LAMC2⁺ Epithelial Cells Drive Bladder Cancer Progression and Predict Immunotherapy Response via SERPINB3/STAT3/CD44 Axis

Laminin subunit gamma 2 (LAMC2) is a molecule related to the extracellular matrix. It plays a vital role in many cancers. But its effect in bladder cancer (BCa) is still undefined. This study was aimed at exploring the biological function, downstream mechanism, and therapeutic potential of LAMC2 in BCa. We combined single-cell RNA sequencing data from 13 BCa samples and data from TCGA-BLCA, GSE13507, and IMvigor210 cohorts. Bioinformatics analyses were carried out, including epithelial cell subclustering, pathway enrichment, GSVA, HdWGCNA, and RNA sequencing. The expression of LAMC2 in BCa tissues was confirmed through immunohistochemistry and immunofluorescence. Then shRNA was used to knock down LAMC2 in 5637 and T24 cells to test its effects in vitro and in vivo. These results were also tested in a xenograft tumor model. Potential inhibitors of LAMC2 were screened by molecular docking and in vitro experiments. We found that LAMC2 was enriched in a malignant epithelial cell subgroup and was linked to higher tumor grade, advanced tumor stage, poor prognosis and inferior response to immunotherapy. LAMC2 regulated bladder cancer cell proliferation, migration, and invasion through the SerpinB3/STAT3/CD44 axis based on the results of in vitro and single-cell analysis. Diosmetin was found to suppress LAMC2-related signaling in bladder cancer cells, providing a new strategy for BCa treatment.