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1
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Xin MJ, Yuan Y. Centromere protein A knockdown inhibits rectal cancer through O6-methylguanine DNA methyltransferase/protein tyrosine phosphatase nonreceptor type 4 axis. World J Gastrointest Oncol 2025; 17:102619. [DOI: 10.4251/wjgo.v17.i4.102619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/07/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Centromere protein A (CENPA) exhibits an increased expression level in primary human rectal cancer tissues, but its role has not been investigated.
AIM To clarify the specific role and mechanism of CENPA in rectal cancer progression.
METHODS CENPA protein expression in rectal cancer tissues and cell lines were detected. CENPA was overexpressed and knocked down in SW837 and SW480 cells, and proliferation, invasion, apoptosis and epithelial-mesenchymal transition (EMT) marker protein levels were examined. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was assessed with methylation-specific polymerase chain reaction. Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4 (PTPN4). SW837 cells with CENPA knockdown were injected subcutaneously into mice, and tumor growth was examined.
RESULTS CENPA was upregulated in rectal cancer tissues and cell lines. CENPA overexpression promoted proliferation, invasion and EMT, and inhibited apoptosis in rectal cancer cells. Whereas CENPA knockdown showed the opposite results. Moreover, CENPA inhibited MGMT expression by promoting DNA methyltransferase 1-mediated MGMT promoter methylation. MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression. MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation via competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4. PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression. Moreover, CENPA knockdown inhibited xenograft tumor growth in vivo.
CONCLUSION CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.
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Affiliation(s)
- Ming-Jie Xin
- Medical College, Henan Vocational University of Science and Technology, Zhoukou 466000, Henan Province, China
| | - Yong Yuan
- Medical College, Henan Vocational University of Science and Technology, Zhoukou 466000, Henan Province, China
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2
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Zheng Y, Yang Y, Xiong Q, Ma Y, Zhu Q. Establishment and Verification of a Novel Gene Signature Connecting Hypoxia and Lactylation for Predicting Prognosis and Immunotherapy of Pancreatic Ductal Adenocarcinoma Patients by Integrating Multi-Machine Learning and Single-Cell Analysis. Int J Mol Sci 2024; 25:11143. [PMID: 39456925 PMCID: PMC11508839 DOI: 10.3390/ijms252011143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has earned a notorious reputation as one of the most formidable and deadliest malignant tumors. Within the tumor microenvironment, cancer cells have acquired the capability to maintain incessant expansion and increased proliferation in response to hypoxia via metabolic reconfiguration, leading to elevated levels of lactate within the tumor surroundings. However, there have been limited studies specifically investigating the association between hypoxia and lactic acid metabolism-related lactylation in PDAC. In this study, multiple machine learning approaches, including LASSO regression analysis, XGBoost, and Random Forest, were employed to identify hub genes and construct a prognostic risk signature. The implementation of the CERES score and single-cell analysis was used to discern a prospective therapeutic target for the management of PDAC. CCK8 assay, colony formation assays, transwell, and wound-healing assays were used to explore both the proliferation and migration of PDAC cells affected by CENPA. In conclusion, we discovered two distinct subtypes characterized by their unique hypoxia and lactylation profiles and developed a risk score to evaluate prognosis, as well as response to immunotherapy and chemotherapy, in PDAC patients. Furthermore, we indicated that CENPA may serve as a promising therapeutic target for PDAC.
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Affiliation(s)
| | | | | | | | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, China; (Y.Z.)
