Abstract
Ferroptosis induced by lipid peroxidation is closely related to cancer biology. Prostate cancer (PCa) is not only a malignant tumor but also a lipid metabolic disease. Previous studies have identified ferroptosis as an important pathophysiological pathway in PCa development and treatment, but its role in the prognosis of PCa is less well known. In this study, we constructed a nine-ferroptosis-related gene risk model that demonstrated strong prognostic and therapeutic predictive power. The higher risk score calculated by the model was significantly associated with a higher ferroptosis potential index, higher Ki67 expression, higher immune infiltration, higher probability of biochemical recurrence, worse clinicopathological characteristics, and worse response to chemotherapy and antiandrogen therapy in PCa. The mechanisms identified by the gene set enrichment analysis suggested that this signature can accurately distinguish high- and low-risk populations, which is possibly closely related to variations in steroid hormone secretion, regulation of endocrine processes, positive regulation of humoral immune response, and androgen response. Results of this study were confirmed in two independent PCa cohorts, namely, The Cancer Genome Atlas cohort and the MSK-IMPACT Clinical Sequencing Cohort, which contributed to the body of scientific evidence for the prediction of biochemical recurrence in patients with PCa. In addition, as the main components of this signature, the effects of the AIFM2 and NFS1 genes on ferroptosis were evaluated and verified by in vivo and in vitro experiments, respectively. The above findings provided new insights and presented potential clinical applications of ferroptosis in PCa.
Highlights
The latest cancer statistics show that prostate cancer (PCa) has surpassed lung cancer, as it becomes the malignant tumor with the highest incidence in men and ranks second to lung cancer in terms of mortality rate (Siegel et al, 2020)
This study identified ferroptosis-related genes associated with long-term biochemical recurrence (BCR) of Prostate cancer (PCa) and constructed a prognostic signature based on nine ferroptosis-related genes, which can accurately identify patients with high-risk PCa
Data of the MSK-IMPACT Clinical Sequencing Cohort (MSKCC) PCa cohort were obtained from the Cbioportal database2 and used as the validation set, which included 138 patients with complete expression profile and clinicopathological information
Summary
The latest cancer statistics show that prostate cancer (PCa) has surpassed lung cancer, as it becomes the malignant tumor with the highest incidence in men and ranks second to lung cancer in terms of mortality rate (Siegel et al, 2020). Patients with BCR who did not receive secondary therapy will develop clinical progression within 5–8 years, and 32–45% will die of the disease within 15 years (Brockman et al, 2015). Identifying new biomarkers is crucial to predict high-risk PCa patients with high BCR risk. Over the past 5 years, basic and clinical researchers have shown a growing interest in the role of ferroptosis in the pathogenesis of cancer (Chen et al, 2021). At present, triggering ferroptosis, as a new method of treating cancer, has received high expectations and has been an area of active research (Hassannia et al, 2019; Liang et al, 2019)
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