FOLLOWUS
1.Central Laboratory of the Fifth Affiliated Hospital of Harbin Medical University, Daqing 163711, Heilongjian Province, China
2. Clinical Laboratory of the Fifth Affiliated Hospital of Harbin Medical University, Daqing 163316, Heilongjian Province, China
E-mail: yudejun100@126.com
Received:16 January 2024,
Accepted:2024-04-18,
Published Online:20 May 2024,
Published:30 September 2024
Scan QR Code
.UBE2C as an Immune-Related Biomarker for Breast Cancer: A Study Based on Multiple Databases[J]. 中国医学科学杂志(英文),2024,39(03):171-181.
Cui Yue, Wang Hong-Zhi, Song Ye, et al.
.UBE2C as an Immune-Related Biomarker for Breast Cancer: A Study Based on Multiple Databases[J]. 中国医学科学杂志(英文),2024,39(03):171-181. DOI: 10.24920/004340.
Cui Yue, Wang Hong-Zhi, Song Ye, et al.
目的
2
利用多种基因表达数据库和公共生物信息学平台,分析出与乳腺癌预后和免疫相关的关键基因,并对关键基因在乳腺癌中的预后价值和免疫作用情况进行验证和探讨。
方法
2
从Gene Expression Omnibus(GEO)数据库下载乳腺癌基因芯片表达数据集,分析获得差异表达基因(differentially expressed genes,DEGs)。通过构建和可视化DEGs-蛋白相互作用网络获得枢纽基因,利用R语言、STRING和Cytoscape等工具在枢纽基因中确定关键基因,利用外部数据集和The Cancer Genome Atlas(TCGA)验证关键基因差异表达情况,利用定量实时聚合酶链式反应(quantitative real-time polymerase chain reaction,qRT-PCR)验证关键基因在37个乳腺癌组织和相对应的癌旁组织中的差异表达情况,使用R语言、TIMER和Gene Set Enrichment Analysis(GSEA)等生物信息学工具和平台研究关键基因在乳腺癌中的预后价值和免疫学相关性。
结果
2
率先从302个差异基因中获取了10个枢纽基因,并通过生存分析筛选出关键基因UBE2C。GEO独立数据集、TCGA和qRT-PCR均证实UBE2C在乳腺癌组织中差异上调。预后分析显示UBE2C是一个独立的预后因素。UBE2C高表达降低乳腺癌组织中B细胞、CD4+ T细胞、CD8+ T细胞、巨噬细胞和髓系树突状细胞免疫浸润水平。UBE2C在乳腺癌中的表达与免疫检查点基因PDCD1、CD274和CTLA4的表达显著相关。UBE2C的表达与肿瘤突变负荷水平和微卫星不稳定性水平呈显著正相关。GSEA分析显示,在786个免疫相关基因集中UBE2C表达显著富集。
结论
2
UBE2C在乳腺癌组织中的表达与乳腺癌免疫微环境密切相关,其表达情况对预测乳腺癌患者的生存、预后和免疫治疗效果具有一定价值。UBE2C是乳腺癌的一种潜在的免疫相关的预后生物标志物。
Objective
2
To screen the target genes that are associated with survival of breast cancer (BRCA) and explore their prognostic values and immune correlations with BRCA using multiple databases..
Methods
2
The microarray expression datasets of BRCA were downloaded from the Gene Expresssion Omnibus database (GEO) and analyzed to obtain differentially expressed genes (DEGs). Hub genes were obtained by constructing and visualizing the protein-protein interaction network of DEGs. The key gene was determined using R language
STRING
and Cytoscape
and the differential expression of the key gene was verified using external datasets The Cancer Genome Atlas (TCGA) and quantitative real-time PCR (qRT-PCR) for BRCA tissues of 37 patients. The prognostic value and immunological correlation of
UBE2C
in BRCA were explored using R language
TIMER
and Gene Set Enrichment Analysis (GSEA).
Results
2
Of 10 hub genes seleceed from 302 DEGS
UBE2C
was identified as the gene associated with BRCA survival. The expression of
UBE2C
was differentially upregulated in BRCA
as verified by TCGA and qRT-PCR. Prognostic analysis revealed that
UBE2C
served as an independent prognostic factor. High expression of
UBE2C
was associated with decreased immune infiltration levels of B cells
CD4+ T cells
CD8+ T cells
macrophages
and myeloid dendritic cells in BRCA tissue. The expression of
UBE2C
in BRCA showed a significant correlation with immune checkpoints genes
PDCD1
CD274
and
CTLA4
expressions. There was a positive correlation between the expression of
UBE2C
and the tumor mutational burden and microsatellite instability. GSEA demonstrated that
UBE2C
expression significantly enriched 786 immune-related gene sets.