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3
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Ma X, Huang T, Li X, Zhou X, Pan H, Du A, Zeng Y, Yuan K, Wang Z. Exploration of the link between COVID-19 and gastric cancer from the perspective of bioinformatics and systems biology. Front Med (Lausanne) 2024; 11:1428973. [PMID: 39371335 PMCID: PMC11449776 DOI: 10.3389/fmed.2024.1428973] [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: 05/07/2024] [Accepted: 09/04/2024] [Indexed: 10/08/2024] Open
Abstract
Background Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic. Gastric cancer (GC) poses a great threat to people's health, which is a high-risk factor for COVID-19. Previous studies have found some associations between GC and COVID-19, whereas the underlying molecular mechanisms are not well understood. Methods We employed bioinformatics and systems biology to explore these links between GC and COVID-19. Gene expression profiles of COVID-19 (GSE196822) and GC (GSE179252) were obtained from the Gene Expression Omnibus (GEO) database. After identifying the shared differentially expressed genes (DEGs) for GC and COVID-19, functional annotation, protein-protein interaction (PPI) network, hub genes, transcriptional regulatory networks and candidate drugs were analyzed. Results We identified 209 shared DEGs between COVID-19 and GC. Functional analyses highlighted immune-related pathways as key players in both diseases. Ten hub genes (CDK1, KIF20A, TPX2, UBE2C, HJURP, CENPA, PLK1, MKI67, IFI6, IFIT2) were identified. The transcription factor/gene and miRNA/gene interaction networks identified 38 transcription factors (TFs) and 234 miRNAs. More importantly, we identified ten potential therapeutic agents, including ciclopirox, resveratrol, etoposide, methotrexate, trifluridine, enterolactone, troglitazone, calcitriol, dasatinib and deferoxamine, some of which have been reported to improve and treat GC and COVID-19. Conclusion This research offer valuable insights into the molecular interplay between COVID-19 and GC, potentially guiding future therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | | | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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4
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Lai PM, Gong X, Chan KM. Roles of Histone H2B, H3 and H4 Variants in Cancer Development and Prognosis. Int J Mol Sci 2024; 25:9699. [PMID: 39273649 PMCID: PMC11395991 DOI: 10.3390/ijms25179699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
Histone variants are the paralogs of core histones (H2A, H2B, H3 and H4). They are stably expressed throughout the cell cycle in a replication-independent fashion and are capable of replacing canonical counterparts under different fundamental biological processes. Variants have been shown to take part in multiple processes, including DNA damage repair, transcriptional regulation and X chromosome inactivation, with some of them even specializing in lineage-specific roles like spermatogenesis. Several reports have recently identified some unprecedented variants from different histone families and exploited their prognostic value in distinct types of cancer. Among the four classes of canonical histones, the H2A family has the greatest number of variants known to date, followed by H2B, H3 and H4. In our prior review, we focused on summarizing all 19 mammalian histone H2A variants. Here in this review, we aim to complete the full summary of the roles of mammalian histone variants from the remaining histone H2B, H3, and H4 families, along with an overview of their roles in cancer biology and their prognostic value in a clinical context.
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Affiliation(s)
| | | | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China; (P.M.L.); (X.G.)
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5
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Sethi SC, Shrestha RL, Balachandra V, Durairaj G, Au WC, Nirula M, Karpova TS, Kaiser P, Basrai MA. β-TrCP-Mediated Proteolysis of Mis18β Prevents Mislocalization of CENP-A and Chromosomal Instability. Mol Cell Biol 2024; 44:429-442. [PMID: 39135477 PMCID: PMC11486186 DOI: 10.1080/10985549.2024.2382445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/08/2024] [Accepted: 07/12/2024] [Indexed: 10/15/2024] Open
Abstract
Restricting the localization of evolutionarily conserved histone H3 variant CENP-A to the centromere is essential to prevent chromosomal instability (CIN), an important hallmark of cancers. Overexpressed CENP-A mislocalizes to non-centromeric regions and contributes to CIN in yeast, flies, and human cells. Centromeric localization of CENP-A is facilitated by the interaction of Mis18β with CENP-A specific chaperone HJURP. Cellular levels of Mis18β are regulated by β-transducin repeat containing protein (β-TrCP), an F-box protein of SCF (Skp1, Cullin, F-box) E3-ubiquitin ligase complex. Here, we show that defects in β-TrCP-mediated proteolysis of Mis18β contributes to the mislocalization of endogenous CENP-A and CIN in a triple-negative breast cancer (TNBC) cell line, MDA-MB-231. CENP-A mislocalization in β-TrCP depleted cells is dependent on high levels of Mis18β as depletion of Mis18β suppresses mislocalization of CENP-A in these cells. Consistent with these results, endogenous CENP-A is mislocalized in cells overexpressing Mis18β alone. In summary, our results show that β-TrCP-mediated degradation of Mis18β prevents mislocalization of CENP-A and CIN. We propose that deregulated expression of Mis18β may be one of the key mechanisms that contributes to chromosome segregation defects in cancers.
