Integrated profiling reveals polarity protein dysregulation during oral cancer progression

Malignant transformation of oral precancerous lesions is a multistep process intricately linked to the disruption of epithelial cell polarity and activation of the epithelial-mesenchymal transition (EMT) program. This study provides an integrated analysis of the polarity regulators PAR3, SCRIBBLE, and DLG7, elucidating their differential expression across normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). By combining histopathological evaluation, immunohistochemical profiling, and whole-transcriptome sequencing, this work offers novel insights into polarity disruption as a driving mechanism in oral tumorigenesis. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens were obtained from 50 habitual tobacco users from West Bengal, India. Sections were stained with hematoxylin and eosin (H&E) for histopathological assessment and classification into normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC) (well- and moderately-differentiated grades). Immunohistochemical (IHC) analysis was conducted to evaluate the expression and localization patterns of the polarity-associated proteins PAR3, SCRIBBLE, and DLG7. Complementing this, whole-transcriptome RNA sequencing was performed on biopsy specimens from an independent cohort of 25 oral cancer patients exhibiting both OED and OSCC lesions, enabling comparative gene expression profiling of the same polarity regulators. Statistical analysis using IBM SPSS (version 20.0) and Chi-square testing revealed a significant reduction or complete loss of PAR3, SCRIBBLE, and DLG7 expression in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), compared to their moderate to strong expression in normal oral mucosa (NOM). This study reveals a striking decline in epithelial polarity protein expression from normal oral mucosa (NOM) to oral epithelial dysplasia (OED), followed by a modest resurgence in oral squamous cell carcinoma (OSCC). The strong concordance between immunohistochemical and transcriptomic profiles-with the exception of DLG7-highlights the disruption of cell polarity as an early and central molecular event in oral carcinogenesis. Collectively, the polarity regulators PAR3, SCRIBBLE, and DLG7 emerge as promising biomarkers for early malignant transformation in oral potentially malignant disorders (OPMDs) and as potential modulators of tumor initiation, progression, and invasive behavior.