Abstract
Background Mounting evidence has confirmed that peroxisome proliferator-activated receptors (PPARs) played a crucial role in the development and progression of bladder cancer (BLCA). The purpose of this study is to comprehensively investigate the function and prognostic value of PPAR-targeted genes in BLCA. Methods The RNA sequencing data and clinical information of BLCA patients were acquired from The Cancer Genome Atlas (TCGA). The differentially expressed PPAR-targeted genes were investigated. Cox analysis and least absolute shrinkage and selection operator (LASSO) analysis were performed for screening prognostic PPAR-targeted genes and constructing the prognostic PPAR signature and then validated by GSE13507 cohort and GSE32894 cohort. A nomogram was constructed to predict the outcomes of BLCA patients in combination with PPAR signature and clinical factors. Gene set enrichment analysis (GSEA) and immune cell infiltration were implemented to explore the molecular characteristics of the signature. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to predict the chemotherapy responses of the prognostic signature. The candidate small molecule drugs targeting PPAR-targeted genes were screened by the CMAP database. Results We constructed and validated the prognostic signature comprising of 4 PPAR-targeted genes (CPT1B, CALR, AHNAK, and FADS2), which was an independent prognostic biomarker in BLCA patients. A nomogram based on the signature and clinical factors was established in the TCGA set, and the calibration plots displayed the excellent predictive capacity. GSEA analysis indicated that PPAR signature was implicated in multiple oncogenic signaling pathways and correlated with tumor immune cell infiltration. Patients in the high-risk groups showed greater sensitivity to chemotherapy than those in the low-risk groups. Moreover, 11 candidate small molecule drugs were identified for the treatment of BLCA. Conclusion We constructed and validated a novel PPAR signature, which showed the excellent performance in predicting prognosis and chemotherapy sensitivity of BLCA patients.
Highlights
Bladder cancer (BLCA) is one of the common causes of cancer-related deaths with elevated heterogeneity, accounting for over 200,000 cancer-related deaths in 2020 [1]
The result of Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEPPARGs were mainly involved in the peroxisome proliferator-activated receptors (PPARs) signaling pathway, cholesterol metabolism, ovarian steroidogenesis, platinum drug resistance, and microRNAs in cancer (Supplementary Figure 1(b)), which suggested that DEPPARGs might function as the crucial role in the tumorigenesis, progression, and drug resistance of bladder cancer (BLCA)
We comprehensively explored the clinical significance of PPAR-targeted genes and constructed and validated a novel PPAR signature, which showed the excellent performance in predicting prognosis and chemotherapy sensitivity of BLCA patients
Summary
Bladder cancer (BLCA) is one of the common causes of cancer-related deaths with elevated heterogeneity, accounting for over 200,000 cancer-related deaths in 2020 [1]. According to the tumor with or without muscle invasion, BLCA is classified into non-muscle-invasive BLCA (NMIBLCA) and muscle-invasive BLCA (MIBLCA) The former is characterized by recurrence and progression while the latter is characterized by metastasis and unfavorable prognosis [2]. Identifying novel biomarkers for predicting prognosis and response to therapeutic drug in BLCA is of considerable clinical meaning. A nomogram was constructed to predict the outcomes of BLCA patients in combination with PPAR signature and clinical factors. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to predict the chemotherapy responses of the prognostic signature. We constructed and validated the prognostic signature comprising of 4 PPAR-targeted genes (CPT1B, CALR, AHNAK, and FADS2), which was an independent prognostic biomarker in BLCA patients. We constructed and validated a novel PPAR signature, which showed the excellent performance in predicting prognosis and chemotherapy sensitivity of BLCA patients
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