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Lee HK, Shin CM, Chang YH, Yoon H, Park YS, Kim N, Lee DH. Gastric microbiome signature for predicting metachronous recurrence after endoscopic resection of gastric neoplasm. Gastric Cancer 2024; 27:1031-1045. [PMID: 38970748 DOI: 10.1007/s10120-024-01532-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
BACKGROUND Changes in gastric microbiome are associated with gastric carcinogenesis. Studies on the association between gastric mucosa-associated gastric microbiome (MAM) and metachronous gastric cancer are limited. This study aimed to identify gastric MAM as a predictive factor for metachronous recurrence following endoscopic resection of gastric neoplasms. METHOD Microbiome analyses were conducted for 81 patients in a prospective cohort to investigate surrogate markers to predict metachronous recurrence. Gastric MAM in non-cancerous corporal biopsy specimens was evaluated using Illumina MiSeq platform targeting 16S ribosomal DNA. RESULTS Over a median follow-up duration of 53.8 months, 16 metachronous gastric neoplasms developed. Baseline gastric MAM varied with Helicobacter pylori infection status, but was unaffected by initial pathologic diagnosis, presence of atrophic gastritis, intestinal metaplasia, or synchronous lesions. The group with metachronous recurrence did not exhibit distinct phylogenetic diversity compared with the group devoid of recurrence but showed significant difference in β-diversity. The study population could be classified into two distinct gastrotypes based on baseline gastric MAM: gastrotype 1, Helicobacter-abundant; gastrotype 2: Akkermansia-abundant. Patients in gastrotype 2 showed higher risk of metachronous recurrence than gastrotype (Cox proportional hazard analysis, adjusted hazard ratio [95% confidence interval]: 5.10 [1.09-23.79]). CONCLUSIONS Gastric cancer patients can be classified into two distinct gastrotype groups by their MAM profiles, which were associated with different risk of metachronous recurrence.
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Affiliation(s)
- Ho-Kyoung Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea.
| | - Young Hoon Chang
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
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2
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Tang W, Du J, Li L, Hu S, Ma S, Xue M, Zhu L. Hypoxia-related THBD + macrophages as a prognostic factor in glioma: Construction of a powerful risk model. J Cell Mol Med 2024; 28:e18393. [PMID: 38809929 PMCID: PMC11135907 DOI: 10.1111/jcmm.18393] [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: 01/19/2024] [Revised: 04/10/2024] [Accepted: 04/30/2024] [Indexed: 05/31/2024] Open
Abstract
Glioma is a prevalent malignant tumour characterized by hypoxia as a pivotal factor in its progression. This study aims to investigate the impact of the most severely hypoxic cell subpopulation in glioma. Our findings reveal that the THBD+ macrophage subpopulation is closely associated with hypoxia in glioma, exhibiting significantly higher infiltration in tumours compared to non-tumour tissues. Moreover, a high proportion of THBD+ cells correlates with poor prognosis in glioblastoma (GBM) patients. Notably, THBD+ macrophages exhibit hypoxic characteristics and epithelial-mesenchymal transition features. Silencing THBD expression leads to a notable reduction in the proliferation and metastasis of glioma cells. Furthermore, we developed a THBD+ macrophage-related risk signature (THBDMRS) through machine learning techniques. THBDMRS emerges as an independent prognostic factor for GBM patients with a substantial prognostic impact. By comparing THBDMRS with 119 established prognostic features, we demonstrate the superior prognostic performance of THBDMRS. Additionally, THBDMRS is associated with glioma metastasis and extracellular matrix remodelling. In conclusion, hypoxia-related THBD+ macrophages play a pivotal role in glioma pathogenesis, and THBDMRS emerges as a potent and promising prognostic tool for GBM, contributing to enhanced patient survival outcomes.
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Affiliation(s)
- Weichun Tang
- Blood Transfusion DepartmentThe Third People's Hospital of BengbuBengbuChina
| | - Juntao Du
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Bengbu Medical CollegeBengbuChina
- Anhui Key Laboratory of Tissue TransplantationBengbu Medical CollegeBengbuChina
| | - Lin Li
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Bengbu Medical CollegeBengbuChina
- Anhui Key Laboratory of Tissue TransplantationBengbu Medical CollegeBengbuChina
| | | | - Shuo Ma
- Medical School of Southeast UniversityNanjingChina
| | - Mengtong Xue
- Department of Rehabilitation MedicineThe First Affiliated Hospital of Bengbu Medical CollegeBengbuChina
- Anhui Key Laboratory of Tissue TransplantationBengbu Medical CollegeBengbuChina
| | - Linlin Zhu
- School of Medical TechnologyXinxiang Medical UniversityXinxiangChina
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Li J, Xu S, Zhu F, Shen F, Zhang T, Wan X, Gong S, Liang G, Zhou Y. Multi-omics Combined with Machine Learning Facilitating the Diagnosis of Gastric Cancer. Curr Med Chem 2024; 31:6692-6712. [PMID: 38351697 DOI: 10.2174/0109298673284520240112055108] [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: 09/27/2023] [Revised: 11/28/2023] [Accepted: 01/03/2024] [Indexed: 10/19/2024]
Abstract
Gastric cancer (GC) is a highly intricate gastrointestinal malignancy. Early detection of gastric cancer forms the cornerstone of precision medicine. Several studies have been conducted to investigate early biomarkers of gastric cancer using genomics, transcriptomics, proteomics, and metabolomics, respectively. However, endogenous substances associated with various omics are concurrently altered during gastric cancer development. Furthermore, environmental exposures and family history can also induce modifications in endogenous substances. Therefore, in this study, we primarily investigated alterations in DNA mutation, DNA methylation, mRNA, lncRNA, miRNA, circRNA, and protein, as well as glucose, amino acid, nucleotide, and lipid metabolism levels in the context of GC development, employing genomics, transcriptomics, proteomics, and metabolomics. Additionally, we elucidate the impact of exposure factors, including HP, EBV, nitrosamines, smoking, alcohol consumption, and family history, on diagnostic biomarkers of gastric cancer. Lastly, we provide a summary of the application of machine learning in integrating multi-omics data. Thus, this review aims to elucidate: i) the biomarkers of gastric cancer related to genomics, transcriptomics, proteomics, and metabolomics; ii) the influence of environmental exposure and family history on multiomics data; iii) the integrated analysis of multi-omics data using machine learning techniques.
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Affiliation(s)
- Jie Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Siyi Xu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Feng Zhu
- Physical and Chemical Laboratory, Jiangsu Provincial Center for Disease Control & Prevention, 172 Jiangsu Rd, Nanjing, 210009, China
| | - Fei Shen
- Physical and Chemical Laboratory, Jiangsu Provincial Center for Disease Control & Prevention, 172 Jiangsu Rd, Nanjing, 210009, China
| | - Tianyi Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Xin Wan
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Saisai Gong
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Geyu Liang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Yonglin Zhou
- Physical and Chemical Laboratory, Jiangsu Provincial Center for Disease Control & Prevention, 172 Jiangsu Rd, Nanjing, 210009, China
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Yang HJ, Seo SI, Lee J, Huh CW, Kim JS, Park JC, Kim H, Shin H, Shin CM, Park CH, Lee SK. Sample Collection Methods in Upper Gastrointestinal Research. J Korean Med Sci 2023; 38:e255. [PMID: 37582502 PMCID: PMC10427214 DOI: 10.3346/jkms.2023.38.e255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/16/2023] [Indexed: 08/17/2023] Open
Abstract
In recent years, significant translational research advances have been made in the upper gastrointestinal (GI) research field. Endoscopic evaluation is a reasonable option for acquiring upper GI tissue for research purposes because it has minimal risk and can be applied to unresectable gastric cancer. The optimal number of biopsy samples and sample storage is crucial and might influence results. Furthermore, the methods for sample acquisition can be applied differently according to the research purpose; however, there have been few reports on methods for sample collection from endoscopic biopsies. In this review, we suggested a protocol for collecting study samples for upper GI research, including microbiome, DNA, RNA, protein, single-cell RNA sequencing, and organoid culture, through a comprehensive literature review. For microbiome analysis, one or two pieces of biopsied material obtained using standard endoscopic forceps may be sufficient. Additionally, 5 mL of gastric fluid and 3-4 mL of saliva is recommended for microbiome analyses. At least one gastric biopsy tissue is necessary for most DNA or RNA analyses, while proteomics analysis may require at least 2-3 biopsy tissues. Single cell-RNA sequencing requires at least 3-5 tissues and additional 1-2 tissues, if possible. For successful organoid culture, multiple sampling is necessary to improve the quality of specimens.
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Affiliation(s)
- Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung In Seo
- Division of Gastroenterology, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jin Lee
- Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Cheal Wung Huh
- Division of Gastroenterology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Joon Sung Kim
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hakdong Shin
- Department of Food Science and Biotechnology, Sejong University, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
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Gutierrez-Angulo M, Ayala-Madrigal MDLL, Moreno-Ortiz JM, Peregrina-Sandoval J, Garcia-Ayala FD. Microbiota composition and its impact on DNA methylation in colorectal cancer. Front Genet 2023; 14:1037406. [PMID: 37614819 PMCID: PMC10442805 DOI: 10.3389/fgene.2023.1037406] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 07/20/2023] [Indexed: 08/25/2023] Open
Abstract
Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor suppressor genes to promote cancer development. Several factors are associated with changes in the DNA methylation pattern, and recently, the gastrointestinal microbiota could be associated with this epigenetic change. The predominant phyla in gut microbiota are Firmicutes and Bacteroidetes; however, an enrichment of Bacteroides fragilis, Fusobacterium nucleatum, and Streptococcus bovis, among others, has been reported in colorectal cancer, although the composition could be influenced by several factors, including diet, age, sex, and cancer stage. Fusobacterium nucleatum, a gram-negative anaerobic bacillus, is mainly associated with colorectal cancer patients positive for the CpG island methylator phenotype, although hypermethylation in genes such as MLH1, CDKN2A, MTSS1, RBM38, PKD1, PTPRT, and EYA4 has also been described. Moreover, Hungatella hathewayi, a gram-positive, rod-shaped bacterium, is related to hypermethylation in SOX11, THBD, SFRP2, GATA5, ESR1, EYA4, CDX2, and APC genes. The underlying epigenetic mechanism is unclear, although it could be implicated in the regulation of DNA methyltransferases, enzymes that catalyze the transfer of a methyl group on cytosine of CpG sites. Since DNA methylation is a reversible event, changes in gut microbiota could modulate the gene expression through DNA methylation and improve the colorectal cancer prognosis.
