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

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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.

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Most cited references 37

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Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

Robert Motzer, Bernard Escudier, David F McDermott … (2016)

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.

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CD8 + T cells regulate tumor ferroptosis during cancer immunotherapy

Weimin Wang, Michael Green, Jae Eun Choi … (2019)

Summary Cancer immunotherapy restores and/or enhances effector function of CD8+ T cells in the tumor microenvironment 1,2 . CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways 3,4 . Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation 5,6 . Although it was mechanistically illuminated in vitro 7,8 , emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios 9,10 . However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Expression of system xc- is negatively associated with CD8+ T cell signature, IFNγ expression, and cancer patient outcome. Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

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Autophagy promotes ferroptosis by degradation of ferritin.

Wen Hou, Yangchun Xie, Xinxin Song … (2016)

Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death.

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Author and article information

Contributors

Bin Li: bincsuxy@csu.edu.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 5 January 2021

Publication date PMC-release: 5 January 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 18

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oncology, Xiangya Hospital, , Central South University, ; Changsha, Hunan 410008 P.R. China

[2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Oncology, Hubei Cancer Hospital, , Affiliated Hubei Cancer Hospital of Huazhong University of Science and Technology, ; Wuhan, 430079 P.R. China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, , Central South University, ; Changsha, Hunan 410008 P.R. China

[4 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, State Key Laboratory of Reproductive Medicine and Department of Urology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu 210029 P.R. China

[5 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Thoracic Surgery, Xiangya Hospital, , Central South University, ; Changsha, Hunan 410008 P.R. China

[6 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, , Central South University, ; Changsha, Hunan 410008 P.R. China

Article

Publisher ID: 7726

DOI: 10.1186/s12885-020-07726-z

PMC ID: 7786469

PubMed ID: 33402128

SO-VID: 8e3deef2-88b6-43f7-be64-3de7dbc57101

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 July 2020

Date accepted : 11 December 2020

Funding

Funded by: Province Natural Science Foundation of Hunan

Award ID: No.14JJ6004

Award Recipient : Bin Li

Funded by: the Key Subject Education Department of Hunan

Award ID: [2012]594

Award Recipient : Bin Li

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81200366

Award ID: 81702278

Award ID: 81974367

Award Recipient : Chaojun Duan Bin Li

Funded by: National Natural Science Foundation of China (CN)

Award ID: 81572281

Award Recipient : Chaojun Duan

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ferritinophagy,ncoa4,clear cell renal carcinoma,immune cells,ferroptosis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: ferritinophagy, ncoa4, clear cell renal carcinoma, immune cells, ferroptosis

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

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Abstract

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Conclusion

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Karger: Oncology

Most cited references 37

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

CD8 + T cells regulate tumor ferroptosis during cancer immunotherapy

Autophagy promotes ferroptosis by degradation of ferritin.

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