Identification of a novel signature based on unfolded protein response-related gene for predicting prognosis in bladder cancer

Abstract

Background The unfolded protein response (UPR) served as a vital role in the progression of tumors, but the molecule mechanisms of UPR in bladder cancer (BLCA) have been not fully investigated. Methods We identified differentially expressed unfolded protein response-related genes (UPRRGs) between BLCA samples and normal bladder samples in the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and the least absolute shrinkage and selection operator penalized Cox regression analysis were used to construct a prognostic signature in the TCGA set. We implemented the validation of the prognostic signature in GSE13507 from the Gene Expression Omnibus database. The ESTIMATE, CIBERSORT, and ssGSEA algorithms were used to explore the correlation between the prognostic signature and immune cells infiltration as well as key immune checkpoints (PD-1, PD-L1, CTLA-4, and HAVCR2). GDSC database analyses were conducted to investigate the chemotherapy sensitivity among different groups. GSEA analysis was used to explore the potential mechanisms of UPR-based signature. Results A prognostic signature comprising of seven genes (CALR, CRYAB, DNAJB4, KDELR3, CREB3L3, HSPB6, and FBXO6) was constructed to predict the outcome of BLCA. Based on the UPRRGs signature, the patients with BLCA could be classified into low-risk groups and high-risk groups. Patients with BLCA in the low-risk groups showed the more favorable outcomes than those in the high-risk groups, which was verified in GSE13507 set. This signature could serve as an autocephalous prognostic factor in BLCA. A nomogram based on risk score and clinical characteristics was established to predict the over survival of BLCA patients. Furthermore, the signature was closely related to immune checkpoints (PD-L1, CTLA-4, and HAVCR2) and immune cells infiltration including CD8+ T cells, follicular helper T cells, activated dendritic cells, and M2 macrophages. GSEA analysis indicated that immune and carcinogenic pathways were enriched in high-risk group. Conclusions We identified a novel unfolded protein response-related gene signature which could predict the over survival, immune microenvironment, and chemotherapy response of patients with bladder cancer.

Immunogenic cell death mediation patterns reveal novel paradigm for characterizing the immune microenvironment and immunotherapeutic responses in bladder cancer

“…We found increased CALR expression in BCA which correlated with poor prognosis ( Figure 2B ). This is consistent with all reported findings ( Liu et al, 2020 ; Zhu et al, 2021 ). The results of our in vitro experiments validated that the mRNA expression of CALR was higher in BCA cells T24 than in normal urothelial cells SV-HUC-1 ( Figure 9B ); upon knocking down the gene expression of CALR in T24 cells, the viability of tumor cells reduced significantly ( Figure 9D ), a phenomenon consistent with the clinical outcomes.…”

Identification and validation of a novel prognostic model based on platinum resistance-related genes in bladder cancer

“…Genetic biomarkers would be viable to represent heterogeneity among BC, predicting the sensitivity of urothelial neoplasms tissues toward platinum. Previous studies have reported several prognostic gene signatures that are related to tumor microenvironment, immune cell infiltrating, unfolded protein response, and so on ( 40 – 42 ). However, signature associated with platinum-based chemotherapy resistance has not been recorded yet.…”

Identification and Validation of a Novel Prognostic Model Based on Platinum Resistance-Related Genes in Bladder Cancer

“…Genetic biomarkers would be viable to represent heterogeneity among BC, thus predicting the sensitivity of urothelial neoplasms tissues toward platinum. Previous studies have reported several prognostic gene signatures that are related to tumor microenvironment, immune cell in ltrating, unfolded protein response, and so on [39][40][41] . But signature that is associated with platinum-based chemotherapy resistance has not been recorded yet.…”