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Li H, Li F, Wang BS, Zhu BL. Prognostic significance of exportin-5 in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:3069-3081. [PMID: 39072169 PMCID: PMC11271777 DOI: 10.4251/wjgo.v16.i7.3069] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/05/2024] [Accepted: 05/22/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. As liver cancer often presents no noticeable symptoms in its early stages, most patients are diagnosed at an advanced stage, complicating treatment. Therefore, the identification of new biomarkers is crucial for the early detection and treatment of HCC. Research on exportin-5 (XPO5) could offer new avenues for early diagnosis and improve treatment strategies. AIM To explore the role of XPO5 in HCC progression and its potential as a prognostic biomarker. METHODS This study assessed XPO5 mRNA expression in HCC using The Cancer Genome Atlas, TIMER, and International Cancer Genome Consortium databases, correlating it with clinical profiles and disease progression. We performed in vitro experiments to examine the effect of XPO5 on liver cell growth. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology were used to elucidate the biological roles and signaling pathways. We also evaluated XPO5's impact on immune cell infiltration and validated its prognostic potential using machine learning. RESULTS XPO5 was significantly upregulated in HCC tissues, correlating with tumor grade, T-stage, and overall survival, indicating poor prognosis. Enrichment analyses linked high XPO5 expression with tumor immunity, particularly CD4 T cell memory activation and macrophage M0 infiltration. Drug sensitivity tests identified potential therapeutic agents such as MG-132, paclitaxel, and WH-4-023. Overexpression of XPO5 in HCC cells, compared to normal liver cells, was confirmed by western blotting and quantitative real-time polymerase chain reaction. The lentiviral transduction-mediated knockdown of XPO5 significantly reduced cell proliferation and metastasis. Among the various machine learning algorithms, the C5.0 decision tree algorithm achieved accuracy rates of 95.5% in the training set and 92.0% in the validation set. CONCLUSION Our analysis shows that XPO5 expression is a reliable prognostic indicator for patients with HCC and is significantly associated with immune cell infiltration.
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Affiliation(s)
- Hao Li
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210000, Jiangsu Province, China
- Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, Jiangsu Province, China
| | - Fei Li
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210000, Jiangsu Province, China
- Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, Jiangsu Province, China
| | - Bo-Shen Wang
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210000, Jiangsu Province, China
- Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, Jiangsu Province, China
| | - Bao-Li Zhu
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Southeast University, Nanjing 210000, Jiangsu Province, China
- Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210000, Jiangsu Province, China
- Committee, Jiangsu Preventive Medical Association, Nanjing 210000, Jiangsu Province, China
- Center for Global Health, Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
- Public Health Sector, Jiangsu Province Engineering Research Center Jiangsu Province Engineering Research Center of Health Emergency, Nanjing 210000, Jiangsu Province, China
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Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:210. [PMID: 37217462 PMCID: PMC10203321 DOI: 10.1038/s41392-023-01480-x] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/17/2023] [Accepted: 04/28/2023] [Indexed: 05/24/2023] Open
Abstract
Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed.
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Affiliation(s)
- Jing Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Li Q, Xu Z, Fang F, Shen Y, Lei H, Shen X. Identification of key pathways, genes and immune cell infiltration in hypoxia of high-altitude acclimatization via meta-analysis and integrated bioinformatics analysis. Front Genet 2023; 14:1055372. [PMID: 37035734 PMCID: PMC10080023 DOI: 10.3389/fgene.2023.1055372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 03/15/2023] [Indexed: 04/11/2023] Open
Abstract
Background: For individuals acutely exposed to high-altitude regions, environmental hypobaric hypoxia induces several physiological or pathological responses, especially immune dysfunction. Therefore, hypoxia is a potentially life-threatening factor, which has closely related to high-altitude acclimatization. However, its specific molecular mechanism is still unclear. Methods: The four expression profiles about hypoxia and high altitude were downloaded from the Gene Expression Omnibus database in this study. Meta-analysis of GEO datasets was performed by NetworkAnalyst online tool. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) enrichment analysis, and visualization were performed using R (version 4.1.3) software, respectively. The CIBERSORT analysis was conducted on GSE46480 to examine immune cell infiltration. In addition, we experimentally verified the bioinformatics analysis with qRT-PCR. Results: The meta-analysis identified 358 differentially expressed genes (DEGs), with 209 upregulated and 149 downregulated. DEGs were mostly enriched in biological processes and pathways associated with hypoxia acclimatization at high altitudes, according to both GO and KEGG enrichment analyses. ERH, VBP1, BINP3L, TOMM5, PSMA4, and POLR2K were identified by taking intersections of the DEGs between meta-analysis and GSE46480 and verified by qRT-PCR experiments, which were inextricably linked to hypoxia. Immune infiltration analysis showed significant differences in immune cells between samples at sea level and high altitudes. Conclusion: Identifying the DEGs and pathways will improve our understanding of immune function during high-altitude hypoxia at a molecular level. Targeting hypoxia-sensitive pathways in immune cells is interesting in treating high-altitude sickness. This study provides support for further research on high-altitude acclimatization.
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Affiliation(s)
- Qiong Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Zhichao Xu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Fujin Fang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Yan Shen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Huan Lei
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Xiaobing Shen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu, China
- *Correspondence: Xiaobing Shen,
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Gu Y, Wu X, Zhang J, Fang Y, Pan Y, Shu Y, Ma P. The evolving landscape of N 6-methyladenosine modification in the tumor microenvironment. Mol Ther 2021; 29:1703-1715. [PMID: 33839323 DOI: 10.1016/j.ymthe.2021.04.009] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/22/2021] [Accepted: 04/06/2021] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N6-methylation of adenosine (m6A) modification is the most common type of RNA methylation that occurs in the N6-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that m6A regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of m6A modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the m6A modification modulates and interacts with it. We also focus on various factors and pathways involved in m6A methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and m6A modification.
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Affiliation(s)
- Yunru Gu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Xi Wu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Jingxin Zhang
- Department of General Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang Clinic School of Nanjing Medical University, Zhenjiang 212002, People's Republic of China
| | - Yuan Fang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Yutian Pan
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Yongqian Shu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, People's Republic of China.
| | - Pei Ma
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.
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Mo Z, Liu D, Rong D, Zhang S. Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma. Front Immunol 2021; 12:611058. [PMID: 33679749 PMCID: PMC7928397 DOI: 10.3389/fimmu.2021.611058] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/28/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC. Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score. Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts. Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.
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Affiliation(s)
- Zhuomao Mo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Daiyuan Liu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Dade Rong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shijun Zhang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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