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Reyila A, Gao X, Yu J, Nie Y. Insight into the role of DNA methylation in prognosis and treatment response prediction of gastrointestinal cancers. Epigenomics 2025; 17:475-488. [PMID: 40084815 PMCID: PMC12026041 DOI: 10.1080/17501911.2025.2476380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastrointestinal (GI) cancers impose a significant disease burden, underscoring the critical importance of accurate prognosis prediction and treatment response evaluation. DNA methylation, one of the most extensively studied epigenetic modifications, has gained prominence due to its reliable measurement across various sample types. Numerous studies have reported that DNA methylation was linked to the diagnosis, prognosis and treatment response in malignancies, including GI cancers. While its diagnostic role in GI cancers has been comprehensively reviewed. Recent research has increasingly highlighted its potential in prognosis prediction and treatment response evaluation. However, no existing reviews have exclusively focused on these two aspects. In this review, we retrieved relevant studies and included 230 of them in our discussion, thereby providing an overview of the clinical applicability of aberrant DNA methylation in these two fields among patients with esophageal, gastric, colorectal, pancreatic cancers, and hepatocellular carcinomas. Additionally, we discuss the limitations of the current literature and propose directions for future research. Specifically, we emphasize the need for standardized DNA methylation methodologies and advocate for the integration of gene panels, rather than single genes, to address tumor heterogeneity more effectively.
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Affiliation(s)
- Abudurousuli Reyila
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jun Yu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
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Bian G, Cao J, Li W, Huang D, Ding X, Zang X, Ye Y, Li P. Identification and Validation of a Cancer-Testis Antigen-Related Signature to Predict the Prognosis in Stomach Adenocarcinoma. J Cancer 2024; 15:3596-3611. [PMID: 38817874 PMCID: PMC11134429 DOI: 10.7150/jca.91842] [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: 11/02/2023] [Accepted: 03/06/2024] [Indexed: 06/01/2024] Open
Abstract
Background: Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate in the pathogenesis and development of multiple cancers and are aberrantly overexpressed in various types of cancer. This study aimed to develop a CTA-related gene signature (CTARSig) to predict prognosis in STAD patients and explore its underlying mechanisms. Methods: We performed differential and prognostic analyses of CTA-related genes and constructed a CTA-related signature (CTARSig) along with a novel nomogram to predict the prognosis of patients with STAD based on the Cox and The Least Absolute Shrinkage and Selection Operator. CTARSig was further validated in an external cohort (GSE84437). Additionally, univariate and multivariate Cox regression, as well as receiver operating characteristic (ROC) analyses, were performed to assess the CTARSig systematically. Single-sample gene set enrichment analysis and ESTIMATE were used to characterise the Tumor Immune Microenvironment (TIME) in patients with STAD. Furthermore, Gene Set Variation Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology analyses revealed the biological functions and signalling pathways associated with CTARSig. Finally, the human gastric cancer cell lines, HCG-27 and AGS, were used for in vitro and in vivo experiments, respectively, to further validate the role of ELOVL4. Results: Eleven CTA-related genes were identified to construct the CTARSig. Kaplan-Meier curves, independent prognostic analysis, and ROC curves revealed that CTARSig could better predict survival in patients with STAD. Moreover, in our study, we demonstrated that ELOVL4 is upregulated in gastric cancer tissues and that its high expression is associated with poor survival. Additionally, in vitro and in vivo experiments demonstrated that ELOVL4 promotes the metastatic and invasive potential of STAD cells, suggesting it may be a potential therapeutic target for STAD. Conclusion: In this study, a novel signature associated with CTAs was constructed for STAD, which may be a good predictor of patient prognosis. Thus, ELOVL4 may be a potential therapeutic target for gastric cancer. This study provides new insights into the potential roles of CTAs in gastric cancer.