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Affiliation(s)
- Melva Gutierrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Maria de la Luz Ayala-Madrigal
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Jose Miguel Moreno-Ortiz
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Jorge Peregrina-Sandoval
- Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Fernando Daniel Garcia-Ayala
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
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Zhou H, Nie C, Tian W, Han X, Wang J, Du X, Wang Q, Zhu X, Xiang G, Zhao Y. Joint Effects Between CDKN2B/P15 Methylation and Environmental Factors on the Susceptibility to Gastric Cancer. Dig Dis Sci 2023:10.1007/s10620-023-07917-1. [PMID: 36961670 DOI: 10.1007/s10620-023-07917-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/14/2022] [Indexed: 03/25/2023]
Abstract
BACKGROUND The incidence of gastric cancer has long been at a high level in China, seriously affecting the health of Chinese people. AIMS This case‒control study was performed to identify gene methylation biomarkers of gastric cancer susceptibility. METHODS A total of 393 gastric cancer cases and 397 controls were included in this study. Gene methylation in peripheral blood leukocytes was detected by a methylation-sensitive high-resolution melting method, and the Helicobacter pylori antibody presence was semi-quantified in serum by ELISA. RESULTS Individuals with total methylation of CDKN2B/P15 had a 1.883-fold (95%CI: 1.166-3.040, P = 0.010) risk of gastric cancer compared with unmethylated individuals. Individuals with both CDKN2B/P15 and NEUROG1 methylation had a higher risk of gastric cancer (OR = 2.147, 95% CI: 1.137-4.073, P = 0.019). The interaction between CDKN2B/P15 and NEUROG1 total methylation on gastric cancer risk was affected by the pattern of adjustment. In addition, the joint effects between CDKN2B/P15 total methylation and environmental factors, such as freshwater fish intake (OR = 6.403, 95% CI = 2.970-13.802, P < 0.001), irregular diet (OR = 5.186, 95% CI = 2.559-10.510, P < 0.001), unsanitary water intake (OR = 2.238, 95% CI = 1.144-4.378, P = 0.019), smoking (OR = 2.421, 95% CI = 1.456-4.026, P = 0.001), alcohol consumption(OR = 2.163, 95% CI = 1.309-3.576, P = 0.003), and garlic intake(OR = 0.373, 95% CI = 0.196-0.709, P = 0.003) on GC risk were observed, respectively. However, CDKN2B/P15 and NEUROG1 total methylation were not associated with gastric cancer prognosis. CONCLUSION CDKN2B/P15 methylation in peripheral blood may be a potential biomarker for evaluating susceptibility to gastric cancer. The joint effects between CDKN2B/P15 methylation and environmental factors may also contribute to gastric cancer susceptibility.
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Affiliation(s)
- Haibo Zhou
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Chuang Nie
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Wenjing Tian
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Xu Han
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Jing Wang
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Xinyu Du
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Qi Wang
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Xiaojie Zhu
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Guanghui Xiang
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, 197 Xuefu Road, Harbin, 150081, Heilongjiang Province, People's Republic of China.
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Pathophysiology and Clinical Biomarkers in Interstitial Cystitis. Urol Clin North Am 2023; 50:39-52. [DOI: 10.1016/j.ucl.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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8
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Spagnol LW, Polettini J, Silveira DA, Wegner GRM, Paiva DFF. P16 gene promoter methylation is associated with oncogenesis and progression of gastric carcinomas: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2022; 180:103843. [DOI: 10.1016/j.critrevonc.2022.103843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/02/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
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Shao C, Wang R, Kong D, Gao Q, Xu C. Identification of potential core genes in gastric cancer using bioinformatics analysis. J Gastrointest Oncol 2021; 12:2109-2122. [PMID: 34790378 DOI: 10.21037/jgo-21-628] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022] Open
Abstract
Background Gastric cancer is the third leading cause of cancer-related mortality in China. Most patients with gastric cancer have no obvious early symptoms; thus, many of them are in the middle and late stages of gastric cancer at first diagnosis and miss the best treatment opportunity. Molecular targeted therapy is particularly important in changing this status quo. Methods Three microarray datasets (GSE29272, GSE33651, and GSE54129) were selected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using GEO2R. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the functional features of these DEGs and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape software. The expressions of hub genes were evaluated based on Gene Expression Profiling Interactive Analysis (GEPIA). Moreover, we used the online Kaplan-Meier plotter survival analysis tool to evaluate the prognostic values of hub genes. The Target Scan database was used to predict microRNAs that could regulate the target gene, collagen type IV alpha 1 chain (COL4A1). The OncomiR database was used to analyze the expression levels of three microRNAs, as well as the relationships with tumor stage, grade, and prognosis. Results We identified 78 DEGs, including 53 upregulated genes and 25 downregulated genes. The DEGs were mainly enriched in extracellular matrix organization, extracellular structure organization, and response to wounding. Moreover, three KEGG pathways were markedly enriched, including focal adhesion, complement and coagulation cascades, and extracellular matrix (ECM)-receptor interaction. Among these 78 genes, we selected 10 hub genes. The overexpression levels of these hub genes were closely related to poor prognosis and the development of gastric cancer (except for COL3A1, LOX, and CXCL8). Moreover, we found that microRNA-29a-3p, miR-29b-3p, and miR-29c-3p were the potential microRNAs that could regulate the target gene, COL4A1. Conclusions Our results showed that FN1, COL1A1, TIMP1, COL1A2, SPARC, COL4A1, and SERPINE1 could contribute to the development of novel molecular targets and biomarker-driven treatments for gastric cancer.
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Affiliation(s)
- Changjiang Shao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Gastroenterology, The Second People's Hospital of Lianyungang City, Lianyungang, China
| | - Rong Wang
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dandan Kong
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qian Gao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
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Kim HJ, Kim N, Kim HW, Park JH, Shin CM, Lee DH. Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation. Gastric Cancer 2021; 24:302-313. [PMID: 32915372 DOI: 10.1007/s10120-020-01117-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 08/23/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE It remains unknown whether individuals with a family history (FH) of gastric cancer (GC) are associated with aberrant DNA methylation. The aim of this study was to investigate the association between aberrant DNA methylation and FH of GC. DESIGN Using quantitative MethyLight assay, MOS, miR124a-3, NKX6-1, EMX1, CDH1, and TWIST1 methylation levels in the noncancerous gastric mucosa was compared between subjects with and without FH based on GC and Helicobacter pylori (Hp) infection. Changes in the methylation levels were evaluated over time after Hp eradication. RESULTS In Hp-positive GC patients, MOS (P < 0.001), CDH1 (P < 0.001), and TWIST1 (P = 0.004) methylation were decreased in subjects with FH (n = 64) than in those without FH (n = 58). In Hp-positive controls, MOS methylation was lower in subjects with FH (n = 73) than in those without FH (n = 50) (P = 0.042), while miR124a-3 (P = 0.006), NKX6-1 (P < 0.001), and CDH1 (P < 0.001) methylation were higher in subjects with FH. CDH1 methylation constantly decreased from 2 years in GC patients and 3-4 years in controls after Hp eradication (all P < 0.001). A persistent decrease in methylation over time was not observed in other genes after eradication. CONCLUSION The methylation of MOS and CDH1 provided an association between aberrant DNA methylation and gastric carcinogenesis in FH of GC, a useful marker for GC risk in individuals with FH. Furthermore, CDH1 methylation decreased after Hp eradication.
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Affiliation(s)
- Hee Jin Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine, Gyeongsang National University College of Medicine and Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea. .,Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea. .,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
| | - Hyoung Woo Kim
- Department of Internal Medicine, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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Zhou H, Sun H, Liu X, Chen J, Zhang L, Lin S, Han X, Nie C, Liu Y, Tian W, Zhao Y. Combined effect between WT1 methylation and Helicobacter pylori infection, smoking, and alcohol consumption on the risk of gastric cancer. Helicobacter 2019; 24:e12650. [PMID: 31361067 DOI: 10.1111/hel.12650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Peripheral blood leukocyte DNA methylation status has been proposed to be a surrogate marker for evaluating susceptibility to gastric cancer (GC). Helicobacter pylori (H pylori) infection, smoking, and alcohol consumption are known to induce gene methylation. A case-control study was performed to investigate the interactions between the methylation of two candidate genes and H pylori infection, smoking, and alcohol consumption in the risk of GC. METHODS A total of 400 GC cases and 402 controls were included in this study. The methylation status of WT1 and IGF2 was semiquantitatively determined by using methylation-sensitive high-resolution melting assays. H pylori IgG antibodies were detected by ELISA method. RESULTS Based on the area under the curve (AUC), 0% methylated DNA and 0.5% methylated DNA were used as the cutoff values for WT1 and IGF2, respectively. WT1 methylation was significantly associated with increased GC risk (OR = 1.65, 95% CI = 1.09-2.51, P = .019), especially in males (OR = 1.80, 95% CI: 1.10-2.95, P = .019) and older individuals (≥60 years) (OR = 2.03, 95% CI: 1.15-3.57, P = .014). A significant combination was observed between WT1 methylation and H pylori infection, alcohol consumption, and smoking for the risk of GC (ORc = 2.28, 95% CI = 1.47-3.55, P = .003, ORc = 2.19, 95% CI = 1.37-3.51, P = .001, ORc = 2.21, 95% CI = 1.39-3.51, P = .001, respectively). However, no association between IGF2 methylation and the risk of GC was found in this study. CONCLUSIONS WT1 methylation may serve as a new potential biomarker for GC susceptibility and can combine with H pylori infection, smoking, and alcohol consumption to influence GC risk.
