Low expression of ferritinophagy-related NCOA4 gene in relation to unfavorable outcome and defective immune cells infiltration in clear cell renal carcinoma

Abstract

Background Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. Methods NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. Results Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue(p < 0.05). Lower NCOA4 expression was closely associated with high-grade malignancy and advanced TNM stage. Univariate and multivariate analysis indicated the overall survival of ccRCC cases with low NCOA4 level is shorter than those of patients with high NCOA4 expression (p < 0.05). FTL and FTH1 were the important proteins interacting with NCOA4. ccRCC with NCOA4 deficiency presented the paucity of infiltrated immune cells and their matching marker sets, including CD8+ T cells. Conclusion Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

A New Prognostic Risk Signature of Eight Ferroptosis-Related Genes in the Clear Cell Renal Cell Carcinoma

“…Disorders of FRGs have been reported in numerous malignant tumors, suggesting a vital role of FRGs in tumor progression (23,24). The abnormal FRGs are reported to be involved in the initiation and progression of ccRCC (12,25). However, the comprehensive understanding of FRGs and ccRCC prognosis remains largely unknown.…”

“…MT1G is reported to be hypermethylated in RCC (31). Low expression of NCOA4 is associated with ccRCC progression, and poor prognosis and immune infiltration in ccRCC patients (12). Wu et al developed an 11 metabolic gene signature-based prognostic model in ccRCC (32).…”

“…CISD1, a typical ferroptosis-related gene (FRG), negatively regulates ferroptosis (11). In contrast, NCOA4 and MT1G have been found to sustain ferroptosis (12,13). However, the roles of FRGs in the prognosis of ccRCC remain largely unknown.…”

Ferroptosis-Related Gene-Based Prognostic Model and Immune Infiltration in Clear Cell Renal Cell Carcinoma

“…In previous research, different studies from different perspectives have explored the value of prognostic markers in ccRCC, like long non-coding RNAs ( Cheng et al, 2019 ; Yang et al, 2020 ), some key genes ( Yang et al, 2018 ; Luo et al, 2019 ), immune-related genes ( Zhang et al, 2019 ), etc. Some studies have focused on the relationship between ferroptosis and ccRCC ( Abu Aboud et al, 2017 ; Wu G. et al, 2020 ; Mou et al, 2021 ; Wang et al, 2021 ). Wu and colleagues did a remarkable work in clinical significance of ferroptosis-related genes (FRGs) in pan cancer and conducted a new survival model based on five risk-related FRGs for ccRCC ( Wu G. et al, 2020 ).…”

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma

“…An important and relevant example is lysyl oxidase (LOX), an enzyme crucial for collagen maturation, crosslinking collagen and elastin fibers, which is considered to be an unfavorable prognostic marker in ccRCC (The Human Protein Atlas) and, mitochondrial superoxide dismutase SOD2. Studies show the role of iron, iron-binding proteins, and ferroptosis in ccRCC progression [103][104][105][106]. Similarly, the role of the copper transporters in ccRCC advancement was established [107,108].…”