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Affiliation(s)
- Geng Bian
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei, Anhui 230022, China
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Jie Cao
- Department of Respiratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Weiyu Li
- National Clinical Research Center of Digestive Diseases, Beijing 100050, China
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Dabing Huang
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Xiping Ding
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
- Gerontology Institute of Anhui Province, Hefei, Anhui, China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui 230001, China
| | - Xiaodong Zang
- Department of Pediatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Yingquan Ye
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei, Anhui 230022, China
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Ping Li
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei, Anhui 230022, China
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
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Christodoulidis G, Koumarelas KE, Kouliou MN, Thodou E, Samara M. Gastric Cancer in the Era of Epigenetics. Int J Mol Sci 2024; 25:3381. [PMID: 38542354 PMCID: PMC10970362 DOI: 10.3390/ijms25063381] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 11/11/2024] Open
Abstract
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
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Affiliation(s)
- Grigorios Christodoulidis
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Konstantinos-Eleftherios Koumarelas
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Marina-Nektaria Kouliou
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Eleni Thodou
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
| | - Maria Samara
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
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Takada H, Sasagawa Y, Yoshimura M, Tanaka K, Iwayama Y, Hayashi T, Isomura-Matoba A, Nikaido I, Kurisaki A. Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis. Nat Commun 2023; 14:3750. [PMID: 37386010 PMCID: PMC10310803 DOI: 10.1038/s41467-023-39113-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/30/2023] [Indexed: 07/01/2023] Open
Abstract
Defects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.
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Affiliation(s)
- Hitomi Takada
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan
| | - Yohei Sasagawa
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Mika Yoshimura
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Kaori Tanaka
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Yoshimi Iwayama
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan
| | - Tetsutaro Hayashi
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Ayako Isomura-Matoba
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan
| | - Itoshi Nikaido
- Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan.
- Department of Functional Genome Informatics, Biological Data Science, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
- Master's/Doctoral Program in Life Science Innovation (Bioinformatics), Degree Programs in Systems and Information Engineering, Graduate School of Science and Technology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Akira Kurisaki
- Laboratory of Stem Cell Technologies, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Nara, Japan.
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Ahmadi Hedayati M, Ahmadi A, Khatooni Z. DNMT1 Gene Expression in Patients with Helicobacter pylori Infection. ScientificWorldJournal 2022; 2022:2386891. [PMID: 36147796 PMCID: PMC9489387 DOI: 10.1155/2022/2386891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
DNMT1, as a critical enzyme affecting epigenetics through methylation of DNA cytosine-rich sequences, regulates gene expression. Exterior factors including long-term infections, in this study Helicobacter pylori infection, could change host cells' epigenetics by affecting DNMT1 gene expression. This study investigated the statistical correlation between H. pylori virulence genes and DNMT1 gene expression in gastric antral epithelial cells of gastric adenocarcinoma and gastritis patients. In a case-control study, 50 and 53 gastritis and gastric adenocarcinoma antral biopsies, including 23 and 21 patients with H. pylori infection, respectively, were collected from hospitals in the west of Iran. Having extracted total RNA from gastric biopsy samples, cDNA was synthesized and virulence genes of H. pylori were detected by using the PCR method. Relative real-time RT PCR was used to detect ΔΔCt fold changes of the DNMT1 gene expression in divided groups of patients based on H. pylori infection and clinical manifestations. The results showed that along with increasing patients' age, the DNMT1 gene expression will increase in gastric antral epithelial cells of gastric cancer patients (P ≤ 0.05). On the other hand, the biopsy samples with infection of H. pylori cagA, cagY, and cagE genotypes revealed a direct correlation along with increased DNMT1 gene expression. This study revealed the correlations of H. pylori cag pathogenicity island genes with increased DNMT1 gene expression.