Conclusions
2
UBE2C
expression in BRCA tissues is closely related to the BRCA immune microenvironment and showes predictive values on the survivals
and prognosis of BRCA patients and the effecacy of immunotherapy.
UBE2C
may be an potential immune-related prognostic biomarker for BRCA.
Barzaman K , Karami J , Zarei Z , et al . Breast cancer: Biology, biomarkers, and treatments . Int Immunopharmacol 2020 ; 84 : 106535 . doi: 10.1016/j.intimp.2020.106535 http://dx.doi.org/10.1016/j.intimp.2020.106535 .
Bray F , Laversanne M , Sung H . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin 2024 ; 74 ( 3 ): 229 - 63 . doi: 10.3322/caac.21834 http://dx.doi.org/10.3322/caac.21834 .
Zheng RS , Chen R , Han BF , et al . [Cancer incidence and mortality in China, 2022] . Zhong Hua Zhong Liu Za Zhi 2024 ; 46 ( 3 ): 221 - 31 . doi: 10.3760/cma.j.cn112152-20240119-00035. (Chinese http://dx.doi.org/10.3760/cma.j.cn112152-20240119-00035.(Chinese )
Li Z , Chen Z , Hu G , et al . Roles of circular RNA in breast cancer: present and future . Am J Transl Res 2019 ; 11 ( 7 ): 3945 - 54 .
Liang G , Ling Y , Mehrpour M , et al . Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression . Mol Cancer 2020 ; 19 ( 1 ): 65 . doi: 10.1186/s12943-020-01152-2 http://dx.doi.org/10.1186/s12943-020-01152-2 .
Huang GZ , Chen ZQ , Wu J , et al . Pan-cancer analyses of the tumor microenvironment reveal that ubiquitin-conjugating enzyme E2C might be a potential immunotherapy target . J Immunol Res 2021 ; 9250207 . doi: 10.1155/2021/9250207 http://dx.doi.org/10.1155/2021/9250207 .
Mo CH , Gao L , Zhu XF , et al . The clinicopathological significance of UBE2C in breast cancer: a study based on immunohistochemistry, microarray and RNA-sequencing data . Cancer Cell Int 2017 ; 17 : 83 . doi: 10.1186/s12935-017-0455-1 http://dx.doi.org/10.1186/s12935-017-0455-1 .
Wang Y , Wang J , Tang Q , et al . Identification of UBE2C as hub gene in driving prostate cancer by integrated bioinformatics analysis . PLoS One 2021 ; 16 ( 2 ): e0247827 . doi: 10.1371/journal.pone.0247827 http://dx.doi.org/10.1371/journal.pone.0247827 .
Li R , Pang XF , Huang ZG , et al . Overexpression of UBE2C in esophageal squamous cell carcinoma tissues and molecular analysis . BMC Cancer 2021 ; 21 ( 1 ): 996 . doi: 10.1186/s12885-021-08634-6 http://dx.doi.org/10.1186/s12885-021-08634-6 .
Chiang AJ , Li CJ . UBE2C drives human cervical cancer progression and is positively modulated by mTOR . Biomolecules 2020 ; 11 ( 1 ): 37 . doi: 10.3390/biom11010037 http://dx.doi.org/10.3390/biom11010037 .
Li J , Zhi X , Shen X , et al . Depletion of UBE2C reduces ovarian cancer malignancy and reverses cisplatin resistance via downregulating CDK1 . Biochem Bioph Res Co 2020 ; 523 ( 2 ): 434 - 40 . doi: 10.1016/j.bbrc.2019.12.058 http://dx.doi.org/10.1016/j.bbrc.2019.12.058 .