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Affiliation(s)
- Subhash Chandra Sethi
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Roshan Lal Shrestha
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Vinutha Balachandra
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Geetha Durairaj
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA
| | - Wei-Chun Au
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael Nirula
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Tatiana S. Karpova
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Peter Kaiser
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA
| | - Munira A. Basrai
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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6
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Balachandra V, Shrestha RL, Hammond CM, Lin S, Hendriks IA, Sethi SC, Chen L, Sevilla S, Caplen NJ, Chari R, Karpova TS, McKinnon K, Todd MA, Koparde V, Cheng KCC, Nielsen ML, Groth A, Basrai MA. DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains. EMBO J 2024; 43:2166-2197. [PMID: 38600242 PMCID: PMC11148058 DOI: 10.1038/s44318-024-00093-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/12/2024] Open
Abstract
The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3-H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3-H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3-H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.
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Grants
- 75N91019D00024 NCI NIH HHS
- HHSN261201500003I NCI NIH HHS
- ZIA BC 010822 HHS | NIH | NCI | Center for Cancer Research (CCR)
- ZIA BC 011704 HHS | NIH | NCI | Center for Cancer Research (CCR)
- 75N91019D00024 NCI NIH HHS
- HHSN261201500003I NCI NIH HHS
- 0135-00096B and 8020-00220B,EPIC-XS-823839,R146-A9159-16-S2 Independent Research Fund Denmark, European Union's Horizon 2020 research and innovation program, Danish Cancer Society
- ERC CoG 724436,R198-2015-269 and R313-2019-448,7016-00042B,NNF21OC0067425,NNF14CC0001 European Research Council, Lund-beck Foundation, Independent Research Fund Denmark, Novo Nordisk Foundation
- HHS | NIH | National Cancer Institute (NCI)
- Independent Research Fund Denmark, European Union’s Horizon 2020 research and innovation program, Danish Cancer Society
- NIH Intramural Research Program, Intramural Research Program of the National Center for Advancing Translational Sciences (NCATS)
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Affiliation(s)
- Vinutha Balachandra
- Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Roshan L Shrestha
- Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Colin M Hammond
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
| | - Shinjen Lin
- Functional Genomics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Ivo A Hendriks
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Subhash Chandra Sethi
- Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lu Chen
- Functional Genomics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Samantha Sevilla
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Natasha J Caplen
- Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Raj Chari
- Genome Modification Core (GMC), Frederick National Lab for Cancer Research, Frederick, MD, USA
| | - Tatiana S Karpova
- Optical Microscopy Core, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Katherine McKinnon
- Flow Cytometry Core, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Matthew Am Todd
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Vishal Koparde
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Ken Chih-Chien Cheng
- Functional Genomics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Michael L Nielsen
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anja Groth
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Munira A Basrai
- Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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7
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Aldwaik RK, Shian D, Thapa R, Vasudevan S, Ashqar MAA, Reich E, Kravchenko-Balasha N, Klutstein M. Overexpressed kinetochore genes are used by cancer cells as genome destabilizers and transformation catalysts. Transl Oncol 2023; 34:101703. [PMID: 37295219 DOI: 10.1016/j.tranon.2023.101703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer cells have an altered transcriptome, which contributes to their abnormal behavior. Many tumors have high levels of kinetochore genes, which play important roles in genome stability. This overexpression could be utilized to destabilize cancer cell genomes, however this has not been proven specifically. We investigated the link between kinetochore gene overexpression, chromosomal number variations (CNVs) and genomic instability. Data on RNA expression and CNV from 12 different cancer types were evaluated using information theory. In all cancer types, we looked at the relationship between RNA expression and CNVs. Kinetochore gene expression was found to be substantially linked with CNV levels. In all cancer types, with the exception of thyroid cancer, highly expressed kinetochore genes were enriched in the most dominant cancer-specific co-expression subnetworks characterizing the largest patient subgroups. Except for thyroid cancer, kinetochore inner protein CENPA was among the transcripts most strongly associated with CNV values in all cancer types studied, with significantly higher expression levels in patients with high CNVs than in patients with low CNVs. CENPA function was investigated further in cell models by transfecting genomically stable (HCT116) and unstable (MCF7 and HT29) cancer cell lines using CENPA overexpression vectors. This overexpression increased the number of abnormal cell divisions in the stable cancer cell line HCT116 and, to a lesser extent, in the unstable cell lines MCF7 and HT29. Overexpression improved anchorage-independent growth properties of all cell lines. Our findings suggest that overexpression of kinetochore genes in general, and CENPA in particular, can cause genomic instability and cancer progression.
