Development of a propionate metabolism-related gene-based molecular subtypes and scoring system for predicting prognosis in bladder cancer.

ABSTRACT

PURPOSE: Bladder cancer (BLCA) is a prevalent malignancy. Dysregulated propionate metabolism, a key cancer factor, suggests a potential target for treating metastatic cancer. However, a complete understanding of the link between propionate metabolism-related genes (PMRGs) and bladder cancer is lacking. METHODS: From the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we gathered BLCA patient data, which was classified into distinct subgroups using non-negative matrix factorization (NMF). Survival and pathway analyses were conducted between these clusters. The PMRGs model, created through univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses, was assessed for prognostic significance using Kaplan-Meier and receiver operating characteristic (ROC) curves. A comprehensive evaluation included clinical, tumor microenvironment (TME), drug sensitivity, and immunotherapy analyses. Finally, the expression of HSD17B1 essential genes was confirmed via quantitative real-time polymerase chain reaction (qRT-PCR), with further validation through Transwell, wound healing, colony-formation, and EDU assays. RESULTS: We discovered two distinct subcategories (CA and CB) within BLCA using NMF analysis, with CA demonstrating significantly better overall survival compared to CB. Additionally, six PMRGs emerged as critical factors associated with propionate metabolism and prognosis. Kaplan-Meier analysis revealed that high-risk PMRGs were correlated with a poorer prognosis in BLCA patients. Moreover, significant differences were observed between the two groups in terms of infiltrated immune cells, immune checkpoint expression, TME scores, and drug sensitivity. Notably, we found that suppressing HSD17B1 gene expression inhibited the invasion of bladder cancer cells. CONCLUSION: Our study proposes molecular subtypes and a PMRG-based score as promising prognostic indicators in BLCA. Additionally, cellular experiments underscore the pivotal role of HSD17B1 in bladder cancer metastasis and invasion, suggesting its potential as a novel therapeutic target.