Clinical and biological significance of TROY (TNFRSF19) splice variants in colorectal cancer.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, and the development of reliable biomarkers for postoperative recurrence risk stratification is urgently required. TROY (also known as tumor necrosis factor receptor superfamily member 19) is a Wnt/β-catenin-regulated receptor implicated in tumor progression; however, to the best of our knowledge, its isoform-specific biological functions and clinical importance have not been defined. The present study examined the roles of the two major splice variants, TROY variant 1 (TROYv1) and TROY variant 2 (TROYv2), in CRC through integrated functional assays and clinical analyses. In vitro, HCT116 cells overexpressing TROYv1 or TROYv2 exhibited significantly greater proliferation than control cells by day 3 (P<0.0001 vs. mock for TROYv1; P=0.001 vs. mock for TROYv2), with TROYv1 promoting a stronger proliferative effect than TROYv2 (P=0.018), whereas no differences in migration or invasion were observed. Clinically, droplet digital PCR enabled quantitative assessment of TROY isoforms in 108 surgically resected tumor specimens obtained from patients with Stage I-III CRC, among whom 20 experienced recurrence and 27 died. High TROYv1 expression was strongly associated with recurrence (P=0.01) and was significantly associated with shorter recurrence-free survival time (P=0.014). By contrast, TROYv2 exhibited no significant prognostic association. Notably, Cox proportional hazards analyses identified TROYv1 as an independent molecular predictor of recurrence (hazard ratio=1.360; P=0.047). These findings suggested that isoform-specific expression of TROY may serve as a prognostic biomarker in CRC, and that TROYv1 expression is associated with tumor progression. Isoform-specific assessment of TROY, particularly TROYv1, may contribute to refining postoperative risk stratification and could represent a potential therapeutic target in CRC.