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Affiliation(s)
- Manouchehr Ahmadi Hedayati
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Microbiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Amjad Ahmadi
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zahed Khatooni
- School of Pharmacy, Memorial University of Newfoundland, St Johns, NL, Canada
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Organic cation transporter 2 activation enhances sensitivity to oxaliplatin in human pancreatic ductal adenocarcinoma. Biomed Pharmacother 2022; 153:113520. [DOI: 10.1016/j.biopha.2022.113520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/31/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022] Open
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Mazloumi Z, Farahzadi R, Rafat A, Asl KD, Karimipour M, Montazer M, Movassaghpour AA, Dehnad A, Charoudeh HN. Effect of aberrant DNA methylation on cancer stem cell properties. Exp Mol Pathol 2022; 125:104757. [PMID: 35339454 DOI: 10.1016/j.yexmp.2022.104757] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 03/09/2022] [Accepted: 03/19/2022] [Indexed: 12/21/2022]
Abstract
DNA methylation, as an epigenetic mechanism, occurs by adding a methyl group of cytosines in position 5 by DNA methyltransferases and has essential roles in cellular function, especially in the transcriptional regulation of embryonic and adult stem cells. Hypomethylation and hypermethylation cause either the expression or inhibition of genes, and there is a tight balance between regulating the activation or repression of genes in normal cellular activity. Abnormal methylation is well-known hallmark of cancer development and progression and can switch normal stem cells into cancer stem cells. Cancer Stem Cells (CSCs) are minor populations of tumor cells that exhibit unique properties such as self-regeneration, resistance to chemotherapy, and high ability of metastasis. The purpose of this paper is to show how aberrant DNA methylation accumulation affects self-renewal, differentiation, multidrug-resistant, and metastasis processes in cancer stem cells.
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Affiliation(s)
- Zeinab Mazloumi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rafat
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khadijeh Dizaji Asl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Montazer
- Department of Cardiovascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Alireza Dehnad
- Department of Bacterial Disease Research, Razi Vaccine and Serum Research Institute, AREEO, Tabriz, Iran
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Qiang W, Dai Y, Xing X, Sun X. Identification of a metabolic reprogramming-related signature associated with prognosis and immune microenvironment of head and neck squamous cell carcinoma by in silico analysis. Cancer Med 2022; 11:3168-3181. [PMID: 35301800 PMCID: PMC9385599 DOI: 10.1002/cam4.4670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 02/11/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022] Open
Abstract
Background Metabolic reprogramming is one of the essential features of tumorigenesis. Herein, this study aimed to develop a novel metabolism‐related gene signature for head and neck squamous cell carcinoma (HNSCC) patients. Methods The transcriptomic and clinical data of HNSCC samples were collected from The Cancer Genome Atlas (TCGA) and GSE65858 datasets. The metabolism‐related gene‐based prognostic signature (MRGPS) was constructed by the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. The time‐dependent receiver operating characteristic (ROC) and Kaplan‐Meier (K‐M) survival curves were plotted for evaluating its predicting performance. At the same time, univariate along with multivariate analysis was carried out to explore its correlation with clinicopathologic factors. Furthermore, GSEA analysis was performed to explore the signaling pathways affected by MRGPS. We also analyzed the associations of MRGPS with the tumor immune microenvironment (TIME), as well as identified potential compounds via Connectivity Map (CMap) and molecular docking. Results A total of 12 differentially expressed metabolism‐related genes were identified and selected to construct the MRGPS. Notably, this signature performed well in predicting HNSCC patients’ survival and could serve as an independent prognostic factor in multiple datasets. In addition to the metabolism‐related pathway, this signature could also affect some immune‐related pathways. The results indicated that MRGPS is correlated with immune cells infiltration and anti‐cancer immune response. Furthermore, we identified cephaeline as a potential therapeutic compound for HNSCC. Conclusion Taken together, we established an MRGs‐based signature that has the potential to predict the clinical outcome and immune microenvironment, which help to search for potential combination immunotherapy compounds and provide a promising therapeutic strategy for treating HNSCC patients.