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Affiliation(s)
- Haibo Zhou
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Hongru Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Xinyan Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Jie Chen
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lei Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Shangqun Lin
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Xu Han
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Chuang Nie
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yupeng Liu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Wenjing Tian
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
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12
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Pero R, Angrisano T, Brancaccio M, Falanga A, Lombardi L, Natale F, Laneri S, Lombardo B, Galdiero S, Scudiero O. Beta-defensins and analogs in Helicobacter pylori infections: mRNA expression levels, DNA methylation, and antibacterial activity. PLoS One 2019; 14:e0222295. [PMID: 31537016 PMCID: PMC6752957 DOI: 10.1371/journal.pone.0222295] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 08/26/2019] [Indexed: 12/19/2022] Open
Abstract
Antimicrobial peptides can protect the gastric mucosa from bacteria, but Helicobacter pylori (H. pylori) can equally colonize the gastric apparatus. To understand beta-defensin function in H. pylori-associated chronic gastritis, we investigated susceptibility, human beta-defensin mRNA expression, and DNA methylation changes to promoters in the gastric mucosa with or without H. pylori infection. We studied the expression of HBD2 (gene name DEFB4A), HBD3 (DEFB103A), and HBD4 (DEFB104) using real-time PCR in 15 control and 10 H. pylori infection patient gastric specimens. This study demonstrates that H. pylori infection is related to gastric enhancement of inducible HBD2, but inducible HBD3 and HBD4 expression levels remained unchanged. HBD2 gene methylation levels were overall higher in H. pylori-negative samples than in H. pylori-positive samples. We also assessed antimicrobial susceptibility using growth on blood agar. The H. pylori strain Tox+ was susceptible to all defensins tested and their analogs (3N, 3NI). These results show that HBD2 is involved in gastritis development driven by H. pylori, which facilitates the creation of an epigenetic field during H. pylori-associated gastric tumorigenesis.
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Affiliation(s)
- Raffaela Pero
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Napoli, Italy
- Task Force sugli Studi del Microbioma, Università degli Studi di Napoli “Federico II”, Napoli, Italy
- * E-mail: (RP); (OS)
| | - Tiziana Angrisano
- Dipartimento di Biologia, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Mariarita Brancaccio
- Dipartimento di Biologia ed Evoluzione degli Organismi Marini, Stazione Zoologica Anton Dohrn, Napoli, Italy
| | - Annarita Falanga
- Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Lucia Lombardi
- Dipartimento di Agraria, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Francesco Natale
- Dipartimento di Biologia, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Sonia Laneri
- Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Barbara Lombardo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Napoli, Italy
- CEINGE-Biotecnologie Avanzate Scarl, Napoli, Italy
| | - Stefania Galdiero
- Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, Napoli, Italy
| | - Olga Scudiero
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Napoli, Italy
- Task Force sugli Studi del Microbioma, Università degli Studi di Napoli “Federico II”, Napoli, Italy
- CEINGE-Biotecnologie Avanzate Scarl, Napoli, Italy
- * E-mail: (RP); (OS)
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13
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Kim N. Chemoprevention of gastric cancer by Helicobacter pylori eradication and its underlying mechanism. J Gastroenterol Hepatol 2019; 34:1287-1295. [PMID: 30828872 DOI: 10.1111/jgh.14646] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/23/2019] [Accepted: 03/01/2019] [Indexed: 12/11/2022]
Abstract
The cascade of gastric cancer, a leading cause of cancer incidence and mortality, is multifactorial. Helicobacter pylori (HP) infection plays a major role in gastric cancer (GC), and there has been an accumulation of data regarding the chemopreventive effect of HP eradication. However, it remains unclear how HP infection causes GC and how HP eradication prevents GC. To clarify this issue, the following approaches were performed in this review article. First, how HP-induced atrophic gastritis (AG) and intestinal metaplasia (IM) provoke the development of GC is shown, followed by how long HP eradication takes to induce a reversible change in AG and IM. Second, epigenetic studies of PTPN6, MOS, DCC, CRK, and VAV1 were performed in noncancerous gastric specimens in terms of HP status. Among these genes, MOS was found to be a possible surrogate marker for GC development. HP eradication decreased aberrant DNA methylation in a gene-specific manner, and MOS played a role in metachronous gastric neoplasms. Third, transforming growth factor-β1 (TGF-β1) and TGF-β1-induced epithelial-mesenchymal transition (EMT) markers were investigated in gastric mucosa. HP infection triggered the TGF-β1-induced EMT pathway and caused the emergence of GC stem cells, such as CD44v8-10. When HP was eradicated, these two pathways were inhibited. Finally, a 2222 cohort study showed that HP eradication significantly decreased the risk of noncardiac GC. Taken together, HP eradication is effective as a primary GC prevention method, and its underlying mechanism includes reversibility of AG and IM, methylation, EMT, and stem cells.
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Affiliation(s)
- Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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14
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Connor M, Arbibe L, Hamon M. Customizing Host Chromatin: a Bacterial Tale. Microbiol Spectr 2019; 7:10.1128/microbiolspec.bai-0015-2019. [PMID: 30953433 PMCID: PMC11590419 DOI: 10.1128/microbiolspec.bai-0015-2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Indexed: 12/14/2022] Open
Abstract
Successful bacterial colonizers and pathogens have evolved with their hosts and have acquired mechanisms to customize essential processes that benefit their lifestyle. In large part, bacterial survival hinges on shaping the transcriptional signature of the host, a process regulated at the chromatin level. Modifications of chromatin, either on histone proteins or on DNA itself, are common targets during bacterium-host cross talk and are the focus of this article.
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Affiliation(s)
- Michael Connor
- Institut Pasteur, G5 Chromatine et Infection, Paris, France
| | - Laurence Arbibe
- INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades, INEM Institute Department of Immunology, Infectiology and Hematology, Paris, France
| | - Mélanie Hamon
- Institut Pasteur, G5 Chromatine et Infection, Paris, France
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15
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Yu J, Xu Q, Zhang X, Zhu M. Circulating microRNA signatures serve as potential diagnostic biomarkers for Helicobacter pylori infection. J Cell Biochem 2019; 120:1735-1741. [PMID: 30324743 DOI: 10.1002/jcb.27462] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 07/19/2018] [Indexed: 01/24/2023]
Abstract
Helicobacter pylor (H pylori), a Gram-negative, microaerobic human pathogen, has been found to be involved in many gastroduodenal diseases. Accurate diagnosis of H pylori infection is a vital part of the effective management of gastroduodenal diseases. Circulating microRNAs (miRNAs) have shown the potential to be used as noninvasive biomarkers for the diagnosis of infectious diseases. The aim of this study was to explore plasma miRNAs as noninvasive biomarkers for H pylori infection. We performed a plasma miRNA expression profile using Illumina high-throughput sequencing and validated the levels of differentially expressed miRNAs in the plasma of 63 H pylori-infected patients and 41 healthy volunteers by quantitative real-time polymerase chain reaction (qRT-PCR). The sequencing results showed that 37 miRNAs were upregulated in the H pylori-infected patients compared with that in the healthy volunteers, while six miRNAs were downregulated. qRT-PCR and receiver operator characteristic analysis suggested that the expression of miR-28-3p, miR-143-3p, miR-151a-3p, and miR-148a-3p were closely associated with H pylori infection. Therefore, the four plasma miRNA panels mentioned above could serve as promising noninvasive biomarkers of H pylori infection.
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Affiliation(s)
- Jie Yu
- Colorectal Surgery, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Qiaoxia Xu
- Nursing Department, Huaiyin Hospital of Huai'an City, Huai'an, Jiangsu, China
| | - Xiaoyu Zhang
- Department of General Surgery, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Miao Zhu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of TCM, Nanjing, Jiangsu, China
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16
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Maleki Kakelar H, Barzegari A, Dehghani J, Hanifian S, Saeedi N, Barar J, Omidi Y. Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination. Gastric Cancer 2019; 22:23-36. [PMID: 30145749 DOI: 10.1007/s10120-018-0867-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori affect around 50% of the population worldwide. More importantly, the gastric infection induced by this bacterium is deemed to be associated with the progression of distal gastric carcinoma and gastric mucosal lymphoma in the human. H. pylori infection and its prevalent genotype significantly differ across various geographical regions. Based on numerous virulence factors, H. pylori can target different cellular proteins to modulate the variety of inflammatory responses and initiate numerous "hits" on the gastric mucosa. Such reactions lead to serious complications, including gastritis and peptic ulceration, gastric cancer and gastric mucosa-associated lymphoid structure lymphoma. Therefore, H. pylori have been considered as the type I carcinogen by the Global Firm for Research on Cancer. During the two past decades, different reports revealed that H. pylori possess oncogenic potentials in the gastric mucosa through a complicated interplay between the bacterial factors, various facets, and the environmental factors. Accordingly, numerous signaling pathways could be triggered in the development of gastrointestinal diseases (e.g., gastric cancer). Therefore, the main strategy for the treatment of gastric cancer is controlling the disease far before its onset using preventive/curative vaccination. Increasing the efficiency of vaccines may be achieved by new trials of vaccine modalities, which is used to optimize the cellular immunity. Taken all, H. pylori infection may impose severe complications, for resolving of which extensive researches are essential in terms of immune responses to H. pylori. We envision that H. pylori-mediated diseases can be controlled by advanced vaccines and immunotherapies.
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Affiliation(s)
- Hadi Maleki Kakelar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Barzegari
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaber Dehghani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Hanifian
- Department of Food Science and Technology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Nazli Saeedi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran.
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17
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Woo HD, Fernandez-Jimenez N, Ghantous A, Degli Esposti D, Cuenin C, Cahais V, Choi IJ, Kim YI, Kim J, Herceg Z. Genome-wide profiling of normal gastric mucosa identifies Helicobacter pylori- and cancer-associated DNA methylome changes. Int J Cancer 2018; 143:597-609. [PMID: 29574700 DOI: 10.1002/ijc.31381] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/12/2018] [Accepted: 03/02/2018] [Indexed: 12/11/2022]
Abstract
The large geographic variations in the incidence of gastric cancer (GC) are likely due to differential environmental exposures, in particular to Helicobacter pylori (H. pylori) infection. We aimed to investigate the impact of H. pylori on the epigenome in normal gastric mucosa and methylation changes associated with cancer risk independent of H. pylori. A discovery set of normal gastric mucosa from GC cases (n = 42) and controls (n = 42), nested in a large case-control study and stratified by H. pylori status, were subjected to genome-wide methylation profiling. Single-nucleotide polymorphism arrays from peripheral blood leukocytes were used to conduct methylation quantitative trait loci (mQTL) analysis. A validation set of gastric mucosa samples (n = 180) was used in the replication phase. We found 1,924 differentially methylated positions (DMPs) and 438 differentially methylated regions (DMRs) associated with H. pylori infection, most of which were hypermethylated. Significant methylation alterations identified in the initial set were successfully replicated. Furthermore, the H. pylori-associated DMP/Rs showed marked stability ('epigenetic memory') after H. pylori clearance. Interestingly, we found 152 DMRs associated with cancer risk independent of the H. pylori status in normal gastric mucosa. The methylation score derived from three biomarkers was a strong predictor of GC. Finally, the mQTL analysis indicated that the H. pylori- and cancer-specific methylation signatures were minimally affected by genetic variation. The comprehensively characterized methylome changes associated with H. pylori infection and GC risk in our study might serve as potential biomarkers for early cancer progression in tumour-free gastric mucosa.
