Tumor microenvironment exploration and therapeutic target identification in bladder cancer based on Cuproptosis signature and chemotherapy-resistant model: results from bioinformatics and experimental validation

Abstract

BackgroundThe discovery of cuproptosis provides a new way to make full use of the pathophysiological effects of copper for anticancer therapy and could help identify a therapeutic target in bladder cancer. MethodsIn this study, 411 BLCA tumor samples from the Cancer Genome Atlas (TCGA) cohort were obtained. Differentially expressed genes (DEGs) between chemotherapy-sensitive and chemotherapy-resistant mouse bladder cancers were also obtained. Sixteen genes were defined as cuproptosis-related genes (CRGs), and the cutoff score was calculated based on LASSO Cox regression. CCK-8 and Transwell assays were used to detect the migration and proliferation of 5637 and T24 cells, respectively. Liarozole dihydrochloride (L-D), a mild P450, inhibits the expression of CYP26B1. Multiple immunohistochemistry analyses were used to explore the association between the immune microenvironment and CRGs. ResultsA higher Cuproptosis score was significantly associated with worse overall survival in BLCA (p<0.0001, HR=2.32). Single-cell transcriptional data were used to assess the function of CYP26B1 and CYP26B1 may be negatively associated with DNA damage and repair. In vitro experiments indicated that overexpression of CYP26B1 enhanced the migration and proliferation of BLCA cells, while L-D inhibited the migration and proliferation of BLCA cells. A higher expression level of Dihydrolipoamide S-Succinyltransferase (DLST) serves could as a risk factor in patients treated with atezolizumab and higher expression of DLST suggest an immunosuppressive microenvironment. ConclusionsCYP26B1 may be a therapeutic target for bladder cancer, and the higher expression of DLST may suggest an immunosuppressive microenvironment in BLCA. Key MessagesCuproptosis may be associated with the chemotherapy-resistance of bladder cancer and our findings may provide new ideas for the treatment of bladder cancer.