Construction and validation of prognosis and treatment outcome models based on plasma membrane tension characteristics in bladder cancer

Background: Plasma membrane tension-related genes (MTRGs) are known to play a crucial role in tumor progression by influencing cell migration and adhesion. However, their specific mechanisms in bladder cancer (BLCA) remain unclear.

Methods: Transcriptomic, clinical and mutation data from BLCA patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clusters associated with MTRGs were identified by consensus unsupervised cluster analysis. The genes of different clusters were analyzed by GO and KEGG gene enrichment analysis. Differentially expressed genes (DEGs) were screened from different clusters. Consensus cluster analysis of prognostic DEGs was performed to identify gene subtypes. Patients were then randomly divided into training and validation groups, and MTRG scores were constructed by logistic minimum absolute contraction and selection operator (LASSO) and Cox regression analysis. We assessed changes in clinical outcomes and immune-related factors between different patient groups. The single-cell RNA sequencing (scRNA-seq) dataset for BLCA was collected and analyzed from the Tumor Immune Single-cell Hub (TISCH) database. Biological functions were investigated using a series of experiments including quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), wound healing, transwell, etc.

Results: Our MTRG score is based on eight genes (HTRA1, GOLT1A, DCBLD2, UGT1A1, FOSL1, DSC2, IGFBP3 and TAC3). Higher scores were characterized by lower cancer stem cell (CSC) indices, as well as higher tumor microenvironment (TME) stromal and immune scores, suggesting that high scores were associated with poorer prognosis. In addition, some drugs such as cisplatin, paclitaxel, doxorubicin, and docetaxel exhibited lower IC50 values in the high MTRG score group. Functional experiments have demonstrated that downregulation of DCBLD2 affects tumor cell migration, but not proliferation.

Conclusions: Our study sheds light on the prognostic significance of MTRGs within the TME and their correlation with immune infiltration patterns, ultimately impacting patient survival in BLCA. Notably, our findings highlight DCBLD2 as a promising candidate for targeted therapeutic interventions in the clinical management of BLCA.