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

Yanhua Mou,Chaojun Duan,Jinchun Wu,Yao Zhang,Bin Li,Omar Abdihamid

doi:10.1186/s12885-020-07726-z

Abstract

BackgroundClear 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.MethodsNCOA4 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.ResultsContrast 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.ConclusionDeficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

Highlights

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
Patient characteristics In total, the RNA-sequencing data and detailed clinical prognostic information resources of 533 clear cell renal cell carcinoma (RCC) (ccRCC) samples and 72 normal tissue samples from the The Cancer Genome Atlas (TCGA) database were incorporated into our research
The gene expression level of NCOA4 was significantly lower in tumor samples in comparison to normal tissues of ccRCC in TCGA database(p = 7.337e-2) (Fig. 1), which was validated in gene expression omnibus (GEO) database (p = 4.696e-05, 0.018) (Fig. 2)

Summary

Introduction

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 weaken ferroptosis. 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. Recent studies unravel that NCOA4 is an autophagosomes component that participates in the process of ferritinophagy [8, 9]. NCOA4 was gradually considered as a key molecule promoting ferroptosis in various cancer cells and mounting studies displayed that NCOA4 depletion can inhibit ferroptosis by eliminating the accumulation of intracellular free iron, glutathione production and reactive oxygen species (ROS) [11]

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