Functions, Roles, and Biological Processes of Ferroptosis-Related Genes in Renal Cancer: A Pan-Renal Cancer Analysis

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Abstract

Ferroptosis is a cell death process discovered in recent years, highly related to cancer, acute kidney injury, and other diseases. In this study, a pan-renal cancer analysis of ferroptosis-associated genes in renal cancer was performed to construct a multigene joint signature for predicting prognosis in renal cancer patients. First, gene expression profiles were downloaded from the TCGA and GTEx databases to search for genes significantly associated with renal cancer prognosis through differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and survival analysis. Thereafter, the gene-set enrichment analysis (GSEA) was used to identify the biological processes in which ferroptosis-associated genes might be involved. Weighted gene co-expression network analysis resulted in 4,434 differentially expressed genes (DEGs) and 42 co-expression modules, among which ferroptosis-related genes were distributed in 11 gene modules. The survival analysis screening resulted in three DEGs associated with renal cancer prognosis, namely SLC7A11, HMOX1, and MT1G. Specifically, SLC7A11 and HMOX1 were upregulated in renal cancer tissues, while MT1G was downregulated. Receiver operating characteristic (ROC) curves, combined with Kaplan–Meier and Cox regression analysis, revealed that high expression of SLC7A11 was a prognostic risk factor for four different renal cancers, that low expression of HMOX1 was a poor prognostic marker for patients, and that increased expression of MT1G increased the prognostic risk for three additional classes of renal cancer patients, except for renal papillary cell carcinoma. The GSEA results showed that the ferroptosis-related genes from these screens were mainly associated with signaling pathways related to tumor progression and tumor immunity. This study provides potential biological markers for prognosis prediction in renal cancer patients with different subtypes, and these results imply that ferroptosis is highly associated with renal carcinogenesis progression.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: past, present and future

Jie Li, Feng Cao, He-liang Yin … (2020)

Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

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Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

Scott J. Dixon, Darpan N Patel, Matthew Welsch … (2014)

Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc − is implicated in numerous pathologies. Pharmacological agents that inhibit system xc − activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system xc −. RNA sequencing revealed that inhibition of cystine–glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1, providing a pharmacodynamic marker for system xc − inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc − function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis. DOI: http://dx.doi.org/10.7554/eLife.02523.001

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Author and article information

Contributors

Linbao Chen: URI : https://loop.frontiersin.org/people/1377008

Xingang Cui: URI : https://loop.frontiersin.org/people/1309267

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (iso-abbrev): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2234-943X

Publication date (Electronic): 11 March 2022

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 697697

Affiliations

[1] ¹ Department of Urinary Surgery, The Second Affiliated Hospital of Ningxia Medical University (The First People’s Hospital of Yinchuan) , Yinchuan, China

[2] ² Ningxia Medical University , Yinchuan, China

[3] ³ Department of Urinary Surgery, Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University , Yinchuan, China

[4] ⁴ Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University) , Shanghai, China

[5] ⁵ Department of Urology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University , Changzhou, China

[6] ⁶ Department of Urinary Surgery, Xinhua Hospital Affiliated To Shanghai Jiaotong University School of Medicine , Shanghai, China

Author notes

Edited by: Ye Wang, The Second Affiliated Hospital of Medical College of Qingdao University, China

Reviewed by: Li Yan, Shandong University, China; Liu Zhao, Biotranstech Co., Ltd., China

*Correspondence: Guangwen Zhang, guang1wenz@ 123456163.com ; Xingang Cui, cuixingang@ 123456xinhuamed.com.cn

This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology

Article

DOI: 10.3389/fonc.2021.697697

PMC ID: 8962645

PubMed ID: 35360452

SO-VID: 50018ec0-4709-4394-a130-34d4a6e5c53b

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 20 April 2021

Date accepted : 13 December 2021

Page count

Figures: 9, Tables: 1, Equations: 0, References: 37, Pages: 9, Words: 3445

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Functions, Roles, and Biological Processes of Ferroptosis-Related Genes in Renal Cancer: A Pan-Renal Cancer Analysis

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Most cited references 37

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Ferroptosis: past, present and future

Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

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