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Affiliation(s)
- Weijie Qiang
- Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijingChina
| | - Yifei Dai
- School of MedicineTsinghua UniversityBeijingChina
| | - Xiaoyan Xing
- Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijingChina
| | - Xiaobo Sun
- Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine PrescriptionChinese Academy of Medical SciencesBeijingChina
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do Amaral-Silva GK, Morais TMDL, Wagner VP, Martins MD, Fregnani ER, Soares FA, Rocha AC, Pontes HR, Santos-Silva AR, Vargas PA. Expression of DNMTs and H3K9ac in Ameloblastoma and Ameloblastic Carcinoma. FRONTIERS IN ORAL HEALTH 2022; 2:751162. [PMID: 35048062 PMCID: PMC8757744 DOI: 10.3389/froh.2021.751162] [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: 07/31/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Objectives: DNA methyltransferases (DNMTs) and the histone modification H3K9ac are epigenetic markers. This study aimed to describe the immunohistochemical expression of DNMT1, DNMT3A, DNMT3B, and H3K9ac in the dental follicle (DF), ameloblastoma (AME), and ameloblastic carcinoma (AC), correlating these expressions with the recurrence and aggressive behavior in ameloblastoma. Study Design: Immunohistochemical reactions were performed in 10 human DFs, 38 ameloblastomas, and 6 AC samples. Another 59 ameloblastomas assembled in a tissue microarray were used to compare the immunoexpression with the clinical, radiographic, and histopathological characteristics and the presence of BRAFv600e mutation. Each slide was digitized as a high-resolution image and quantified by Aperio ScanScope Nuclear V9 software. All statistical analyzes were performed using GraphPad Prism statistical software. Results: DNMT3B expression was higher in ameloblastomas than in the DFs, while the AC overexpressed all proteins. The ameloblastomas with BRAFv600e mutation, vestibular/lingual, or vestibular/palatine bone cortical disruption and maxilla involvement showed DNMT1 overexpression, while recurrent cases had high DNMT3B levels. Conclusions: DNA methylation and histone modification might play a role in the development, clinical aggressiveness, and recurrence rates of ameloblastoma, such as the progression to AC. Further investigation about gene methylations in ameloblastomas is needed to better understand its relationship with aggressiveness and recurrence.
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Affiliation(s)
| | | | - Vivian Petersen Wagner
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Manoela Domingues Martins
- Department of Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | - André Caroli Rocha
- Medical School, Clinics Hospital, University of São Paulo, São Paulo, Brazil
| | - Helder Rabelo Pontes
- Service of Buccal Pathology, João de Barros Barreto University Hospital, Federal University of Pará, Belém, Brazil
| | - Alan Roger Santos-Silva
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
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Tian R, Lv Y, Yang X, Cui L, Wu X, Liu C, Li J, Yao Y, Yang Y, Mou Y, Song X. DNA methyltransferase 1 inhibits O 6-methylguanine-DNAmethyl-transferase-mediated cell growth and metastasis of hypopharyngeal squamous carcinoma. Arch Oral Biol 2021; 128:105160. [PMID: 34044343 DOI: 10.1016/j.archoralbio.2021.105160] [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: 04/18/2021] [Revised: 05/16/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To explore the role of DNA methyltransferase 1 (DNMT1) in development and progression of hypopharyngeal squamous carcinoma. DESIGN A total of 32 hypopharyngeal squamous carcinoma biopsy samples and 20 normal tissue specimens were collected. Immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot were performed for expression analysis. The mRNA and protein expression in the specimens and subcellular localization were analyzed. hypopharyngeal squamous carcinoma cells (FaDu) were used for small interfering RNA of DNMT1, and proliferation, cell cycle, and apoptosis were determined in the transfected cells. Furthermore, metastatic ability and methylation status of O6-methylguanine-DNAmethyl-transferase (MGMT) promoter was assessed. RESULTS Our results showed that DNMT1 was overexpressed, while MGMT was down expressed in hypopharyngeal squamous carcinoma. DNMT1 overexpression and MGMT down expression were significantly associated with poorly differentiated tumors, lymph node metastasis, and clinical stage. DNMT1 and MGMT were majorly distributed in the nucleus. Furthermore, knockdown of DNMT1 inhibited proliferation and metastasis, induced apoptosis and G1 phase arrest in FaDu cells, and upregulated MGMT expression to reverse methylation status of MGMT promoter. CONCLUSIONS This study for the first time demonstrated the clinical value and the role of DNMT1 and MGMT in the biological function of hypopharyngeal squamous carcinoma. This work suggested that DNMT1 might serve as a potential therapeutic target for patients with hypopharyngeal squamous carcinoma.
