Lozano-Burgos

, et al. (2023) CR5/CCL5 axis is linked to a poor outcome, and inhibition reduces metastasis in oral squamous cell carcinoma. Journal of Cancer Research and Clinical Oncology 149(19): 17335–17346.

83.

McGettrick

O’Neill

LAJ

(2020) The role of HIF in immunity and inflammation. Cell Metabolism 32: 524–536.

84.

Sharma

Shetty

Radhakrishnan

(2018) Oral submucous fibrosis as an overhealing wound: Implications in malignant transformation. Recent Patents on Anti-Cancer Drug Discovery 13(3): 272–291.

85.

Sharma

Shetty

Alhedyan

, et al. (2025) Interplay of epigenetics and epistasis drives oral submucous fibrosis. Discover Applied Sciences 7(8): 878.

86.

Hashimoto

Shimizu

Ueda

, et al. (2022) Feasibility of oral microbiome profiles associated with oral squamous cell carcinoma. Journal of Oral Microbiology 14(1): 2105574.

87.

Cai

Zhu

Mou

, et al. (2024) Integrative analysis reveals associations between oral microbiota dysbiosis and host genetic and epigenetic aberrations in oral cavity squamous cell carcinoma. NPJ Biofilms and Microbiomes 10(1): 39.

88.

Sharma

Radhakrishnan

(2019) A two-way relationship between the head and neck cancer and esophageal cancer. Oral Oncology 97: 139–140.

89.

Hong

Sang

, et al. (2024) Identification and validation of IRF6 related to ovarian cancer and biological function and prognostic value. Journal of Ovarian Research 17(1): 64.