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Affiliation(s)
- Reem Kamal Aldwaik
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Denen Shian
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Roshina Thapa
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Swetha Vasudevan
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Mimi Abo-Ayoub Ashqar
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Eli Reich
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel
| | - Nataly Kravchenko-Balasha
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel.
| | - Michael Klutstein
- The Institute of Biomedical and Oral Research, Faculty of Dental Medicine, The Hebrew University of Jerusalem, P.O.B. 12272, Ein Kerem, Jerusalem 91120, Israel.
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8
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Song S, Gu H, Li J, Yang P, Qi X, Liu J, Zhou J, Li Y, Shu P. Identification of immune-related gene signature for predicting prognosis in uterine corpus endometrial carcinoma. Sci Rep 2023; 13:9255. [PMID: 37286702 DOI: 10.1038/s41598-023-35655-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 05/22/2023] [Indexed: 06/09/2023] Open
Abstract
The objective of this study is to develop a gene signature related to the immune system that can be used to create personalized immunotherapy for Uterine Corpus Endometrial Carcinoma (UCEC). To classify the UCEC samples into different immune clusters, we utilized consensus clustering analysis. Additionally, immune correlation algorithms were employed to investigate the tumor immune microenvironment (TIME) in diverse clusters. To explore the biological function, we conducted GSEA analysis. Next, we developed a Nomogram by integrating a prognostic model with clinical features. Finally, we performed experimental validation in vitro to verify our prognostic risk model. In our study, we classified UCEC patients into three clusters using consensus clustering. We hypothesized that cluster C1 represents the immune inflammation type, cluster C2 represents the immune rejection type, and cluster C3 represents the immune desert type. The hub genes identified in the training cohort were primarily enriched in the MAPK signaling pathway, as well as the PD-L1 expression and PD-1 checkpoint pathway in cancer, all of which are immune-related pathways. Cluster C1 may be a more suitable for immunotherapy. The prognostic risk model showed a strong predictive ability. Our constructed risk model demonstrated a high level of accuracy in predicting the prognosis of UCEC, while also effectively reflecting the state of TIME.
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Affiliation(s)
- Siyuan Song
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Haoqing Gu
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Jingzhan Li
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Peipei Yang
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Xiafei Qi
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Jiatong Liu
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Jiayu Zhou
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Ye Li
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China
| | - Peng Shu
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu Province, China.
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9
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Chen Y, Zhu Z, Ma T, Zhang L, Chen J, Jiang J, Lu C, Ding Y, Guan W, Yi N, Ren H. TP53 mutation-related senescence is an indicator of hepatocellular carcinoma patient outcomes from multiomics profiles. SMART MEDICINE 2023; 2:e20230005. [PMID: 39188277 PMCID: PMC11235654 DOI: 10.1002/smmd.20230005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/13/2023] [Indexed: 08/28/2024]
Abstract
TP53 mutation frequently occurs in hepatocellular carcinoma (HCC). Senescence also plays a vital role in the ongoing process of HCC. P53 is believed to regulate the advancement of senescence in HCC. However, the exact mechanism of TP53 mutation-related senescence remains unclear. In this study, we found the TP53 mutation was positively correlated with senescence in HCC, and the differential expressed genes were primarily located in macrophages. Our results proved that the risk score could have an independent and vital role in predicting the prognosis of HCC patients. In addition, HCC patients with a high risk score may most probably benefit from immune checkpoint block therapy. We also found the risk score is elevated in chemotherapy-treated HCC samples, with a high level of senescence-associated secretory phenotype. Finally, we validated the risk-score genes in the protein level and noticed the risk score is positively related with M2 polarization. Of note, we considered that the risk score under the TP53 mutation and senescence is a promising biomarker with the potential to aid in predicting prognosis, defining tumor environment characteristics, and assessing the benefits of immunotherapy for HCC patients.
