Identification and Validation of a Ferroptosis-Related Signature for Predicting Prognosis and Immune Microenvironment in Papillary Renal Cell Carcinoma

Abstract

Objective We aimed to explore the prognostic patterns of ferroptosis-related genes in papillary renal cell carcinoma (PRCC) and investigate the relationship between ferroptosis-related genes and PRCC tumor immune microenvironment. Methods We obtained the mRNA expression and corresponding clinical data of PRCC from the public tumor cancer genome atlas database (TCGA). The PRCC patients were randomly divided into two cohort, training cohort and verification cohort, respectively. Univariate Cox regression, LASSO Cox regression, multivariate Cox regression analysis were utilized to construct ferroptosis signature for PRCC patients. And then, risk prognostic model was established and verified. The correlation of ferroptosis-related signature with survival and immune microenvironment was systematically analyzed. Results A 4-genes ferroptosis signature (CDKN1A, MIOX, PSAT1, and RRM2) was constructed. Multivariate Cox regression assay indicates that the risk score of ferroptosis signature was an independent prognostic indicator (HR=1.391, p<0.001). The survival curve shows that the high-risk group has a poorer prognosis than the low-risk group (p<0.001). The risk prognostic model was established based on prognostic factors of clinical-stage, hemoglobin, and risk score. The time-dependent receiver operating characteristic curve (ROC) analysis proves the predictive capacity of the ferroptosis signature, the 3 years area under the curve (AUC) is 0.890, and the 5 years AUC is 0.733. Further analysis suggested that cell cycle, pentose phosphate pathway, P53 signaling pathway were significantly enriched in the high-risk group. The significantly different fractions of dendritic cells resting, macrophage cells, and T cells follicular helper were observed in risk groups. Conclusion This study implicates a ferroptosis signature which has a good predict capacity of the prognosis in PRCC patients. Ferroptosis-related genes may have a key role in the process of anti-tumor and serve as therapeutic targets for PRCC.

MIOX inhibits autophagy to regulate the ROS -driven inhibition of STAT3/c-Myc-mediated epithelial-mesenchymal transition in clear cell renal cell carcinoma

“…A close link exists between MIOX and cancer ferroptosis. For example, studies revealed that MIOX is involved in ferroptosis-related gene models in papillary thyroid carcinoma, bladder cancer and papillary renal cell carcinoma [ 12 , 13 , 56 ]. Zhang et al reported that MIOX could suppress the progression of hepatocellular carcinoma by increasing ROS production, reducing the levels of NADPH and GSH and accelerating ferroptosis induced by erastin and RSL3 [ 11 ].…”

Role of anoikis-related gene PLK1 in kidney renal papillary cell carcinoma: a bioinformatics analysis and preliminary verification on promoting proliferation and migration

“…CDKN1A has been shown to be a member of ferroptosis-associated signature genes to predict graft loss after renal allograft transplantation ( Fan et al, 2021 ). Moreover, the prognosis of KIRP patients can also be accurately predicted by the risk model constructed by using CDKN1A as a ferroptosis-related gene signature ( Da et al, 2022 ). A study in a mouse model identified CDKN1A as a target of phagocytosis-mediated immunotherapy of acute leukemia cells, CDKN1A promotes phagocytosis of leukemia cells and subsequently promotes pro-inflammatory reprogramming of phagocytic macrophages via interferon Gamma extends to surrounding macrophages, presenting the therapeutic opportunity for cancer therapy ( Allouch et al, 2022 ).…”

Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy

“… 111 On the other hand, it can inhibit ferroptosis by inhibiting dipeptidyl peptidase 4 (DPP4) activity or by promoting the expression of cell cyclin-dependent kinase inhibitor 1A (CDKN1A/p21). 112 …”