Keratin 18 as a cytoskeletal regulator of epithelial–mesenchymal plasticity and prognostic risk in oral squamous cell carcinoma
Abstract
Background/purpose Oral squamous cell carcinoma (OSCC) shows poor survival, and conventional staging does not fully capture biologic aggressiveness. Keratin 18 (KRT18) has been linked to malignant progression in epithelial cancers, but its prognostic and biologic significance in OSCC remains unclear. This study investigated whether KRT18 expression is associated with aggressive invasion patterns and adverse outcomes in OSCC, and whether KRT18 contributes to epithelial–mesenchymal plasticity-related malignant phenotypes. Materials and methods Eighty-eight non-irradiated OSCC specimens obtained after primary surgical resection at National Taiwan University Hospital were analyzed by immunohistochemistry. Associations between KRT18 expression and clinicopathological variables were assessed, and survival was evaluated using Kaplan–Meier and Cox regression analyses. In SAS OSCC cells, KRT18 knockdown, rescue, and overexpression models were established for proliferation, migration, invasion, RNA sequencing, and epithelial–mesenchymal transition (EMT)-marker analyses. Results KRT18 expression was stronger at the invasive front than at the tumor center and correlated with worst pattern of invasion (WPOI) aggressiveness (Spearman r = 0.4799, P < 0.050). KRT18 positivity was associated with metastasis to >2 lymph nodes and independently predicted poorer overall survival. In multivariate analysis, low and high KRT18 expression showed hazard ratios of 6.93 and 5.67, respectively. KRT18 knockdown suppressed proliferation, collective migration, invasion, and the EMT hallmark gene set (normalized enrichment score = −1.41, adjusted P = 0.037). Conclusion KRT18 is a histopathologic and prognostic marker of invasive, high-risk OSCC and appears to support epithelial–mesenchymal plasticity-related malignant behavior. However, forced KRT18 overexpression did not consistently enhance malignant phenotypes, indicating that its biologic effects are context-dependent.