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Affiliation(s)
- Yu‐Yan Chen
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Zheng‐Yi Zhu
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Tao Ma
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Lu Zhang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
| | - Jing Chen
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Jia‐Wei Jiang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Cui‐Hua Lu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Yi‐Tao Ding
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Wen‐Xian Guan
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Nan Yi
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Hao‐Zhen Ren
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
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10
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Yang Y, Duan M, Zha Y, Wu Z. CENP-A is a potential prognostic biomarker and correlated with immune infiltration levels in glioma patients. Front Genet 2022; 13:931222. [PMID: 36105094 PMCID: PMC9465177 DOI: 10.3389/fgene.2022.931222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/05/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Centromeric protein A (CENP-A), an essential protein involved in chromosomal segregation during cell division, is associated with several cancer types. However, its role in gliomas remains unclear. This study examined the clinical and prognostic significance of CENP-A in gliomas. Methods: Data of patients with glioma were collected from the Cancer Genome Atlas. Logistic regression, the Kruskal–Wallis test, and the Wilcoxon signed-rank test were performed to assess the relationship between CENP-A expression and clinicopathological parameters. The Cox regression model and Kaplan–Meier curve were used to analyze the association between CENP-A and survival outcomes. A prognostic nomogram was constructed based on Cox multivariate analysis. Gene set enrichment analysis (GSEA) was conducted to identify key CENP-A-related pathways and biological processes. Results:CENP-A was upregulated in glioma samples. Increased CENP-A levels were significantly associated with the world health organization (WHO) grade [Odds ratio (OR) = 49.88 (23.52–129.06) for grade 4 vs. grades 2 and 3], primary therapy outcome [OR = 2.44 (1.64–3.68) for progressive disease (PD) and stable disease (SD) vs. partial response (PR) and complete response (CR)], isocitrate dehydrogenase (IDH) status [OR = 13.76 (9.25–20.96) for wild-type vs. mutant], 1p/19q co-deletion [OR = 5.91 (3.95–9.06) for no codeletion vs. co-deletion], and age [OR = 4.02 (2.68–6.18) for > 60 vs. ≤ 60]. Elevated CENP-A expression was correlated with shorter overall survival in both univariate [hazard ratio (HR): 5.422; 95% confidence interval (CI): 4.044–7.271; p < 0.001] and multivariate analyses (HR: 1.967; 95% CI: 1.280–3.025; p < 0.002). GSEA showed enrichment of numerous cell cycle-and tumor-related pathways in the CENP-A high expression phenotype. The calibration plot and C-index indicated the favorable performance of our nomogram for prognostic prediction in patients with glioma. Conclusion: We propose a role for CENP-A in glioma progression and its potential as a biomarker for glioma diagnosis and prognosis.
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Affiliation(s)
- Yuan Yang
- Department of Radiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengyun Duan
- Health Science Center, Department of Medical Imaging, Yangtze University, Jingzhou, China
| | - Yunfei Zha
- Department of Radiology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Yunfei Zha, ; Zijun Wu,
| | - Zijun Wu
- Department of Radiology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Yunfei Zha, ; Zijun Wu,
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11
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Renaud-Pageot C, Quivy JP, Lochhead M, Almouzni G. CENP-A Regulation and Cancer. Front Cell Dev Biol 2022; 10:907120. [PMID: 35721491 PMCID: PMC9201071 DOI: 10.3389/fcell.2022.907120] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
In mammals, CENP-A, a histone H3 variant found in the centromeric chromatin, is critical for faithful chromosome segregation and genome integrity maintenance through cell divisions. Specifically, it has dual functions, enabling to define epigenetically the centromere position and providing the foundation for building up the kinetochore. Regulation of its dynamics of synthesis and deposition ensures to propagate proper centromeres on each chromosome across mitosis and meiosis. However, CENP-A overexpression is a feature identified in many cancers. Importantly, high levels of CENP-A lead to its mislocalization outside the centromere. Recent studies in mammals have begun to uncover how CENP-A overexpression can affect genome integrity, reprogram cell fate and impact 3D nuclear organization in cancer. Here, we summarize the mechanisms that orchestrate CENP-A regulation. Then we review how, beyond its centromeric function, CENP-A overexpression is linked to cancer state in mammalian cells, with a focus on the perturbations that ensue at the level of chromatin organization. Finally, we review the clinical interest for CENP-A in cancer treatment.