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Affiliation(s)
- Hae Dong Woo
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Nora Fernandez-Jimenez
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Akram Ghantous
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Davide Degli Esposti
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Cyrille Cuenin
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Vincent Cahais
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Young-Il Kim
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
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18
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Bravo D, Hoare A, Soto C, Valenzuela MA, Quest AFG. Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects. World J Gastroenterol 2018; 24:3071-3089. [PMID: 30065554 PMCID: PMC6064966 DOI: 10.3748/wjg.v24.i28.3071] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/17/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is present in roughly 50% of the human population worldwide and infection levels reach over 70% in developing countries. The infection has classically been associated with different gastro-intestinal diseases, but also with extra gastric diseases. Despite such associations, the bacterium frequently persists in the human host without inducing disease, and it has been suggested that H. pylori may also play a beneficial role in health. To understand how H. pylori can produce such diverse effects in the human host, several studies have focused on understanding the local and systemic effects triggered by this bacterium. One of the main mechanisms by which H. pylori is thought to damage the host is by inducing local and systemic inflammation. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome. The objective of this review is to discuss how H. pylori has co-evolved with humans, how H. pylori presence is associated with positive and negative effects in human health and how inflammation and/or changes in the microbiome are associated with the observed outcomes.
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Affiliation(s)
- Denisse Bravo
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Anilei Hoare
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Cristopher Soto
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Manuel A Valenzuela
- Advanced Center for Chronic Diseases, Institute for Health-Related Research and Innovation, Faculty of Health Sciences, Universidad Central de Chile, Santiago 8380447, Chile
| | - Andrew FG Quest
- Advanced Center for Chronic Diseases, Center for Studies on Exercise, Metabolism and Cancer, Biomedical Science Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380447, Chile
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19
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Abstract
BACKGROUND This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis. METHODS The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs. RESULTS The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P < 0.001). SFRP1, -2, and DKK3 gene expression was stepwise downregulated from H. pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P < 0.05). Among the Wnt antagonists, only the degrees of methylation and downregulation of DKK3 were significantly reduced after H. pylori eradication (P < 0.05). CONCLUSION Epigenetic silencing of SFRP and DKK family genes may facilitate the formation of an epigenetic field during H. pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation.
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20
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Bradley MS, Burke EE, Grenier C, Amundsen CL, Murphy SK, Siddiqui NY. A genome-scale DNA methylation study in women with interstitial cystitis/bladder pain syndrome. Neurourol Urodyn 2018; 37:1485-1493. [PMID: 29363787 DOI: 10.1002/nau.23489] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 12/13/2017] [Indexed: 12/30/2022]
Abstract
AIMS To assess the feasibility of using voided urine samples to perform a DNA methylation study in females with interstitial cystitis/bladder pain syndrome (IC/BPS) as compared to age- and race-matched controls. A unique methylation profile could lead to a non-invasive, reproducible, and objective biomarker that would aid clinicians in the diagnosis of IC/BPS. METHODS Nineteen IC/BPS patients and 17 controls were included. IC/BPS patients had an Interstitial Cystitis Symptom Index score of >8; controls had no bladder symptoms. DNA was extracted from pelleted urine sediment. Samples with >500 ng of genomic DNA underwent quantitative DNA methylation assessment using the Illumina Infinium MethylationEPIC BeadChip. Age- and race-matching was applied prior to analysis. Linear regression models were used to compare average methylation between IC/BPS cases and controls at each cytosine guanine dinucleotide site (loci where methylation can occur). RESULTS Sixteen participants (eight IC/BPS age- and race-matched to eight controls) had adequate DNA for methylation analysis. The median age was 43.5 years (interquartile range 33.8, 65.0), the median BMI was 27.1 (IQR 22.7, 31.4), and 14 were Caucasian (87.5%). A total of 688 417 CpG sites were analyzed. In exploratory pathway analysis utilizing the top 1000 differentially methylated CpG sites, the mitogen-activated protein kinase (MAPK) pathway was overrepresented by member genes. CONCLUSIONS The results demonstrate the feasibility of using voided urine specimens from women with IC/BPS to perform DNA methylation assessments. Additionally, the data suggest genes within or downstream of the MAPK pathway exhibit altered methylation in IC/BPS.
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Affiliation(s)
- Megan S Bradley
- Division of Urogynecology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Hospital-University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Emily E Burke
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Carole Grenier
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
| | - Cindy L Amundsen
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
| | - Susan K Murphy
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
| | - Nazema Y Siddiqui
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
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21
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Xie Y, Zhou JJ, Zhao Y, Zhang T, Mei LZ. H. pylori modifies methylation of global genomic DNA and the gastrin gene promoter in gastric mucosal cells and gastric cancer cells. Microb Pathog 2017; 108:129-136. [PMID: 28478202 DOI: 10.1016/j.micpath.2017.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/02/2017] [Accepted: 05/02/2017] [Indexed: 01/26/2023]
Abstract
AIMS The aim of this study was to evaluate the correlation between H. pylori infection and global DNA methylation, as well as the methylation levels of the gastrin promoters. MATERIALS AND METHODS We constructed a eukaryotic expression vector, pcDNA3.1::cagA, and transfected it into GES-1 gastric mucosal cells and SGC-7901 gastric cancer cells. Both cell lines were infected with the H. pylori/CagA+ strain NCTC11637. Then, we detected global DNA methylation by capture and detection antibodies, followed by colorimetric quantification. The methylation levels of the gastrin promoter were evaluated by base-specific cleavage and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS In H. pylori/CagA+-infected GES-1 and SGC-7901 cells, the methylation levels of genomic DNA decreased by 49.4% and 18.8%, and in GES-1 and SGC-7901 cells transfected with pcDNA3.1::cagA, the methylation levels of genomic DNA decreased by 17.05% and 25.6%, respectively. Among 24 methylation sites detected in the gastrin promoter region, the methylation levels of 9 CpG sites were significantly decreased in H. pylori/CagA+-infected and pcDNA3.1:: cagA-transfected cells in comparison to corresponding control cells. CONCLUSION These results indicate that H. pylori/CagA+ decreases the methylation of the genome and the gastrin promoter at some CpG sites in gastric mucosal and gastric cancer cells.
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Affiliation(s)
- Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Jian Jiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China; Affiliated Hospital, Guiyang Medical University, No. 9, Beijing Road, Guiyang 550004, China.
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Ting Zhang
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
| | - Liu Zheng Mei
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, China; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guizhou Province, China
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Choi J, Kim SG, Kim BG, Koh SJ, Kim JW, Lee KL. Helicobacter pylori Eradication Modulates Aberrant CpG Island Hypermethylation in Gastric Carcinogenesis. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 68:253-259. [PMID: 27871161 DOI: 10.4166/kjg.2016.68.5.253] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Background/Aims Helicobacter pylori infection induces aberrant DNA methylation in gastric mucosa. We evaluated the long-term effect of H. pylori eradication on promotor CpG island hypermethylation in gastric carcinogenesis. Methods H. pylori-positive patients with gastric adenoma or early gastric cancer who underwent endoscopic resection were enrolled. According to H. pylori eradication after endoscopic resection, the participants were randomly assigned to H. pylori eradication or non-eradication group. H. pylori-negative gastric mucosa from normal participants provided the normal control. CpG island hypermethylation of tumor-related genes (p16, CDH1, and RUNX-3) was evaluated by quantitative MethyLight assay in non-tumorous gastric mucosa. The gene methylation rate and median values of hypermethylation were compared after one year by H. pylori status. Results In H. pylori-positive patients, hypermethylation of p16 was found in 80.6%, of CDH1 in 80.6%, and of RUNX-3 in 48.4%. This is significantly higher than normal control (p16, 10%; CDH1, 44%; RUNX-3, 16%) (p<0.05). In the H. pylori eradication group, methylation rates of p16 and CDH1 decreased in 58.1% and 61.3% of the patients, and the median values of hypermethylation were significantly lower at one year compared with the non-eradication group. However, RUNX-3 hypermethylation did not differ significantly at one year after H. pylori eradication. The non-eradication group hypermethylation did not change after one year. Conclusions H. pylori infection was associated with promotor hypermethylation of genes in gastric carcinogenesis, and H. pylori eradication might reverse p16 and CDH1 hypermethylation.
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Affiliation(s)
- Jeongmin Choi
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Byeong Gwan Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Seong Joon Koh
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Ji Won Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Kook Lae Lee
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
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Lee JW, Kim N, Park JH, Kim HJ, Chang H, Kim JM, Kim JW, Lee DH. Differential MicroRNA Expression Between Gastric Cancer Tissue and Non-cancerous Gastric Mucosa According to Helicobacter pylori Status. J Cancer Prev 2017; 22:33-39. [PMID: 28382284 PMCID: PMC5380187 DOI: 10.15430/jcp.2017.22.1.33] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 03/15/2017] [Accepted: 03/15/2017] [Indexed: 12/28/2022] Open
Abstract
Background MicroRNAs (miRNAs) are key post-translational mechanisms which can regulate gene expression in gastric carcinogenesis. To identify miRNAs responsible for gastric carcinogenesis, we compared expression levels of miRNAs between gastric cancer tissue and non-cancerous gastric mucosa according to Helicobacter pylori status. Methods Total RNA was extracted from the cancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n = 8) or H. pylori-negative (n = 8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays for biopsy samples from 107 patients consisted of control and gastric cancer with or without H. pylori. And then, expression levels of miRNAs were compared according to subgroups. Results A total of 156 miRNAs in the aberrant miRNA profiles across the miRNA microarray showed differential expression (at least a 2-fold change, P < 0.05) in cancer tissue, compared to noncancerous mucosa in both of H. pylori-negative and -positive samples. After 10 promising miRNAs were selected, validations by TaqMan miRNA assays confirmed that two miRNAs (hsa-miR-135b-5p and hsa-miR-196a-5p) were significantly increased and one miRNA (hsa-miR-145-5p) decreased in cancer tissue compared to non-cancerous gastric mucosa at H. pylori-negative group. For H. pylori-positive group, three miRNAs (hsa-miR-18a-5p, hsa-miR-135b-5p, and hsa-miR-196a-5p) were increased in cancer tissue. hsa-miR-135b-5p and hsa-miR-196a-5p were increased in gastric cancer in both of H. pylori-negative and -positive. Conclusions miRNA expression of the gastric cancer implies that different but partially common gastric cancer carcinogenic mechanisms might exist according to H. pylori status.