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Affiliation(s)
- Ruxian Tian
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Yayun Lv
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Xin Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Limei Cui
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Xinxin Wu
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Chuan Liu
- Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 40016, China
| | - Jingjing Li
- Binzhou Medical University, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China
| | - Yao Yao
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Yujuan Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Yakui Mou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China.
| | - Xicheng Song
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China.
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Chaiyawat P, Sirikaew N, Budprom P, Klangjorhor J, Phanphaisarn A, Teeyakasem P, Settakorn J, Pruksakorn D. Expression profiling of DNA methyl transferase I (DNMT1) and efficacy of a DNA-hypomethylating agent (decitabine) in combination with chemotherapy in osteosarcoma. J Bone Oncol 2020; 25:100321. [PMID: 33072501 PMCID: PMC7549121 DOI: 10.1016/j.jbo.2020.100321] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 11/29/2022] Open
Abstract
Background Abnormality in the DNA methylation process is one of the hallmarks of cancer. Emerging evidence strongly supports the idea that defects in DNA methyl transferases (DNMTs) are involved in tumor development and progression. This alteration has major effects at the transcription level of various cancer-associated genes. Methods Expression profiles of DNMT1 were investigated in fresh frozen tissues, patient-derived cells, and formalin-fixed paraffin-embedded tissues using immunoblotting and immunohistochemistry analysis. We also examined an anti-tumor effect of single DNA-hypomethylating agent (decitabine) and a combination of decitabine and chemotherapy in osteosarcoma cell lines. Results The results showed an overexpression of DNMT1 in most cases compared to normal cells and tissue samples. DNMT1 was also expressed at the same levels in paired primary cells derived from biopsy and post-chemotherapy tissues. Expression patterns of DNMT1 were examined in 77 osteosarcoma patients of whom 82% had positive DNMT1 with an IRS score > 0. Most of the cases expressed low to moderate levels of DNMT1 (IRS range 1-8, median = 2.0). Furthermore, we found that a combination of decitabine and chemotherapy had a synergistic effect in most of the tested osteosarcoma cells at a low dose therapeutic range of decitabine. Conclusions Our study revealed DNMT1 expression patterns that indicated potential roles of DNMT1 in osteosarcoma transformation and progression. This finding also suggests the efficacy of a combination therapy of decitabine with chemotherapy for osteosarcoma treatment.
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Affiliation(s)
- Parunya Chaiyawat
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Omics Center for Health Sciences (OCHS), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nutnicha Sirikaew
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Piyaporn Budprom
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jeerawan Klangjorhor
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Areerak Phanphaisarn
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pimpisa Teeyakasem
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jongkolnee Settakorn
- Department of Pathology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros, Sriphoom, Muang, Chiang Mai 50200, Thailand
| | - Dumnoensun Pruksakorn
- Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Omics Center for Health Sciences (OCHS), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Orthopedics, Faculty of Medicine, Chiang Mai University, 110 Intawaroros, Sriphoom, Muang, Chiang Mai 50200, Thailand.,Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand
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Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini PL, Fernández-Barrena MG, Avila MA. Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities. Int J Mol Sci 2020; 21:E5500. [PMID: 32752096 PMCID: PMC7432799 DOI: 10.3390/ijms21155500] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Pier-Luigi Lollini
- Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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Ma TM, Sun LP, Dong NN, Sun MJ, Yuan Y. Protein expression trends of DNMT1 in gastrointestinal diseases: From benign to precancerous lesions to cancer. World J Gastrointest Oncol 2019; 11:1141-1150. [PMID: 31908719 PMCID: PMC6937440 DOI: 10.4251/wjgo.v11.i12.1141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 09/04/2019] [Accepted: 09/13/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In recent years, the incidence of gastrointestinal (GI) cancer in China has increased annually. Early detection and appropriate therapy are considered to be the key to treat GI cancer. DNMT1 takes an active part in the advancement of GI cancer, which will change as the disease progresses. But its expression characteristics in the dynamic variations of GI carcinogenesis are still unclear.
AIM To investigate the expression characteristics of DNMT1 in different GI diseases.
