Distinct Expression Patterns of miR-21-5p and miR-21-3p in Oral Epithelial Dysplasia and Early Oral Squamous Cell Carcinoma

Background/Objectives: Oral leukoplakia (OL) is a common oral potentially malignant disorder, but prediction of malignant progression remains challenging. This study investigated miR-21-5p and miR-21-3p expression in healthy oral mucosa, OL with epithelial dysplasia, and early oral squamous cell carcinoma (OSCC), together with clinicopathological associations. Methods: Sixty participants were divided into three groups: exposure-free healthy controls (n = 20), histopathologically confirmed OL with epithelial dysplasia (n = 20), and early OSCC (pT1–2N0M0; n = 20). Expression was quantified by RT-qPCR and evaluated using exploratory correlation, regression, Welch’s ANOVA, and Games–Howell comparisons. Results: miR-21-5p differed significantly among groups (p < 0.001). Expression was lower in OL than in healthy controls and early OSCC (both p < 0.001), whereas early OSCC and controls did not differ (p = 0.997). miR-21-5p was inversely associated with dysplasia grade (Spearman’s ρ = −0.54, p = 0.013; unstandardized regression coefficient B = −0.646, p = 0.017). miR-21-3p was numerically higher in early OSCC, but its overall group difference was not significant (p = 0.051). Conclusions: The two mature miR-21 strands showed distinct, non-linear expression patterns across the three groups. These findings are preliminary and hypothesis-generating; the cross-sectional design does not establish predictive or prognostic value, and validation in larger longitudinal cohorts is required. The unexpected miR-21-5p pattern remains unexplained and requires independent validation.