Liu Y , Huang F , Chen H , et al . Expression of UBE2C in lung adenocarcinoma based on database analysis and its clinical significance . Zhong Nan Da Xue Xue Bao Yi Xue Ban 2020 ; 45 ( 9 ): 1044 - 52 . doi: 10.11817/j.issn.1672-7347.2020.190189. (Article in English, Chinese http://dx.doi.org/10.11817/j.issn.1672-7347.2020.190189.(ArticleinEnglish,Chinese )
Hao Z , Zhang H , Cowell J . Ubiquitin-conjugating enzyme UBE2C: molecular biology, role in tumorigenesis, and potential as a biomarker . Tumour Biol 2012 ; 33 ( 3 ): 723 - 30 . doi: 10.1007/s13277-011-0291-1 http://dx.doi.org/10.1007/s13277-011-0291-1 .
Chen DT , Nasir A , Culhane A , et al . Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue . Breast Cancer Res Treat 2010 ; 119 ( 2 ): 335 - 46 . doi: 10.1007/s10549-009-0344-y http://dx.doi.org/10.1007/s10549-009-0344-y .
Liu RZ , Graham K , Glubrecht DD , et al . Association of FABP5 expression with poor survival in triple-negative breast cancer: implication for retinoic acid therapy . Am J Pathol 2011 ; 178 ( 3 ): 997 - 1008 . doi: 10.1016/j.ajpath.2010.11.075 http://dx.doi.org/10.1016/j.ajpath.2010.11.075 .
Sinn BV , Fu C , Lau R , et al . SET ER/PR : a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer . NPJ Breast Cancer 2019 ; 5 : 16 . doi: 10.1038/s41523-019-0111-0 http://dx.doi.org/10.1038/s41523-019-0111-0 .
Edgar R , Domrachev M , Lash AE . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository . Nucleic Acids Res 2002 ; 30 ( 1 ): 207 - 10 . doi: 10.1093/nar/30.1.207 http://dx.doi.org/10.1093/nar/30.1.207 .
Barrett T , Wilhite SE , Ledoux P , et al . NCBI GEO: archive for functional genomics data sets—update . Nucleic Acids Res 2013; 41 (Database issue) : D991- 5 . doi: 10.1093/nar/gks1193 http://dx.doi.org/10.1093/nar/gks1193 .
Zhang X , Zhang W , Jiang Y , et al . Identification of functional lncRNAs in gastric cancer by integrative analysis of GEO and TCGA data . J Cell Biochem 2019 ; 120 ( 10 ): 17898 - 911 . doi: 10.1002/jcb.29058 http://dx.doi.org/10.1002/jcb.29058 .
Sun J , Huang J , Lan J , et al . Overexpression of CENPF correlates with poor prognosis and tumor bone metastasis in breast cancer . Cancer Cell Int 2019 ; 19 : 264 . doi: 10.1186/s12935-019-0986-8 http://dx.doi.org/10.1186/s12935-019-0986-8 .
Yu G , Wang LG , Han Y , et al . clusterProfiler: an R package for comparing biological themes among gene clusters . Omics 2012 ; 16 ( 5 ): 284 - 7 . doi: 10.1089/omi.2011.0118 http://dx.doi.org/10.1089/omi.2011.0118 .
Mootha VK , Lindgren CM , Eriksson KF , et al . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes . Nat Genet 2003 ; 34 ( 3 ): 267 - 73 . doi: 10.1038/ng1180 http://dx.doi.org/10.1038/ng1180 .
Subramanian A , Tamayo P , Mootha VK , et al . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles . Proc Natl Acad Sci U S A 2005 ; 102 ( 43 ): 15545 - 50 . doi: 10.1073/pnas.0506580102 http://dx.doi.org/10.1073/pnas.0506580102 .
Szklarczyk D , Gable AL , Nastou KC , et al . The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets . Nucleic Acids Res 2021 ; 49 (D 1 ): D605 - 12 . doi: 10.1093/nar/gkaa1074 http://dx.doi.org/10.1093/nar/gkaa1074 .
von Mering C , Huynen M , Jaeggi D , et al . STRING: a database of predicted functional associations between proteins . Nucleic Acids Res 2003 ; 31 ( 1 ): 258 - 61 . doi: 10.1093/nar/gkg034 http://dx.doi.org/10.1093/nar/gkg034 .
Shannon P , Markiel A , Ozier O , et al . Cytoscape: a software environment for integrated models of biomolecular interaction networks . Genome Res 2003 ; 13 ( 11 ): 2498 - 504 . doi: 10.1101/gr.1239303 http://dx.doi.org/10.1101/gr.1239303 .
