Impact of IL31RA Genetic Variants and Expression on Metastatic Progression in Oral Cavity Squamous Cell Carcinoma

Background: Interleukin-31 receptor alpha (IL31RA) has been implicated in cancer progression and tumor cell migration, but its genetic associations across cancers remain unclear. This study aimed to examine IL31RA polymorphisms in relation to lymph node involvement in oral cavity squamous cell carcinoma (OCSCC). Methods: In this case-control study, 2845 participants were enrolled, including 1352 patients with OCSCC and 1493 cancer-free controls. Associations between IL31RA SNPs and OCSCC susceptibility and clinicopathological characteristics were evaluated. Functional analyses, including cell migration assays, together with bioinformatic database analyses, were performed to investigate the biological significance of IL31RA and genotype-expression correlations. Logistic regression and other appropriate statistical methods were used to assess these associations. Results: IL31RA polymorphisms did not significantly influence OCSCC development. However, subsite-specific analysis revealed that gingival cancer patients with minor alleles at rs6876491 and rs10055201 had significantly higher lymph node involvement rates than wild-type carriers. IL31RA rs6876491 was also an independent predictor of lymph node involvement in gingival cancer after adjusting for clinical characteristics, with adjusted odds ratios of 2.172 (95% Confidence Interval: 1.095-4.310). Bioinformatic databases also showed that minor genotypes correlated with increased IL31RA expression. Patients with higher IL31RA expression tended to have poorer survival in head and neck squamous cell carcinoma (HNSCC) based on TCGA public database analyses (p = 0.053). Moreover, functional studies confirmed that IL31RA overexpression enhanced cellular migration (p < 0.05), while knockdown suppressed migratory capacity (p < 0.05). Conclusions: IL31RA polymorphisms may be associated with an increased propensity for lymph node involvement, particularly in gingival cancer, suggesting that IL31RA may have potential clinical relevance in OCSCC progression.