Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells
机构：[1]Department of Oncology, Jiulongpo People’s Hospital of Chongqing, Chongqing, China,[2]Department of Urology Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,重庆医科大学附属第一医院[3]Department of Critical Care Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China international Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China,[4]Department of Pathology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,四川省人民医院四川省肿瘤医院[5]Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China,[6]Department of Orthopaedics, Jiulongpo People’s Hospital of Chongqing, Chongqing, China,[7]Department of Patient Service Center, Jiulongpo People’s Hospital of Chongqing, Chongqing, China,[8]College of Bioengineering, “111 Project” Laboratory of Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing, China
Purpose Ferroptosis is a type of cell death that is iron dependent, a characteristic that distinguishes it from necrosis, apoptosis, and autophagy. However, the ferroptotic mechanisms for hepatitis B virus-associated hepatocellular carcinoma (HCC) remain incompletely described. Methods Two hepatitis B virus-associated HCC public datasets, GSE22058 (n=192) and GSE54238 (n=23), were obtained from the NCBI Gene Expression Omnibus (GEO) database. Bioinformatics methods, including weighted gene coexpression network analysis (WGCNA), Cox regression, and LASSO analysis, were used to identify signature markers for diagnosis and prognosis. CCK8, wound healing, Transwell migration/invasion, and ferroptosis assays were employed to explore the biological function of novel candidate markers weight gene coexpression network analysis. Results In total, 926 differentially expressed genes (DEGs) were common between the GSE22058 and GSE54238 datasets. Following WGCNA, 515 DEGs derived from the MEturquoise gene module were employed to establish diagnosis and prognosis models in The Cancer Genome Atlas (TCGA) HCC RNA-Seq cohort (n=423). The score of the diagnostic model was strikingly upregulated in the TCGA HCC group (p<2.2e-16). The prognostic model exhibited high specificity and sensitivity in both training and validation (AUC=0.835 and 0.626, respectively), and the high-risk group showed dismal prognostic outcomes compared with the low-risk group (training: p=1.416e-10; validation: p=4.495e-02). Ubiquitin-like modifier activating enzyme 1 (UBA1) was identified among both diagnosis and prognosis signature genes, and its overexpression was associated with poor survival. We validated the expression level of UBA1 in eight pairs of HCC patient tissues and liver cancer cell lines. UBA1 silencing decreased proliferation, migration, and invasion in Huh7 cells while elevating the Fe2+ and malondialdehyde (MDA) levels. Additionally, these biological effects were recovered by oltipraz (an Nrf2 activator). Furthermore, blocking UBA1 strikingly repressed the protein expression levels of Nrf2, HO-1, NQO1, and FTH1 in the Nrf2 signal transduction pathway. Conclusion Our findings demonstrated that UBA1 participates in the development of HCC by modulating Huh7 phenotypes and ferroptosis via the Nrf2 signal transduction pathway and might be a promising diagnostic and prognostic indicator for HCC.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81904218, 82074437]; China Postdoctoral Science Found [2019M653831XB]; Natural Science Foundation of Chongqing, ChinaNatural Science Foundation of Chongqing [cstc2019jcyjmsxmX0095]
第一作者机构：[1]Department of Oncology, Jiulongpo People’s Hospital of Chongqing, Chongqing, China,
共同第一作者：
通讯作者：
通讯机构：[5]Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China,[8]College of Bioengineering, “111 Project” Laboratory of Biomechanics & Tissue Repair Engineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing, China
推荐引用方式(GB/T 7714)：
Shan Yiru,Yang Guang,Huang Haixia,et al.Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells[J].FRONTIERS IN ONCOLOGY.2020,10:doi:10.3389/fonc.2020.592413.
APA：
Shan, Yiru,Yang, Guang,Huang, Haixia,Zhou, Yehan,Hu, Xiangyu...&Pan, Qi.(2020).Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells.FRONTIERS IN ONCOLOGY,10,
MLA：
Shan, Yiru,et al."Ubiquitin-Like Modifier Activating Enzyme 1 as a Novel Diagnostic and Prognostic Indicator That Correlates With Ferroptosis and the Malignant Phenotypes of Liver Cancer Cells".FRONTIERS IN ONCOLOGY 10.(2020)
