High SLC7A3 Levels Regulate Migration and Invasion and Predict Better Survival in Oral Squamous Cell Carcinoma

Introduction: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with high rates of recurrence and poor survival. The identification of reliable prognostic biomarkers remains a major challenge. Solute carrier family 7 member 3 (SLC7A3), a cationic amino acid transporter involved in arginine uptake, has been implicated in cancer progression; however, its role in OSCC remains poorly understood. This study investigated the clinical and biological significance of SLC7A3 in OSCC.

Methods: SLC7A3 mRNA expression was analyzed in The Cancer Genome Atlas OSCC cohort (TCGA-OSCC). Protein expression was assessed by immunohistochemistry in a tissue microarray containing 67 primary OSCCs, matched normal oral mucosa, and 18 lymph node metastases. Associations with clinicopathological parameters and survival were evaluated using Kaplan–Meier and Cox regression analyses. Functional assays evaluating apoptosis, cell cycle, migration, and invasion, were performed in HSC3 cells following lentiviral shRNA-mediated SLC7A3 knockdown.

Results: SLC7A3 protein expression was significantly higher in OSCC than in normal oral mucosa (p<0.01). High SLC7A3 levels were associated with early clinical stage (p=0.007), reduced tumor-related mortality (p=0.0004), and significantly improved disease-specific survival (p=0.001). Multivariate Cox regression identified SLC7A3 as an independent prognostic factor (HR=0.18, 95% CI: 0.07–0.50, p=0.001). Functional analyses showed that SLC7A3 knockdown did not alter apoptosis or cell-cycle distribution but significantly enhanced OSCC cell migration and invasion in a dose-dependent manner. Cells with approximately 50% SLC7A3 knockdown exhibited a 100% increase in migration and invasion, whereas cells with near-complete SLC7A3 silencing exhibited a 200% increase compared with control cells.

Conclusions: Our findings demonstrate that high SLC7A3 expression is associated with favorable clinical outcomes in OSCC and may contribute to a less aggressive tumor phenotype by limiting cell migration and invasion. These findings support SLC7A3 as a promising prognostic biomarker and provide insights into the biological role of amino acid transporters in OSCC progression.