Abstract
Bladder cancer (BLCA) remains a major health challenge due to its high incidence and poor prognosis. This study delves into the role of Actin Gamma 1 (ACTG1) in modulating the splicing of the P4HB gene, leading to the formation of the circular RNA circ_0046263, and its impact on epithelial-mesenchymal transition (EMT) and BLCA progression. Utilizing transcriptome and clinical data from The Cancer Genome Atlas (TCGA) and splicing data from the TCGA SpliceSeq database, we identified survival-associated splicing events through least absolute shrinkage and selection operator (LASSO) regression and Cox analysis. A meta-analysis of BLCA-related mRNA sequencing datasets from the gene expression omnibus (GEO) database validated the differential expression of ACTG1. Immune infiltration analysis and circRNA sequencing data revealed significant upregulation of ACTG1 in BLCA, correlating with various immune cells and checkpoints. Functional assays confirmed that ACTG1 promotes the splicing of P4HB to form circ_0046263, enhancing BLCA cell proliferation, migration, and invasion. Silencing ACTG1 in vivo suppressed tumor growth and metastasis, effects that were reversed by overexpression of circ_0046263. These findings highlight the pivotal role of ACTG1 in regulating EMT in BLCA through its splicing activity on P4HB, suggesting new therapeutic targets for intervention. This study underscores the critical importance of splicing regulation in cancer biology, offering novel insights for diagnostic and therapeutic strategies in BLCA.