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Affiliation(s)
- Jung Won Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine, Samsung Changwon Hospital, Changwon, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jin Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine, Myongji Hospital, Goyang, Korea
| | - Hyun Chang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jung Min Kim
- NAR Center, Inc., Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Akter H, Yoo YS, Park WS, Kang MJ. Cholecystokinin as a potent diagnostic marker for gastric cancer. BIOCHIP JOURNAL 2017; 11:14-20. [DOI: 10.1007/s13206-016-1103-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Yoshida S, Yamashita S, Niwa T, Mori A, Ito S, Ichinose M, Ushijima T. Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric Cancer 2017; 20:136-145. [PMID: 26792292 DOI: 10.1007/s10120-016-0593-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 01/05/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) is highly influenced by aberrant methylation, and accumulation of aberrant methylation in gastric mucosae produces an epigenetic field for cancerization. Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC. METHODS A transcription start site was determined by the 5' rapid amplification of complementary DNA ends method. DNA methylation was analyzed by bisulfite sequencing with use of a next-generation sequencer or quantitative methylation-specific PCR. Gene expression was analyzed by quantitative reverse transcription PCR. RESULTS A single transcription start site was identified for FAT4 in gastric epithelial cells, and a CpG island was located in the FAT4 promoter region. FAT4 was highly methylated in two of 13 GC cell lines and was not expressed in them. Removal of FAT4 methylation by a DNA demethylating agent (5-aza-2'-deoxycytidine) restored its expression in the two cell lines. In primary GC samples, FAT4 was methylated in 12 of 82 GCs (14.6 %). FAT4 methylation was associated with the presence of the CpG island methylator phenotype but not with prognosis, tumor invasion, lymph node metastasis, or histological types. In noncancerous gastric mucosae, high FAT4 methylation levels were associated with the presence of GC and Helicobacter pylori infection. CONCLUSIONS FAT4 was methylation-silenced in GCs. Its methylation in gastric mucosae was associated with H. pylori infection and likely contributed to epigenetic field cancerization.
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Affiliation(s)
- Satoshi Yoshida
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tohru Niwa
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akiko Mori
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Masao Ichinose
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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26
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Yoon H, Kim N, Shin CM, Lee HS, Kim BK, Kang GH, Kim JM, Kim JS, Lee DH, Jung HC. Risk Factors for Metachronous Gastric Neoplasms in Patients Who Underwent Endoscopic Resection of a Gastric Neoplasm. Gut Liver 2016; 10:228-36. [PMID: 26087797 PMCID: PMC4780452 DOI: 10.5009/gnl14472] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background/Aims To identify the risk factors for metachronous gastric neoplasms in patients who underwent an endoscopic resection of a gastric neoplasm. Methods We prospectively collected clinicopathologic data and measured the methylation levels of HAND1, THBD, APC, and MOS in the gastric mucosa by methylation-specific real-time polymerase chain reaction in patients who underwent endoscopic resection of gastric neoplasms. Results A total of 257 patients with gastric neoplasms (113 low-grade dysplasias, 25 high-grade dysplasias, and 119 early gastric cancers) were enrolled. Metachronous gastric neoplasm developed in 7.4% of patients during a mean follow-up of 52 months. The 5-year cumulative incidence of metachronous gastric neoplasm was 4.8%. Multivariate analysis showed that moderate/severe corpus intestinal metaplasia and family history of gastric cancer were independent risk factors for metachronous gastric neoplasm development; the hazard ratios were 4.12 (95% confidence interval [CI], 1.23 to 13.87; p=0.022) and 3.52 (95% CI, 1.09 to 11.40; p=0.036), respectively. The methylation level of MOS was significantly elevated in patients with metachronous gastric neoplasms compared age- and sex-matched patients without metachronous gastric neoplasms (p=0.020). Conclusions In patients who underwent endoscopic resection of gastric neoplasms, moderate/severe corpus intestinal metaplasia and a family history of gastric cancer were independent risk factors for metachronous gastric neoplasm, and MOS was significantly hypermethylated in patients with metachronous gastric neoplasms.
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Affiliation(s)
- Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bo Kyoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Samadani AA, Nikbakhsh N, Pilehchian M, Fattahi S, Akhavan-Niaki H. Epigenetic changes of CDX2 in gastric adenocarcinoma. J Cell Commun Signal 2016; 10:267-272. [PMID: 27139434 PMCID: PMC5143315 DOI: 10.1007/s12079-016-0327-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/27/2016] [Indexed: 01/01/2023] Open
Abstract
Gastric cancer is one of the most commonplace and lethal cancers in the world. Molecular investigation of this disease, in order to obtain diagnostic and treatments achievements is important and vital. Relatively, in this research study, one of the most important epigenetic factors, the methylation of CDX2 gene was investigated in tumoral and non-tumoral tissues of gastric cancer patients by bisulfite treatment followed by sequencing of the 5'UTR region of CDX2 in both tissues. The results indicated a hypomethylation in tumoral tissues of adenocarcinoma. Consequently, the methylation amount of CDX2 in tumoral tissues was significantly reduced compared with non-tumoral tissues.
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Affiliation(s)
- Ali Akbar Samadani
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Novin Nikbakhsh
- Department of Surgery, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Pilehchian
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran.
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Follow-Up Study on CDX1 and CDX2 mRNA Expression in Noncancerous Gastric Mucosae After Helicobacter pylori Eradication. Dig Dis Sci 2016; 61:1051-9. [PMID: 26841784 DOI: 10.1007/s10620-016-4048-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 01/19/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Changes in CDX1/CDX2 in gastric mucosae following Helicobacter pylori eradication have not been clarified yet. AIMS To evaluate the changes in CDX1/CDX2 expression after H. pylori eradication, in relation to the reversibility of intestinal metaplasia (IM). METHODS Time course of CDX1/CDX2 expressions was investigated in 176 subjects with various gastroduodenal disorders. Among them, 132 patients were H. pylori positives; H. pylori were eradicated in 107 of them; 13 failed to eradicate; and 12 did not receive H. pylori eradication therapy. Forty-four subjects were H. pylori negatives. Expression levels in CDX1 and CDX2 from noncancerous gastric mucosae of the corpus, as well as the histologic findings of gastric mucosae, were evaluated during the follow-up. RESULTS Average follow-up duration was 33.7 months (range 2-97 months). Expression levels in both CDX1 and CDX2 mRNAs were correlated with IM grade in the corpus (ρ = 0.633 and 0.554, respectively, all P < 0.001). Changes in CDX1/CDX2 mRNA expressions following H. pylori eradication showed only insignificant results; IM grade at the antrum and corpus showed a tendency to decrease after H. pylori eradication without statistical significance (P > 0.05). However, histologic improvement of IM at the corpus was associated with a decrease in CDX2 mRNA expression during the follow-up (linear mixed model, P for slope = 0.015). CONCLUSIONS In this study, eradication of H. pylori did not show any beneficial effects on aberrant CDX1/CDX2 expressions or IM. Reversibility of IM may be associated with a decrease in CDX2 mRNA expression.
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Zhou J, Wang W, Xie Y, Zhao Y, Chen X, Xu W, Wang Y, Guan Z. Proteomics-Based Identification and Analysis of Proteins Associated with Helicobacter pylori in Gastric Cancer. PLoS One 2016; 11:e0146521. [PMID: 26745502 PMCID: PMC4706351 DOI: 10.1371/journal.pone.0146521] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/19/2015] [Indexed: 01/22/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacterium that causes the most common chronic infection in the human stomach. Approximately 1%-3% of infected individuals develop gastric cancer. However, the mechanisms by which H. pylori induces gastric cancer are not completely understood. The available evidence indicates a strong link between the virulence factor of H. pylori, cytotoxin-associated gene A (CagA), and gastric cancer. To further characterize H. pylori virulence, we established three cell lines by infecting the gastric cancer cell lines SGC-7901 and AGS with cagA+H. pylori and transfecting SGC-7901 with a vector carrying the full-length cagA gene. We detected 135 differently expressed proteins from the three cell lines using proteome technology, and 10 differential proteins common to the three cell lines were selected and identified by LC-MS/MS as well as verified by western blot: β-actin, L-lactate dehydrogenase (LDH), dihydrolipoamide dehydrogenase (DLD), pre-mRNA-processing factor 19 homolog (PRPF19), ATP synthase, calmodulin (CaM), p64 CLCP, Ran-specific GTPase-activating protein (RanGAP), P43 and calreticulin. Detection of the expression of these proteins and genes encoding these proteins in human gastric cancer tissues by real-time PCR (RT-qPCR) and western blot revealed that the expression of β-ACTIN, LDH, DLD, PRPF19 and CaM genes were up-regulated and RanGAP was down-regulated in gastric cancer tissues and/or metastatic lymph nodes compared to peri-cancerous tissues. High gene expression was observed for H. pylori infection in gastric cancer tissues. Furthermore, the LDH, DLD and CaM genes were demethylated at the promoter -2325, -1885 and -276 sites, respectively, and the RanGAP gene was highly methylated at the promoter -570 and -170 sites in H. pylori-infected and cagA-overexpressing cells. These results provide new insights into the molecular pathogenesis and treatment targets for gastric cancer with H. pylori infection.