METHODS We detected the expression of DNMT1 in 650 cases of different GI diseases by immunohistochemistry, including 90 cases of chronic superficial gastritis (CSG), 72 cases of atrophic gastritis with intestinal metaplasia (AG/GIM), 54 cases of low-grade intraepithelial neoplasia (GLIN), 66 cases of high-grade intraepithelial neoplasia (GHIN), 71 cases of early gastric cancer (EGC), 90 cases of normal intestinal mucosa (NIM), 54 cases of intestinal low-grade intraepithelial neoplasia (ILIN), 71 cases of intestinal high-grade intraepithelial neoplasia (IHIN), and 82 cases of early colorectal cancer (ECRC).
RESULTS In the CSG group, all cases showed weakly positive or negative expression of DNMT1. However, in other four groups (AG/GIM, GLIN, GHIN, and EGC), the positive expression rate gradually increased with the severity of the diseases; the negative or weakly positive cases accounted for 55.56% (40/72), 38.89% (21/54), 1.52% (1/66), and 1.41% (1/71), respectively. Besides, the moderately positive cases were 44.44% (32/72), 57.41% (31/54), 80.30% (53/66), and 43.66% (31/71), respectively. The strongly positive cases only existed in the GLIN (3.70%, 2/54), GHIN (18.18%, 12/66), and EGC (54.93%, 39/71) groups. The differences between any two groups were statistically significant (P < 0.05). Similarly, in the NIM group, cases with weakly positive expression of DNMT1 were predominant (91.11%, 82/90), and the rest were moderately positive cases (8.89%, 8/90). In the ILIN, IHIN, and ECRC groups, the rates of cases with weak or negative expression of DNMT1 were 46.30% (25/54), 12.68% (9/71), and 4.88% (4/82), respectively; with moderately positive expression were 53.70% (29/54), 71.83% (51/71), and 34.15% (28/82), respectively; and with strongly positive expression were 0.00% (0/54), 15.49% (11/71), and 60.98% (50/82), respectively. The differences between any two groups were also statistically significant (P < 0.05).
CONCLUSION The overexpression of DNMT1 protein could effectively predict early GI cancers and severe precancerous lesions, which may have potential clinical application value.
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Affiliation(s)
- Tian-Miao Ma
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Nan-Nan Dong
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ming-Jun Sun
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Sarne V, Braunmueller S, Rakob L, Seeboeck R. The Relevance of Gender in Tumor-Influencing Epigenetic Traits. EPIGENOMES 2019; 3:epigenomes3010006. [PMID: 34991275 PMCID: PMC8594720 DOI: 10.3390/epigenomes3010006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/20/2019] [Accepted: 01/24/2019] [Indexed: 12/22/2022] Open
Abstract
Tumorigenesis as well as the molecular orchestration of cancer progression are very complex mechanisms that comprise numerous elements of influence and regulation. Today, many of the major concepts are well described and a basic understanding of a tumor's fine-tuning is given. Throughout the last decade epigenetics has been featured in cancer research and it is now clear that the underlying mechanisms, especially DNA and histone modifications, are important regulators of carcinogenesis and tumor progression. Another key regulator, which is well known but has been neglected in scientific approaches as well as molecular diagnostics and, consequently, treatment conceptualization for a long time, is the subtle influence patient gender has on molecular processes. Naturally, this is greatly based on hormonal differences, but from an epigenetic point of view, the diverse susceptibility to stress and environmental influences is of prime interest. In this review we present the current view on which and how epigenetic modifications, emphasizing DNA methylation, regulate various tumor diseases. It is our aim to elucidate gender and epigenetics and their interconnectedness, which will contribute to understanding of the prospect molecular orchestration of cancer in individual tumors.
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Fluctuations of epigenetic regulations in human gastric Adenocarcinoma: How does it affect? Biomed Pharmacother 2019; 109:144-156. [DOI: 10.1016/j.biopha.2018.10.094] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 10/15/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022] Open
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Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation. Cancer Gene Ther 2018; 26:94-102. [PMID: 30190513 DOI: 10.1038/s41417-018-0046-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/31/2018] [Accepted: 08/05/2018] [Indexed: 12/13/2022]
Abstract
We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.
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