Downregulation of Gastrokine 1 expression facilitates tumor progression in urothelial carcinomas

Abstract Objectives Gastrokine 1 (GKN1) is a gastric mucosal protein implicated in epithelial protection and tumor suppression, yet its role in urothelial carcinoma (UC) remains largely unexplored. This study aims to investigate the relationship between GKN1 expression and key clinicopathological parameters in urothelial carcinoma (UC), as well as its potential biological roles. Methods We retrospectively evaluated GKN1 protein expression in tumor and adjacent normal tissues from UC patients using immunohistochemistry and H -score quantification, and further assessed the effects of GKN1 overexpression in several UC-derived cell lines. Results In a cohort comprising upper tract urothelial carcinomas (UTUCs; n =340) and UBUCs ( n =295), high GKN1 protein expression was observed in 77 (22.6 %) and 108 (36.6 %) patients, respectively. Elevated GKN1 levels were significantly associated with favorable clinicopathological parameters and improved patient outcomes. Conversely, GKN1 downregulation correlated with adverse features, including advanced primary tumor stage, nodal metastasis, high histological grade, vascular and perineural invasion, and increased mitotic activity (per 10 high-power fields). Multivariate analysis confirmed that high GKN1 protein expression independently predicted superior disease-specific survival and metastasis-free survival in both the UTUC and UBUC cohorts. Functional assays using UTUC-derived (BFTC909) and UBUC-derived (HT1197, UMUC3) cell lines stably overexpressing GKN1 (GKN1-OE) demonstrated significant suppression of cell migration and invasion. Additionally, conditioned media from GKN1-OE cells markedly inhibited tube formation in human umbilical vein endothelial cells, suggesting an antiangiogenic effect. Conclusions These findings establish GKN1 downregulation as an independent adverse prognostic factor in UC, suggesting that its loss promotes tumor aggressiveness through increased migration, invasion, and angiogenesis.