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12
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Zhong X, Yu X, Chang H. Exploration of a Novel Prognostic Nomogram and Diagnostic Biomarkers Based on the Activity Variations of Hallmark Gene Sets in Hepatocellular Carcinoma. Front Oncol 2022; 12:830362. [PMID: 35359370 PMCID: PMC8960170 DOI: 10.3389/fonc.2022.830362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/10/2022] [Indexed: 12/12/2022] Open
Abstract
Background The initiation and progression of tumors were due to variations of gene sets rather than individual genes. This study aimed to identify novel biomarkers based on gene set variation analysis (GSVA) in hepatocellular carcinoma. Methods The activities of 50 hallmark pathways were scored in three microarray datasets with paired samples with GSVA, and differential analysis was performed with the limma R package. Unsupervised clustering was conducted to determine subtypes with the ConsensusClusterPlus R package in the TCGA-LIHC (n = 329) and LIRI-JP (n = 232) cohorts. Differentially expressed genes among subtypes were identified as initial variables. Then, we used TCGA-LIHC as the training set and LIRI-JP as the validation set. A six-gene model calculating the risk scores of patients was integrated with the least absolute shrinkage and selection operator (LASSO) and stepwise regression analyses. Kaplan–Meier (KM) and receiver operating characteristic (ROC) curves were performed to assess predictive performances. Multivariate Cox regression analyses were implemented to select independent prognostic factors, and a prognostic nomogram was integrated. Moreover, the diagnostic values of six genes were explored with the ROC curves and immunohistochemistry. Results Patients could be separated into two subtypes with different prognoses in both cohorts based on the identified differential hallmark pathways. Six prognostic genes (ASF1A, CENPA, LDHA, PSMB2, SRPRB, UCK2) were included in the risk score signature, which was demonstrated to be an independent prognostic factor. A nomogram including 540 patients was further integrated and well-calibrated. ROC analyses in the five cohorts and immunohistochemistry experiments in solid tissues indicated that CENPA and UCK2 exhibited high and robust diagnostic values. Conclusions Our study explored a promising prognostic nomogram and diagnostic biomarkers in hepatocellular carcinoma.
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Affiliation(s)
- Xiongdong Zhong
- Department of Cardiothoracic Surgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xianchang Yu
- Department of Cardiothoracic Surgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Hao Chang
- Department of Protein Modification and Cancer Research, Hanyu Biomed Center Beijing, Beijing, China
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13
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Liu X, Liu Y. Comprehensive Analysis of the Expression and Prognostic Significance of the CENP Family in Breast Cancer. Int J Gen Med 2022; 15:3471-3482. [PMID: 35378917 PMCID: PMC8976518 DOI: 10.2147/ijgm.s354200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/23/2022] [Indexed: 12/13/2022] Open
Abstract
Background Centromere proteins (CENPs) are a set of protein-coding genes involved in the transient assembly of the kinetochore which occurs during mitosis. This study intended to clarify the expression patterns, prognosis and potential mechanisms of CENPs in breast cancer (BC). Methods Coexpedia was used to screen GEO datasets and PubMed articles related to CENPs and BC. CENPs expressions, prognosis and alteration were analyzed by Oncomine, Ualcan and Kaplan Meier plotter and cBioPortal. The correlation and interaction of CENPs was performed by Breast Cancer Gene-Expression Miner, GeneMANIA and STRING portal. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to clarify the functional roles of CENPs. CENPF, E, U, A, N, I, K, W, M, L were selected for further analysis. Results All CENPs were highly expressed in BC compared to normal tissue. High expression of CENPF, E, U, A, N, I, W, M, L and CENPF, E, U, A, N, I, M correlated with worse relapse free survival (RFS) and worse overall survival (OS), respectively. All of 10 CENPs indicated positive correlations and complex interactions between each other at mRNA expression and protein level. CENPs were enriched GO terms mainly in centromere complex assembly and KEGG terms in progesterone-mediated oocyte maturation, cell cycle and oocyte meiosis. Conclusion The 10 CENPs could be diagnostic biomarkers and all of them except CENPK can be used as prognosis biomarkers in BC. CENPs play an oncogenic role and may be the potential therapy targets of treatment for BC patients.