Chin CH , Chen SH , Wu HH , et al . cytoHubba: identifying hub objects and sub-networks from complex interactome . BMC Sys Bio 2014 ; 8 Suppl 4 (Suppl 4): S11 . doi: 10.1186/1752-0509-8-s4-s11 http://dx.doi.org/10.1186/1752-0509-8-s4-s11 .
Gruosso T , Mieulet V , Cardon M , et al . Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients . EMBO Mol Med 2016 ; 8 ( 5 ): 527 - 49 . doi: 10.15252/emmm.201505891 http://dx.doi.org/10.15252/emmm.201505891 .
Liu Z , Mi M , Li X , et al . A lncRNA prognostic signature associated with immune infiltration and tumour mutation burden in breast cancer . J Cell Mol Med 2020 ; 24 ( 21 ): 12444 - 56 . doi: 10.1111/jcmm.15762 http://dx.doi.org/10.1111/jcmm.15762 .
Xiong Y , Yuan L , Xiong J , et al . An outcome model for human bladder cancer: A comprehensive study based on weighted gene co-expression network analysis . J Cell Mol Med 2020 ; 24 ( 3 ): 2342 - 55 . doi: 10.1111/jcmm.14918 http://dx.doi.org/10.1111/jcmm.14918 .
Jeong SH , Kim RB , Park SY , et al . Nomogram for predicting gastric cancer recurrence using biomarker gene expression . Eur J Surg Oncol 2020 ; 46 ( 1 ): 195 - 201 . doi: 10.1016/j.ejso.2019.09.143 http://dx.doi.org/10.1016/j.ejso.2019.09.143 .
Becht E , Giraldo NA , Lacroix L , et al . Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression . Genome Biol 2016 ; 17 ( 1 ): 218 . doi: 10.1186/s13059-016-1070-5 http://dx.doi.org/10.1186/s13059-016-1070-5 .
Sturm G , Finotello F , Petitprez F , et al . Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology . Bioinformatics (Oxford, England) 2019 ; 35 ( 14 ): i436 - 45 . doi: 10.1093/bioinformatics/btz363 http://dx.doi.org/10.1093/bioinformatics/btz363 .
Racle J , de Jonge K , Baumgaertner P , et al . Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data . Elife 2017 ; 6 : e26476 . doi: 10.7554/eLife.26476 http://dx.doi.org/10.7554/eLife.26476 .
Li T , Fu J , Zeng Z , et al . TIMER2.0 for analysis of tumor-infiltrating immune cells . Nucleic Acids Res 2020 ; 48 (W 1 ): W509 - 14 . doi: 10.1093/nar/gkaa407 http://dx.doi.org/10.1093/nar/gkaa407 .
Dastsooz H , Cereda M . A comprehensive bioinformatics analysis of UBE2C in cancers . Int J Mol Sci 2019 ; 20 ( 9 ). doi: 10.3390/ijms20092228 http://dx.doi.org/10.3390/ijms20092228 .
Jiang X , Yuan Y , Tang L , et al . Comprehensive pan-cancer analysis of the prognostic and immunological roles of the METTL3/lncRNA-SNHG1/miRNA-140-3p/UBE2C Axis . Front Cell Dev Biol 2021 ; 9 : 765772 . doi: 10.3389/fcell.2021.765772 http://dx.doi.org/10.3389/fcell.2021.765772 .
Lu ZN , Song J , Sun TH , et al . UBE2C affects breast cancer proliferation through the AKT/mTOR signaling pathway . Chin Med J (Engl) 2021 ; 134 ( 20 ): 2465 - 74 . doi: 10.1097/cm9.0000000000001708 http://dx.doi.org/10.1097/cm9.0000000000001708 .
Xiang C , Yan HC . Ubiquitin conjugating enzyme E2 C (UBE2C) may play a dual role involved in the progression of thyroid carcinoma . Cell Death Discov 2022 ; 8 ( 1 ): 130 . doi: 10.1038/s41420-022-00935-4 http://dx.doi.org/10.1038/s41420-022-00935-4 .
Huang R , Liu J , Li H , et al . Identification of hub genes and their correlation with immune infiltration cells in hepatocellular carcinoma based on GEO and TCGA databases . Front Genet 2021 ; 12 : 647353 . doi: 10.3389/fgene.2021.647353 http://dx.doi.org/10.3389/fgene.2021.647353 .
Publicity Resources
Related Articles
Related Author
Related Institution