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Affiliation(s)
- Jianjiang Zhou
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Clinical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
- * E-mail:
| | - Wenling Wang
- Department of Oncology, Guizhou Cancer Hospital, Guiyang, Guizhou, China
| | - Yuan Xie
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yan Zhao
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xian Chen
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
| | - Wenjie Xu
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yan Wang
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhizhong Guan
- Molecular Biology Key Laboratory, Guizhou Medical University, Guiyang, Guizhou, China
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Chang H, Kim N, Park JH, Nam RH, Choi YJ, Lee HS, Yoon H, Shin CM, Park YS, Kim JM, Lee DH. Different microRNA expression levels in gastric cancer depending on Helicobacter pylori infection. Gut Liver 2015; 9:188-96. [PMID: 25167801 PMCID: PMC4351025 DOI: 10.5009/gnl13371] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIMS This study was conducted to identify microRNAs (miRNAs) that are differentially expressed in Helicobacter pylori-infected patients with an intestinal type of gastric cancer using miRNA microarray and to confirm the candidate miRNA expression levels. METHODS Total RNA was extracted from the cancerous and noncancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n=8) or H. pylori-negative (n=8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays. RESULTS A total of 219 miRNAs in the aber-rant miRNA profiles across the miRNA microarray showed at least a 2-fold change differential expression in H. pylori-positive and H. pylori-negative cancer tissues. After candi-date miRNAs were selected using online miRNA databases, TaqMan miRNA assays confirmed that three miRNAs (miR-99b-3p, miR-564, and miR-638) were significantly increased in three H. pylori-positive cancer tissues compared to the H. pylori-negative cancer tissues. Additionally, four miRNAs (miR-204-5p, miR-338-5p, miR-375, and miR-548c-3p) were significantly increased in H. pylori-negative cancer tissues compared to H. pylori-positive cancer tissues. CONCLUSIONS miRNA expression in the intestinal type of H. pylori infection-dependent gastric cancer suggests that different gastric can-cer pathogenesis mechanisms could exist between H. pylori-positive and H. pylori-negative gastric cancer. Additional functional studies are required. (Gut Liver, 2015;9188-196).
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Affiliation(s)
- Hyun Chang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jeong Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Min Kim
- NAR Center, Inc., Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam and Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Necula LG, Mambet C, Albulescu R, Diaconu CC. Epigenetics in gastric carcinogenesis: TET genes as important players. J Immunoassay Immunochem 2015; 36:445-455. [PMID: 25714048 DOI: 10.1080/15321819.2015.1017402] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenetic processes including aberrant promoter methylation of tumor suppressor gene play a key role in gastric carcinogenesis. TET proteins are involved in DNA demethylation; many cancers, haematological or solid, present loss-of-function mutations and aberrant expression/regulation of TET. In gastric cancer there are few studies reporting a decreased expression of TET and associations between these proteins and signaling pathways involved in carcinogenesis. Identifying connections between aberrant expression of TET, disruption of the balance between DNA methylation and demethylation and their association with gastric carcinogenesis might be useful for the development of novel therapeutic approaches.
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Affiliation(s)
- Laura Georgiana Necula
- a Cellular and Molecular Pathology Department , Stefan S. Nicolau Institute of Virology , Bucharest , Romania
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Shi J, Qu YP, Hou P. Pathogenetic mechanisms in gastric cancer. World J Gastroenterol 2014; 20:13804-13819. [PMID: 25320518 PMCID: PMC4194564 DOI: 10.3748/wjg.v20.i38.13804] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review.
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Chen YZ, Liu D, Zhao YX, Wang HT, Gao Y, Chen Y. Relationships between p16 gene promoter methylation and clinicopathologic features of colorectal cancer: a meta-analysis of 27 cohort studies. DNA Cell Biol 2014; 33:729-38. [PMID: 24979649 DOI: 10.1089/dna.2013.2253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.
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Affiliation(s)
- Yan-Zhi Chen
- Department of Radiotherapy, The Fourth Affiliated Hospital of China Medical University , Shenyang, People's Republic of China
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Barros SP, Offenbacher S. Modifiable risk factors in periodontal disease: epigenetic regulation of gene expression in the inflammatory response. Periodontol 2000 2014; 64:95-110. [PMID: 24320958 DOI: 10.1111/prd.12000] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Epigenetics as a modifiable risk factor in periodontal diseases has been investigated in light of the current knowledge of how chronic infection and inflammation can affect gene-specific epigenetic reprogramming in periodontal tissues. Epigenomic programming might be particularly sensitive to environmental influences, and a combination of physiological stressors and environmental exposures appears to affect the epigenomic program acquired by a cell during differentiation and throughout the cellular lineage lifespan. Viral and bacterial infections can establish several types of epigenetic modifications, which sometimes engage in a complex epigenetic crosstalk also reflecting in the establishment and progress of periodontal diseases. The inflammatory and metabolic states of the periodontal tissues are driven by the infectious stimuli, and the magnitude of the cellular and molecular signature response is further dictated by the host genetic and epigenetic traits associated with various systemic exposures, including smoking, obesity and diabetes/hyperglycemia. This review discusses the advances in epigenetics, focusing on the role of DNA methylation in the pathogenesis of periodontal disease and the potential of epigenetic therapy.
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Abstract
Helicobacter pylori-associated gastric cancer is a major cause of morbidity and mortality worldwide, and is predicted to become even more common in developing countries as the population ages. Since gastric cancer develops slowly over years to decades, and typically progresses though a series of well-defined histologic stages, cancer biomarkers have potential to identify asymptomatic individuals in whom surgery might be curative, or even those for whom antibiotics to eradicate H. pylori could prevent neoplastic transformation. Here we describe some of the challenges of biomarker discovery, summarize current approaches to biomarkers of gastric cancer, and explore some recent novel strategies.
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Affiliation(s)
- Cara L Cooke
- Departments of Medicine and Microbiology & Immunology; University of California; Davis School of Medicine; Davis, CA USA,Center for Comparative Medicine; University of California; Davis School of Medicine; Davis, CA USA
| | - Javier Torres
- Infectious Diseases Research Unit; Instituto Mexicano del Seguro Social; Mexico City, Mexico
| | - Jay V Solnick
- Departments of Medicine and Microbiology & Immunology; University of California; Davis School of Medicine; Davis, CA USA,Center for Comparative Medicine; University of California; Davis School of Medicine; Davis, CA USA,California National Primate Research Center; University of California; Davis School of Medicine; Davis, CA USA,Correspondence to: Jay V Solnick,
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Hong SJ, Lee HJ, Oh JH, Jung SH, Min KO, Choi SW, Rhyu MG. Age-related methylation patterning of housekeeping genes and tissue-specific genes is distinct between the stomach antrum and body. Epigenomics 2013; 5:283-99. [PMID: 23750644 DOI: 10.2217/epi.13.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM The methylation-variable sites around CpG islands are frequently overmethylated in Helicobacter pylori-infected stomachs. Age-related patterns of the overmethylation changes were compared between the fast-growing antrum cells and the slow-growing body cells. MATERIALS & METHODS A total of 316 H. pylori-positive tissues and 380 H. pylori-negative tissues were obtained by endoscopic biopsy. The methylation-variable sites of ten housekeeping genes and nine tissue-specific genes were semiquantitatively analyzed, based on the ten-level classification of methylation-specific PCR intensity. The overmethylated genes were scored when their methylation levels were higher than an intermediate level of each gene common in the H. pylori-negative mucosa. RESULTS The age-dependent methylation level of the inactive APC gene observed similarly in the antrum and the body was used as an age standard of methylation variation in a biopsy tissue. The overmethylation of housekeeping genes and stomach-specific genes rapidly increased to a high plateau frequency in the young-aged APC methylation cases (mean age: 43 years) in the H. pylori-positive antrum. In the H. pylori-positive body, most of the overmethylated housekeeping genes slowly increased to a peak frequency in the middle-aged APC methylation cases (mean age: 53 years). The housekeeping gene pairs showed high correlations (Spearman's correlation coefficient > 0.4) in both the antrum and the body. CONCLUSION The overmethylation of housekeeping genes rapidly and slowly increased to a high frequency in concordance with a rapid and slow growth of epithelial cells in the H. pylori-infected stomach.
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Affiliation(s)
- Seung-Jin Hong
- Department of Microbiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong Socho-gu, Seoul 137-701, Republic of Korea
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Ayed-Guerfali DB, Hassairi B, Khabir A, Sellami-Boudawara T, Gargouri A, Mokdad-Gargouri R. Expression of APC, β-catenin and E-cadherin in Tunisian patients with gastric adenocarcinoma: clinical significance. Tumour Biol 2013; 35:1775-83. [PMID: 24197976 DOI: 10.1007/s13277-013-1236-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/18/2013] [Indexed: 12/13/2022] Open
Abstract
Aberrant activation of the Wnt signalling pathway is a key feature of many cancers. β-Catenin, adenomatous polyposis coli (APC) and E-cadherin are major players in this pathway. The aim of this study is to examine the expression of β-catenin, APC and E-cadherin in tumour tissues of 80 Tunisian patients with gastric carcinoma and to determine the methylation status of the APC promoter in tumour tissues. Associations between protein expression and clinico-pathological parameters, including prognosis, were performed. Positive expression of β-catenin, APC and E-cadherin was observed in 77.5, 68.7 and 60% of cases, respectively. Tumours lacking membranous expression of β-catenin had greater extent of lymph node metastasis, poor differentiation and advanced T-stage. The expression of E-cadherin correlated with poor differentiation (P = 0.05) and β-catenin expression (P = 0.004). With regards to prognosis, the overall survival time was significantly prolonged for patients showing normal β-catenin expression (exclusively or predominantly membranous staining) alone or combined with positive APC expression (P log rank = 0.008 and 0.003, respectively). The methylated pattern of APC promoter 1A was detected in 43.8% of cases and correlated with T-stage (P = 0.046) and distant metastasis (P = 0.037). No correlation was found between the methylated profile of APC promoter 1A and the expression of APC protein in tumour tissues. Our findings suggest that deregulation of the Wnt pathway via abnormal expression of β-catenin and E-cadherin occurred frequently in gastric carcinoma and correlated with worse clinical behaviour.
