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The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer

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Abstract

Background

Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown.

Methods

Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis.

Results

The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers.

Conclusions

We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

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Data availability

The data sets analyzed during the current study are available in the UCSC Xena database (http://xena.ucsc.edu/), CPTAC database (https://pdc.cancer.gov/pdc/), Human Protein Atlas database (http://www.proteinatlas.org/), CellMiner database (https://discover.nci.nih.gov/cellminer/home.do), and RCSB PDB database (https://www.rcsb.org/). Other data may be obtained from the corresponding author upon reasonable request.

Abbreviations

ACC:

Adrenocortical carcinoma

BLCA:

Bladder urothelial carcinoma

BRCA:

Breast carcinoma

CESC:

Cervical squamous cell carcinoma and endocervical adenocarcinoma

CHOL:

Cholangiocarcinoma

CI:

Confidence interval

COAD:

Colon adenocarcinoma

CPTAC:

Clinical Proteomic Tumor Analysis Consortium

DFI:

Disease-free interval

DLBC:

Lymphoid neoplasm diffuse large B-cell lymphoma

DSS:

Disease-specific survival

ESCA:

Esophageal carcinoma

GBM:

Glioblastoma multiforme

GSEA:

Gene Set Enrichment Analysis

GTEx:

Genote-Tissue Expression

HNSC:

Head and neck squamous cell carcinoma

HPA:

Human Protein Atlas

HR:

Hazard ratio

IC50:

Half maximal inhibitory concentration

ICIs:

Immune checkpoint inhibitors

KEGG:

Kyoto Encyclopedia of Genes and Genomes

KICH:

Kidney chromophobe

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

LAML:

Acute myeloid leukemia

LGG:

Brain lower grade glioma

LIHC:

Liver hepatocellular carcinoma

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

MESO:

Mesothelioma

MSI:

Microsatellite instability

NK:

Natural killer

OS:

Overall survival

OV:

Ovarian serous cystadenocarcinoma

PAAD:

Pancreatic adenocarcinoma

PCPG:

Pheochromocytoma and paraganglioma

PDB:

Protein Data Bank

PFI:

Progression-free interval

PRAD:

Prostate adenocarcinoma

READ:

Rectum adenocarcinoma

SARC:

Sarcoma

SKCM:

Skin cutaneous melanoma

STAD:

Stomach adenocarcinoma

TCA:

Tricarboxylic acid

TCGA:

The Carcinoma Genome Atlas

TGCT:

Testicular germ cell tumors

THCA:

Thyroid carcinoma

THYM:

Thymoma

TIDE:

Tumor immune dysfunction and exclusion

TMB:

Tumor mutational burden

TME:

Tumor microenvironment

UCEC:

Uterine corpus endometrial carcinoma

UCS:

Uterine carcinosarcoma

UVM:

Uveal melanomas

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Funding

This work was supported by the National Natural Science Foundation of China (82373155, 82103293, 82172651), the Natural Science Foundation of Anhui Province (2108085MH287), the Natural Science Foundation of Anhui Education Department for Distinguished Young Scholars (2022AH020074), the Natural Science Foundation of Anhui Education Department for Excellent Young Scholars (2022AH030123), the Support Plan for Outstanding Young Talents of Anhui Education Department (gxyq2021257), the Key Research and Development Project of Anhui Province (202104j07020019), the Science and Technology Project of Wuhu City (2022jc52) and the Talent Introduction Science Foundation of Yijishan Hospital, Wannan Medical College (No. YR202109 and YR202110).

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Author notes

  1. Yao Fei and Danping Cao contributed equally to this work.

    Juan Cai is the primary corresponding author.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China

    Yao Fei, Danping Cao, Runyu Dong, Yanna Li, Zhixiong Wang, Peng Gao, Menglin Zhu & Xueliang Zuo

  2. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China

    Xiaoming Wang

  3. Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, China

    Xueliang Zuo & Juan Cai

  4. Department of Oncology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China

    Juan Cai

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  1. Yao Fei
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  3. Runyu Dong
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Contributions

YF: conceptualization, data curation, formal analysis, investigation, methodology, software, validation, writing—original draft preparation, writing—review and editing. DC: conceptualization, data curation, formal analysis, methodology, validation, visualization, writing—original draft preparation, writing—review and editing. RD: methodology, software, validation. YL: data curation, investigation, supervision, validation. ZW: investigation, supervision, visualization. PG: software, supervision, visualization. MZ: software, supervision, visualization. XW: supervision, writing—review and editing. XZ: conceptualization, data curation, methodology, resources, validation, writing—review and editing, funding acquisition. JC: conceptualization, project administration, resources, validation, funding acquisition.

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Correspondence to Xueliang Zuo or Juan Cai.

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Fei, Y., Cao, D., Dong, R. et al. The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03495-4

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