TNFRSF19: een nieuw tumorsuppressorgen gericht op ER-stress en LGR5/Wnt/β-catenine bij colorectale kanker

TNF Receptor Superfamily Member 19 (TNFRSF19) has been implicated in the advancement of several types of cancer. However, its function and mechanism in cervical cancer (CC) remain unclear. Additionally, while ER stress is proposed as a therapeutic target in cancer, its relationship with TNFRSF19 in CC is unknown. This study aimed to investigate the role and underlying mechanisms of TNFRSF19 in CC. The expression of TNFRSF19 was investigated utilizing the GEPIA database and subsequently validated in 35 paired clinical CC tissue samples. The impact of TNFRSF19 overexpression on cellular proliferation, apoptosis, and endoplasmic reticulum (ER) stress was evaluated in C33A and HeLa cell lines through CCK-8 assays, colony formation assays, and flow cytometry. The interaction between TNFRSF19 and LGR5, along with its inhibitory effect on the Wnt/β-catenin pathway, was analyzed using co-immunoprecipitation (Co-IP), immunofluorescence, and western blotting techniques. Additionally, an in vivo xenograft tumor model in nude mice was developed to substantiate the tumor-suppressive function of TNFRSF19. TNFRSF19 expression was significantly reduced in CC tissues and cell lines. TNFRSF19 overexpression substantially inhibited cell proliferation and colony formation, and induced apoptosis in vitro, while also suppressing tumor growth in vivo. Mechanistically, TNFRSF19 facilitated apoptosis through the activation of ER stress and directly interacted with LGR5 to inhibit the LGR5/Wnt/β-catenin pathway. The pro-apoptotic and tumor growth-inhibitory effects induced by TNFRSF19 were diminished by the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Moreover, the inhibitory effect on cell proliferation mediated by TNFRSF19 was effectively reversed upon the restoration of LGR5 expression. This study demonstrates that TNFRSF19 functions as a novel tumor suppressor in CC by activating ER stress and inhibiting the LGR5/Wnt/β-catenin pathway, highlighting its potential as a therapeutic target for CC treatment.