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Affiliation(s)
- Xueliang Liu
- Breast Cancer Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People’s Republic of China
| | - Yunjiang Liu
- Breast Cancer Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People’s Republic of China
- Correspondence: Yunjiang Liu, Tel +86-13703297890, Email
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14
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Wang Q, Xu J, Xiong Z, Xu T, Liu J, Liu Y, Chen J, Shi J, Shou Y, Yue C, Liu D, Liang H, Yang H, Yang X, Zhang X. CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway. J Transl Med 2021; 19:417. [PMID: 34627268 PMCID: PMC8502268 DOI: 10.1186/s12967-021-03087-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/24/2021] [Indexed: 12/15/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the kidney. New and reliable biomarkers are in urgent need for ccRCC diagnosis and prognosis. The CENP family is overexpressed in many types of cancers, but its functions in ccRCC have not been fully clarified. In this paper, we found that several CENP family members were highly expressed in ccRCC tissues. Also, CENPA expression level was related to clinicopathological grade and prognosis by weighted gene co-expression network analysis (WGCNA). CENPA served as a representative CENP family member as a ccRCC biomarker. Further in vitro experiments verified that overexpression of CENPA promoted ccRCC proliferation and metastasis by accelerating the cell cycle and activating the Wnt/β-catenin signaling pathway. The elevated β-catenin led by CENPA overexpression translocated to nucleus for downstream effect. Functional recovery experiment confirmed that Wnt/β-catenin pathway was essential for ccRCC progression and metastasis. Developing selective drugs targeting CENPA may be a promising direction for cancer treatment.
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Affiliation(s)
- Qi Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiaju Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhiyong Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tianbo Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jingchong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuenan Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiaping Chen
- Department of Thoracic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jian Shi
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yi Shou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Changjie Yue
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Di Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huageng Liang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hongmei Yang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiong Yang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Leo L, Colonna Romano N. Emerging Single-Cell Technological Approaches to Investigate Chromatin Dynamics and Centromere Regulation in Human Health and Disease. Int J Mol Sci 2021; 22:ijms22168809. [PMID: 34445507 PMCID: PMC8395756 DOI: 10.3390/ijms22168809] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
Epigenetic regulators play a crucial role in establishing and maintaining gene expression states. To date, the main efforts to study cellular heterogeneity have focused on elucidating the variable nature of the chromatin landscape. Specific chromatin organisation is fundamental for normal organogenesis and developmental homeostasis and can be affected by different environmental factors. The latter can lead to detrimental alterations in gene transcription, as well as pathological conditions such as cancer. Epigenetic marks regulate the transcriptional output of cells. Centromeres are chromosome structures that are epigenetically regulated and are crucial for accurate segregation. The advent of single-cell epigenetic profiling has provided finer analytical resolution, exposing the intrinsic peculiarities of different cells within an apparently homogenous population. In this review, we discuss recent advances in methodologies applied to epigenetics, such as CUT&RUN and CUT&TAG. Then, we compare standard and emerging single-cell techniques and their relevance for investigating human diseases. Finally, we describe emerging methodologies that investigate centromeric chromatin specification and neocentromere formation.
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16
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Lu XQ, Zhang JQ, Zhang SX, Qiao J, Qiu MT, Liu XR, Chen XX, Gao C, Zhang HH. Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis. BMC Cancer 2021; 21:697. [PMID: 34126961 PMCID: PMC8201699 DOI: 10.1186/s12885-021-08358-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 05/13/2021] [Indexed: 02/07/2023] Open
Abstract
Background Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. Methods Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan–Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. Results Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. Conclusions We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08358-7.
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Affiliation(s)
- Xiao-Qing Lu
- Department of Breast Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Jia-Qian Zhang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jun Qiao
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Meng-Ting Qiu
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiang-Rong Liu
- Department of Breast Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Xiao-Xia Chen
- Department of Breast Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Chong Gao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Huan-Hu Zhang
- Department of Gastroenterology, Shanxi Cancer Hospital, Taiyuan, 030001, Shanxi, China.
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