The circ-GLG1/miR-346/KCNJ9 axis drives malignant progression of bladder cancer by modulating KCNJ9 expression

Bladder cancer is a common malignant tumor of the urinary system, with its malignant progression mechanisms remaining unclear. In this study, a circular RNA (hsa_circ_0040457, hereinafter referred to as "circ-GLG1″), which has been less characterized in bladder cancer, was identified. It is significantly overexpressed in bladder cancer tissues and cells, and closely associated with patients' pTNM stage and poor prognosis. Circ-GLG1 is formed by back-splicing of exons 23-26 of the GLG1 gene, with circular stability and IRES-dependent translational potential. Functional studies confirmed that silencing circ-GLG1 inhibits cellular malignant phenotypes and tumor formation in nude mice, while overexpression promotes progression by activating TGF-β, PI3K-AKT, and MAPK pathways. Mechanistically, transcriptome sequencing identified 555 differentially expressed genes, with GO/KEGG enrichment in cancer-related pathways. Combined with database prediction, KCNJ9 was identified as a key target. Luciferase assays confirmed that circ-GLG1 may sponge miR-346, relieving its inhibitory effect on KCNJ9's 3'UTR. Functional rescue experiments showed that KCNJ9 overexpression reversed the phenotypic and pathway inactivation induced by circ-GLG1 silencing, verifying the "circ-GLG1/miR-346/KCNJ9″ regulatory axis. This study reveals that circ-GLG1 acts as a ceRNA to target KCNJ9, relieving miR-346-mediated post-transcriptional inhibition, with concurrent activation of TGF-β, PI3K-AKT, and MAPK pathways via KCNJ9 that are associated with bladder cancer progression.