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Affiliation(s)
- Dorra Ben Ayed-Guerfali
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, 3038, Sfax, Tunisia
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Yoshida T, Kato J, Maekita T, Yamashita S, Enomoto S, Ando T, Niwa T, Deguchi H, Ueda K, Inoue I, Iguchi M, Tamai H, Ushijima T, Ichinose M. Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis. Gastric Cancer 2013; 16:488-97. [PMID: 23292007 DOI: 10.1007/s10120-012-0230-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Accepted: 12/17/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic inflammation triggered by Helicobacter pylori causes altered DNA methylation in stomach mucosae, which is deeply involved in gastric carcinogenesis. This study aimed to elucidate the correlation between altered mucosal DNA methylation levels and activity of H. pylori-related gastritis, because inflammatory activity shows particular correlations with the development of diffuse-type cancer. METHODS Methylation levels in stomach mucosae of 78 healthy volunteers were determined by real-time methylation-specific PCR or bisulfite pyrosequencing. Examined loci were the promoter CpG islands of six genes (FLNc, HAND1, THBD, p41ARC, HRASLS, and LOX) and the CpG sites of non-coding repetitive elements (Alu and Satα) that are reportedly altered by H. pylori infection. Activity of H. pylori-related gastritis was evaluated using two serum markers: H. pylori antibody titer and pepsinogen II. RESULTS Methylation levels of the six CpG islands were consistently increased, and those of the two repetitive elements were consistently decreased in a stepwise manner with the activity of gastric inflammation as represented by serum marker levels. Each serum marker level was well correlated with the overall DNA methylation status of stomach mucosa, and these two serologic markers were additive in the detection of the mucosa with severely altered DNA methylation. CONCLUSIONS Alteration in mucosal DNA methylation level was closely correlated with activity of H. pylori-related gastritis as evaluated by serum markers. The observed correlation between altered DNA methylation levels and activity of H. pylori-related gastritis appears to be one of the relevant molecular mechanisms underlying the development of diffuse-type cancer.
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Affiliation(s)
- Takeichi Yoshida
- Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-0012, Japan,
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Shin CM, Kim N, Lee HS, Park JH, Ahn S, Kang GH, Kim JM, Kim JS, Lee DH, Jung HC. Changes in aberrant DNA methylation after Helicobacter pylori eradication: a long-term follow-up study. Int J Cancer 2013; 133:2034-42. [PMID: 23595635 DOI: 10.1002/ijc.28219] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 04/03/2013] [Indexed: 12/12/2022]
Abstract
Changes of DNA methylation in gastric mucosae after eradication of Helicobacter pylori have not been clarified yet. From this background, we investigated time course of DNA methylation following H. pylori eradication in 221 successfully H. pylori eradicated subjects with endoscopic follow-up at least for 6 months, including 114 controls, 53 subjects with gastric dysplasia and 54 patients with early gastric cancer. All dysplasia and gastric cancer patients underwent endoscopic resection at the time of enrollment. The methylation levels in LOX, APC and MOS genes from noncancerous gastric mucosae using quantitative methylation-specific PCR, as well as the histologic findings of gastric mucosae, were compared before and after eradication. Average follow-up duration was 26.0 months (range: 6 to 76 months). H. pylori eradication decreased methylation levels in LOX (p-value for slope < 0.001) but not in APC. In MOS, decrease of its methylation level following H. pylori eradication was significant among controls without intestinal metaplasia (IM) (p-value for slope < 0.05); however, it was not observed among patients with IM or those with dysplasia or gastric cancer. After H. pylori eradication, methylation level in MOS persistently increased in patients with dysplasia or gastric cancer (p < 0.01). In conclusion, H. pylori eradication decreases aberrant DNA methylation with gene-specific manner. Methylation level in MOS is associated with IM and may be used as a surrogate marker for gastric cancer risk, regardless of H. pylori eradication history.
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Affiliation(s)
- Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
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Herceg Z, Lambert MP, van Veldhoven K, Demetriou C, Vineis P, Smith MT, Straif K, Wild CP. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis 2013; 34:1955-67. [PMID: 23749751 DOI: 10.1093/carcin/bgt212] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the 'normal' epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing.
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Affiliation(s)
- Zdenko Herceg
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, F-69008 Lyon, France
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Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta 2013; 424:53-65. [PMID: 23669186 DOI: 10.1016/j.cca.2013.05.002] [Citation(s) in RCA: 279] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 05/03/2013] [Accepted: 05/03/2013] [Indexed: 02/07/2023]
Abstract
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.
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Key Words
- 5-hmC
- 5-hydroxymethylcytosine
- 5-mC
- 5-methylcytosine
- ADAM metallopeptidase domain 23
- ADAM metallopeptidase with thrombospondin type 1 motif, 9
- ADAM23
- ADAMTS9
- AML
- APC
- ARID1A
- AT motif-binding factor 1
- AT rich interactive domain 1A (SWI-like)
- ATBF1
- Acute myelocytic leukemia
- Adenomatosis polyposis coli
- B-cell translocation gene 4
- BCL2/adenovirus E1B 19kDa interacting protein 3
- BMP-2
- BNIP3
- BS
- BTG4
- Biomarkers
- Bisulfite sequencing
- Bone morphogenetic protein 2
- C-MET
- CACNA1G
- CACNA2D3
- CD44
- CD44 molecule (Indian blood group)
- CDH1
- CDK4
- CDK6
- CDKN1C
- CDKN2A
- CDX2
- CGI
- CHD5
- CHFR
- CKLF-like MARVEL transmembrane domain containing 3
- CMTM3
- CNS
- CRBP1
- Cadherin 1 or E-cadherin
- Calcium channel, voltage-dependent, T type, alpha 1G subunit
- Calcium channel, voltage-dependent, alpha 2/delta subunit 3
- Caudal type homeobox 2
- Central nervous system
- Checkpoint with forkhead and ring finger domains, E3 ubiquitin protein ligase
- Chromodomain helicase DNA binding protein 5
- Chromosome 2 open reading frame 40
- Clinical outcomes
- CpG islands
- Cyclin-dependent kinase 4
- Cyclin-dependent kinase 6
- Cyclin-dependent kinase inhibitor 1A
- Cyclin-dependent kinase inhibitor 1B
- Cyclin-dependent kinase inhibitor 1C
- Cyclin-dependent kinase inhibitor 2A
- Cyclin-dependent kinase inhibitor 2B
- DAB2 interacting protein
- DACT1
- DAPK
- DNA
- DNA methylatransferases
- DNA mismatch repair
- DNMT
- Dapper, antagonist of beta-catenin, homolog 1 (Xenopus laevis)
- Death-associated protein kinase
- Deoxyribose Nucleic Acid
- Dickkopf 3 homolog (Xenopus laevis)
- Dkk-3
- EBV
- ECRG4
- EDNRB
- EGCG
- ERBB4
- Endothelin receptor type B
- Epigallocatechin gallate
- Epigenetics
- Epstein–Barr Virus
- FDA
- FLNc
- Filamin C
- Food and Drug Administration
- GC
- GDNF
- GI endoscopy
- GPX3
- GRIK2
- GSTP1
- Gastric cancer
- Gene methylation
- Glutamate receptor, ionotropic, kainate 2
- Glutathione S-transferase pi 1
- Glutathione peroxidase 3 (plasma)
- H. pylori
- HACE1
- HAI-2/SPINT2
- HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1
- HGFA
- HLTF
- HOXA1
- HOXA10
- HRAS-like suppressor
- HRASLS
- Helicase-like transcription factor
- Helicobacter pylori
- Homeobox A1
- Homeobox A10
- Homeobox D10
- HoxD10
- IGF-1
- IGF-1R
- IGFBP3
- IL-1β
- ITGA4
- Insulin-like growth factor 1 (somatomedin C)
- Insulin-like growth factor I receptor
- Insulin-like growth factor binding protein 3
- Integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor)
- Interleukin 1, beta
- KL
- KRAS
- Klotho
- LL3
- LMP2A
- LOX
- LRP1B
- Low density lipoprotein receptor-related protein 1B
- Lysyl oxidase
- MAPK
- MBPs
- MDS
- MGMT
- MINT25
- MLF1
- MLL
- MMR
- MSI
- MSP
- Matrix metallopeptidase 24 (membrane-inserted)
- Met proto-oncogene (hepatocyte growth factor receptor)
- Methyl-CpG binding proteins
- Methylation-specific PCR
- Microsatellite instability
- Myeloid leukemia factor 1
- Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila)
- Myeloid/lymphoid or mixed-lineage leukemia 3
- NDRG family member 2
- NDRG2
- NPR1
- NR3C1
- Natriuretic peptide receptor A/guanylate cyclase A
- Notch 1
- Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
- O-6-methylguanine-DNA methyltransferase
- PCDH10
- PCDH17
- PI3K/Akt
- PIK3CA
- PR domain containing 5
- PRDM5
- PTCH1
- Patched 1
- Phosphatidylethanolamine binding protein 1
- Protein tyrosine phosphatase, non-receptor type 6
- Protocadherin 10
- Protocadherin 17
- Q-MSP
- Quantitative methylation-specific PCR
- RAR-related orphan receptor A
- RARRES1
- RARß
- RAS/RAF/MEK/ERK
- RASSF1A
- RASSF2
- RBP1
- RKIP
- RORA
- ROS
- RUNX3
- Ras association (RalGDS/AF-6) domain family member 1
- Ras association (RalGDS/AF-6) domain family member 2
- Rb
- Retinoic acid receptor responder (tazarotene induced) 1
- Retinoic acid receptor, beta
- Retinol binding protein 1, cellular
- Runt-related transcription factor 3
- S-adenosylmethionine
- SAM
- SFRP2
- SFRP5
- SHP1
- SOCS-1
- STAT3
- SYK
- Secreted frizzled-related protein 2
- Secreted frizzled-related protein 5
- Serine peptidase inhibitor, Kunitz type, 2
- Spleen tyrosine kinase
- Suppressor of cytokine signaling 1
- TCF4
- TET
- TFPI2
- TGF-β
- TIMP metallopeptidase inhibitor 3
- TIMP3
- TNM
- TP73
- TSP1
- Thrombospondin 1
- Tissue factor pathway inhibitor 2
- Transcription factor 4
- Tumor Node Metastasis
- Tumor protein p73
- V-erb-a erythroblastic leukemia viral oncogene homolog 4
- ZFP82 zinc finger protein
- ZIC1
- ZNF545
- Zinc finger protein of the cerebellum 1
- gastrointestinal endoscopy
- glial cell derived neurotrophic factor
- hDAB2IP
- hMLH1
- hepatocyte growth factor activator
- latent membrane protein
- mutL homolog 1
- myelodysplastic syndromes
- p15
- p16
- p21
- p27
- p53
- p73
- phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
- phosphoinositide 3-kinase (PI3K)/Akt
- reactive oxygen species
- retinoblastoma
- signal transducer and activator of transcription-3
- ten-eleven translocation
- transforming growth factor-β
- tumor protein p53
- tumor protein p73
- v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
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Affiliation(s)
- Yiping Qu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, People's Republic of China
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Rhyu MG, Oh JH, Hong SJ. Epigenetic implication of gene-adjacent retroelements in Helicobacter pylori-infected adults. Epigenomics 2013; 4:527-35. [PMID: 23130834 DOI: 10.2217/epi.12.51] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
A chronic inflammatory condition of gastric mucosa can facilitate the influx of new stem cells into the stomach. Epigenetic codes, such as DNA methylation, may be responsible for the stable maintenance of epigenetic phenotypes established in the new stomach-adapted stem cells. A number of hypotheses have been made for the role of CpG-island methylation, which is common in the Helicobacter pylori-infected stomach. However, they could not explain the plausible role of CpG-island methylation in the re-establishment of epigenetic phenotypes. These islands are highly repetitive sequences densely methylated throughout the human genome, the so-called parasitic retroelements, which expand a number of cDNA copies with reverse transcriptase. The densely methylated retroelements adjacent to the host genes can form the transitional-CpG sites around gene-control regions that are barely methylated. This review focuses on the putative role of transitional CpG methylation in the adaptive differentiation of new stem cells in the H. pylori-infected stomach.
