TRPV4-mediated mechanotransduction of matrix stiffness in the pathogenesis, progression, and malignant transformation of oral submucous fibrosis.

Oral Submucous Fibrosis (OSF) is a long-standing, scarring, inflammatory, potentially malignant disorder induced by areca nut. The transient receptor potential vanilloid 4 (TRPV4), a cation channel permeable to Ca2+, in the TRPV family, is implicated in wound healing, fibrotic changes and malignancy, but its role as a mechanosensor for matrix-stiffness and stress in OSF and its malignant transformation to oral squamous cell carcinoma (OSCC) remains unexplored. The current research sought to investigate the probable involvement of TRPV4 in the onset different OSF stages and its progression to malignancy by immunohistochemistry. Primary antibodies targeting TRPV4 were applied to formalin-fixed paraffin-embedded blocks from ten cases for each category: (a) Stage-1 OSF, (b) Stage 2 OSF, (c) Stage 3 OSF, (d) Stage 4 OSF, (e) OSCC + OSF, and (vi) OSCC - OSF. Additionally, buccal mucosa tissues from ten healthy individuals (NOM) were utilized as control. Mean epithelial quick scores of TRPV4 in NOM, Stages 1-4 OSF, and OSCC with and without OSF were 1.2, 2.5, 3.9, 4.5, 4.6, 5.8, and 6.2, while connective tissue scores were 1.5, 3.5, 4.1, 4.7, 5.3, 5.9, and 6.5, respectively. TRPV4 expression was upregulated in Stages 3 OSF and 4 OSF and OSCC in the presence or absence of OSF compared to NOM and Stage 1 and 2 OSF. This study evaluates the unpaved role of TRPV4 in OSF, mediated by various canonical pathways, contributing to its development by increasing matrix-stiffness and rigidity, which further upregulates TRPV4 expression, ultimately facilitating carcinogenesis.