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Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis

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Abstract

Cuproptosis is a newly discovered cell death induced by excessive copper in mitochondria distinct from any known forms of apoptosis. Role of cuproptosis has not been well-reported in cancer, especially in clear-cell renal cell carcinoma (ccRCC). We comprehensively interrogated cuproptotic gene signature in ccRCC by reproducing multi-omics datasets and found cuproptosis was decreased in ccRCC compared with normal kidney. Cuproptosis identified a subgroup with significantly better prognosis. Functional annotation supported increased tricarboxylic acid cycle activity and decreased hypoxia signaling corroborated by metabolomics. Cuproptotic tumors showed decreased angiogenesis but were sensitive to Sunitinib and Sorafenib. Cuproptotic level in ccRCC cell lines showed robust negative correlation with copper ionophore Elesclomol. All findings support a respiratory subtype of ccRCC identified by cuproptosis.

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Data availability

All data from the current study was retrieved from public genomic datasets and no new dataset was generated.

Abbreviations

ccRCC:

Clear cell renal cell carcinoma

CDF:

The cumulative distribution function

CNV:

Copy number variation

CORE:

Consumption and release

DepMap:

Dependency map portal

GDSC:

Genomics of drug sensitivity in cancer database

GISTIC:

The genomic identification of significant targets in cancer

GSE:

Gene set enrichment

GSEA:

Gene set enrichment analysis

GSVA:

Gene set variation analysis

ICIs:

Immune checkpoints inhibitors

IC50:

The half maximal inhibitory concentration

IHC:

Immunohistochemical

NES:

Normalized enrichment score

OS:

Overall survival

ROC:

The receiver operating characteristic

ssGSEA:

Single sample gene set enrichment analysis

TCA cycle:

Tricarboxylic acid cycle

TCGA-KIRC:

The cancer genome atlas of kidney renal clear cell carcinoma

TILs:

Tumor infiltrating lymphocytes

TKIs:

Tyrosine kinase inhibitors

TPM:

Transcripts per kilobase million

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Acknowledgements

None.

Funding

This study was sponsored in part by National Natural Science Foundation of China (Grant Nos. 81874123 and 81772709) and by Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University (BTBU).

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Author notes

  1. Kunping Li and Linyi Tan have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Huashan Hospital, Fudan University, 12 Middle Urumqi Rd, Shanghai, 200040, China

    Kunping Li, Linyi Tan, Yuqing Li, Yinfeng Lyu, Haowen Jiang, Xiaohua Zhang, Hui Wen & Chenchen Feng

  2. Department of Pharmacology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Xinyi Zheng

  3. Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University (BTBU), Beijing, 100000, China

    Chenchen Feng

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  1. Kunping Li
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Contributions

CF, YL, XZ and YL: carried out in silico analysis. KL, LT and CF: participated in the study design. CF, HJ and HW: retrieved data. CF and KL: drafted the manuscript. LT: undertook revision. All authors read and approved the final manuscript.

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Correspondence to Xiaohua Zhang, Hui Wen or Chenchen Feng.

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Li, K., Tan, L., Li, Y. et al. Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis. Apoptosis 27, 1004–1014 (2022). https://doi.org/10.1007/s10495-022-01769-2

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