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Affiliation(s)
- Mun-Gan Rhyu
- Department of Microbiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong Socho-gu, Seoul 137-701, Korea
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Pogribny IP, Rusyn I. Environmental toxicants, epigenetics, and cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 754:215-32. [PMID: 22956504 PMCID: PMC4281087 DOI: 10.1007/978-1-4419-9967-2_11] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumorigenesis, a complex and multifactorial progressive process of transformation of normal cells into malignant cells, is characterized by the accumulation of multiple cancer-specific heritable phenotypes triggered by the mutational and/or non-mutational (i.e., epigenetic) events. Accumulating evidence suggests that environmental and occupational exposures to natural substances, as well as man-made chemical and physical agents, play a causative role in human cancer. In a broad sense, carcinogenesis may be induced through either genotoxic or non-genotoxic mechanisms; however, both genotoxic and non-genotoxic carcinogens also cause prominent epigenetic changes. This review presents current evidence of the epigenetic alterations induced by various chemical carcinogens, including arsenic, 1,3-butadine, and pharmaceutical and biological agents, and highlights the potential for epigenetic changes to serve as markers for carcinogen exposure and cancer risk assessment.
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Affiliation(s)
- Igor P. Pogribny
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
| | - Ivan Rusyn
- Department of Environmental Sciences & Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
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Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer. PLoS One 2012; 7:e50266. [PMID: 23209692 PMCID: PMC3508917 DOI: 10.1371/journal.pone.0050266] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 10/17/2012] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer. METHODOLOGY/PRINCIPAL FINDINGS We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection. CONCLUSIONS/SIGNIFICANCE Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
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Nanjo S, Asada K, Yamashita S, Nakajima T, Nakazawa K, Maekita T, Ichinose M, Sugiyama T, Ushijima T. Identification of gastric cancer risk markers that are informative in individuals with past H. pylori infection. Gastric Cancer 2012; 15:382-8. [PMID: 22237657 DOI: 10.1007/s10120-011-0126-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 11/26/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epigenomic damage induced by Helicobacter pylori infection is accumulated in gastric mucosae before the development of malignancy. In individuals without current H. pylori infection, DNA methylation levels of specific CpG islands (CGIs) are associated with gastric cancer risk. Because risk estimation in individuals with past infection is clinically important, we here aimed to identify the risk markers that reflect epigenomic damage induced by H. pylori infection, and that are informative in these individuals. METHODS Gastric mucosae were obtained from 55 gastric cancer patients (GC-Pt) (21 with current infection and 34 with past infection) and 55 healthy volunteers (HV) (7 never-infected, 21 with current infection, and 27 with past infection). Hypermethylated CGIs were searched for by methylated DNA immunoprecipitation-CGI microarray, and methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction (PCR). RESULTS By microarray analysis of a pool of three samples from GC-Pt with past infection and another pool of samples from HV with past infection, 15 hypermethylated CGIs in the former pool were isolated. Seven of them had significantly higher methylation levels in GC-Pt with past infection (n = 10) than in HV with past infection (n = 10) (P < 0.001). In a validation cohort (21 GC-Pt with past infection and 14 HV with past infection), the seven new markers had large areas under the receiver-operating characteristic curves (0.78-0.84) and high odds ratios (12.7-36.0) compared with two currently available markers (0.60-0.65, 5.0-5.7). CONCLUSIONS We identified seven novel gastric cancer risk markers that are highly informative in individuals with past infection.
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Affiliation(s)
- Sohachi Nanjo
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Liu JB, Wu XM, Cai J, Zhang JY, Zhang JL, Zhou SH, Shi MX, Qiang FL. CpG island methylator phenotype and Helicobacter pylori infection associated with gastric cancer. World J Gastroenterol 2012; 18:5129-34. [PMID: 23049225 PMCID: PMC3460343 DOI: 10.3748/wjg.v18.i36.5129] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 04/16/2012] [Accepted: 08/15/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between the CpG island methylator phenotype (CIMP) and serum Helicobacter pylori (H. pylori) levels for clinical prediction of gastric cancer (GC) progression.
METHODS: We analyzed the serum CIMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infection in serum was assayed with an anti-H. pylori immunoglobulin G antibody test and a rapid urease test.
RESULTS: The frequencies of high-level methylation in GC tissues for the seven genes were: 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad. The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP+ (defined as ≥ 3 methylated genes) was associated with 47 (62.67%) GC tissue samples and 44 (58.67%) GC serum samples. CIMP+ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 (68%) were H. pylori+, and 24 (32%) were H. pylori-. Of the 51 H. pylori+ cases, 36 were CIMP+ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP+, and 13 were CIMP-. The difference was significant between the H. pylori+ and H. pylori- groups (χ2 = 4.27, P < 0.05). Of the 51 H. pylori+ GC patients, 34 were CIMP+ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP+ and 14 were CIMP-. The difference was significant between the H. pylori+ and H. pylori- groups (χ2 = 4.21, P < 0.05). A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori+/CIMP+ cases and the H. pylori+/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum (P < 0.05). However, there were no significant differences in survival rates between the two groups.
CONCLUSION: H. pylori+/CIMP+ cases are associated with higher rates of metastasis and recurrence than H. pylori+/CIMP- cases. Serum may be useful for examining CIMP status.
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Zhou JJ, Wang Y, Xie Y, Zhao Y, Gu Y. Helicobacter pylori induces demethylation of the Calmodulin gene promoter in gastric cancer cells. Shijie Huaren Xiaohua Zazhi 2012; 20:1838-1842. [DOI: 10.11569/wcjd.v20.i20.1838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the expression of Calmodulin (CaM) gene in gastric cancer tissue and the relationship between the methylation level of the CaM gene promoter and Helicobacter pylori (H. pylori) infection.
METHODS: The expression of the CaM gene in 30 cases of gastric cancer and matched tumor-adjacent gastric tissue and metastatic lymph nodes was assessed by real-time fluorescence quantitative PCR. The relationship between CaM gene expression and H. pylori infection was analyzed. Methylation of CpG islands in the CaM gene promoter was measured by bisulfite modified sequencing method in gastric cancer cells infected with H. pylori and stably transfected with the H. pylori cytotoxin-associated protein A (cagA) gene.
RESULTS: The relative expression level of the CaM gene in cancer tissue was 2.08 times higher than that in tumor-adjacent gastric tissue (P < 0.05). The relative expression level of the CaM gene in H. pylori-positive gastric cancer was 6.11 times higher than that in the H. pylori-negative group (P < 0.05). The demethylation at -276 bp in the CaM gene promoter was detected in H. pylori-infected and cagA-overexpressed gastric cancer cells.
CONCLUSION: H. pylori, though secreting the virulence factor CagA, up-regulates the expression of the CaM gene in gastric cancer possibly by inducing the demethylation of the CaM promoter.
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Rusiecki JA, Al-Nabhani M, Tarantini L, Chen L, Baccarelli A, Al-Moundhri MS. Global DNA methylation and tumor suppressor gene promoter methylation and gastric cancer risk in an Omani Arab population. Epigenomics 2012; 3:417-29. [PMID: 22126203 DOI: 10.2217/epi.11.65] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
AIM We carried out a case-control study in an Omani Arab population to investigate the association between gastric cancer and peripheral blood leukocyte DNA methylation in LINE-1 and in the tumor suppressor genes CDH1, p16, TP53 and RUNX3. MATERIALS & METHODS We quantified methylation (%5-mC) in DNA extracted from peripheral blood leukocytes via pyrosequencing. We calculated odds ratios (ORs) and 95% CIs using logistic regression. RESULTS We found patterns of global hypomethylation (LINE-1: OR(continuous) = 0.59; 95% CI: 0.42-0.82) and TP53 promoter hypomethylation (OR(continuous) = 0.64; 95% CI: 0.16-0.85) for cases versus controls; p16 promoter region hypomethylation was not statistically significant. Evaluating LINE-1, TP53 and p16 jointly yielded a more pronounced negative association with gastric cancer (OR: 0.24; 95% CI: 0.09-0.66). Age was a significant effect modifier. We found no differences by tumor grade, stage or histology. CONCLUSION We found a pattern of global hypomethylation and promoter region hypomethylation of TP53 and p16 in cases versus controls for this population of Omani Arabs.
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Affiliation(s)
- Jennifer A Rusiecki
- Department of Preventive Medicine & Biometrics, Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA.
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Shin CM, Kim N, Park JH, Kang GH, Kim JS, Jung HC, Song IS. Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae. J Pathol 2012; 226:654-65. [PMID: 22252584 DOI: 10.1002/path.2990] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 08/11/2011] [Accepted: 08/19/2011] [Indexed: 12/13/2022]
Abstract
Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender-matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC.
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Affiliation(s)
- Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
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Abstract
Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. A growing number of human diseases including cancer have been found to be associated with aberrant DNA methylation. Recent advancements in the rapidly evolving field of cancer epigenetics have described extensive reprogramming of every component of the epigenetic machinery in cancer, such as DNA demethylation. In this review, we discuss the current understanding of alterations in DNA methylation composing the epigenetic landscape that occurs in gastric cancer compared with normal cells, the roles of these changes in gastric cancer initiation and progression, and the potential use of this knowledge in designing more effective treatment strategies.
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