Construction of a cuproptosis-associated lncRNA prognostic signature for bladder cancer and experimental validation of cuproptosis-related lncRNA UBE2Q1-AS1.

INTRODUCTION

Bladder cancer (BLCA) is the ninth most common malignancy worldwide and the fourth most common cancer in men. Copper levels are significantly altered in patients with thyroid, breast, lung, cervical, ovarian, pancreatic, oral, gastric, bladder, and prostate cancers. Outcomes can be predicted by constructing signatures using lncRNA-related genes associated with outcomes.

METHODS

We identified lncRNAs related to outcomes, those differentially expressed in bladder cancer, and cuproptosis-related lncRNAs from TCGA. We identified the intersection to obtain 12 genes and established a prognostic risk signature consisting of eight genes using LASSO-penalized multivariate Cox analysis. We constructed a training set, performed survival analysis on the high-and low-risk groups, and performed validation in the test and full sets. There existed a substantial contrast in the likelihood of survival among the cohorts of high and low risk. An in-depth analysis of the gene mutations associated with tumors was conducted to evaluate the risk of developing cancer. We also performed gene analysis on neoadjuvant chemotherapy. We conducted experimental validation on the key gene UBE2Q1-AS1 in our prognostic signature.

RESULTS

The risk signature we constructed shows significant differences between the high-risk group and the low-risk group. Univariate survival analysis of the eight genes in our signature showed that each gene distinguished between high- and low-risk groups. Sub-group analysis revealed that our risk score differed significantly in tumor stage, age, and gender. The analysis results of the tumor mutation burden (TMB) showed a significant difference in the TMB between the low- and high-risk groups, which had a direct impact on the outcomes. These findings highlight the importance of TMB as a potential prognostic marker in cancer detection and prevention. We analyzed the immune microenvironment and found significant differences in immune function, validation responses, immunotherapy-related positive markers, and critical steps in the tumor immunity cycle between the high- and low-risk groups. We found that the effect of anti-CTLA4 and PD-1 was higher in the high-risk group than in the low-risk group.Gene analysis of neoadjuvant chemotherapy revealed that the treatment effect in the high-risk group was better than in the low-risk group. The key gene UBE2Q1-AS1 in our prognostic signature can significantly influence the cell viability, migration, and proliferation of cancer cells.

DISCUSSION

We established a signature consisting of eight genes constructed from cuproptosis-related lncRNAs that have potential clinical applications for outcomes prediction, diagnosis, and treatment.