Prognostic value and potential biological functions of ferroptosis‑related gene signature in bladder cancer

Abstract

Bladder cancer (BC), as a genitourinary system tumor, is a highly prevalent tumor type. Ferroptosis is an iron-dependent oxidative cell death mechanism that is becoming increasingly recognized as a promising avenue for cancer therapy. However, further determination of the prospective prognostic value of ferroptosis for BC and investigation of the underlying mechanisms is required. The mRNA expression profiles and associated clinical data were downloaded from public databases such as The Cancer Genome Atlas, Gene Expression Omnibus and the IMvigor210 database. To construct a predictive formula, the least absolute shrinkage and selection operator Cox regression algorithm was used. In addition, a prognostic multigene signature was constructed using previously selected ferroptosis-related genes (FRGs). A total of 28 FRGs were differentially expressed between tumor and normal samples with |log2 fold change| >1 and adjusted P<0.05. A prognostic model was then established and it was validated in the GEO cohort using six genes: Glutamate-cysteine ligase modifier subunit, crystallin α-B, transferrin receptor, zinc finger E-box binding homeobox 1, squalene epoxidase and glucose-6-phosphate dehydrogenase (G6PD). Numerous important pathways involved in the development of the immune system and cancer were indicated to be significantly different between the two risk groups. In addition, it was discovered that G6PD expression subgroups that were associated with immunotherapy response in patients with BC had similar prognostic features to risk score subgroups. In the present study, a gene signature with a prognostic value for ferroptosis in BC was successfully developed and the potential value of G6PD was identified for future research.

Squalene Epoxidase: Its Regulations and Links with Cancers

“…Surprisingly, ferroptosis induction can stabilize SQLE at a post-transcriptional level, while an iron chelator reduces SQLE levels in wild-type cancer cells [14]. Perhaps because of these established studies, SQLE has been categorized as falling into "ferroptosis regulators" or "ferroptosis genes" in some research [84][85][86]. These studies strongly suggest an innate mechanistic link between SQLE and ferroptosis, which deserves further investigation.…”

Ferroptosis: An Emerging Target for Bladder Cancer Therapy

“…Similarly, prognostic models based on ferroptotic genes have also been developed [107][108][109][110]. Ferroptosis might have different impacts on different types of BC.…”

Ferroptosis’s Role in Genitourinary System Cancer

“…Xia et al developed a scoring system based on ferroptosis to predict the prognosis of BCa patients and is closely connected to TNM classification, tumor grade, and other clinical characteristics [38]. There are numerous reports about the prediction of BCa at this time [39][40][41][42]. Treatment of bladder cancer benefits from knowledge of the connection between ferroptosis and bladder cancer.…”