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1
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Ray A, Moore TF, Pandit R, Burke AD, Borsch DM. An Overview of Selected Bacterial Infections in Cancer, Their Virulence Factors, and Some Aspects of Infection Management. BIOLOGY 2023; 12:963. [PMID: 37508393 PMCID: PMC10376897 DOI: 10.3390/biology12070963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/30/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023]
Abstract
In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/β-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/β-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.
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Affiliation(s)
- Amitabha Ray
- College of Medical Science, Alderson Broaddus University, 101 College Hill Drive, Philippi, WV 26416, USA
| | - Thomas F Moore
- College of Medical Science, Alderson Broaddus University, 101 College Hill Drive, Philippi, WV 26416, USA
| | | | | | - Daniel M Borsch
- Lake Erie College of Osteopathic Medicine at Seton Hill, Greensburg, PA 15601, USA
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2
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Zheng SY, Zhu L, Wu LY, Liu HR, Ma XP, Li Q, Wu MD, Wang WJ, Li J, Wu HG. Helicobacter pylori-positive chronic atrophic gastritis and cellular senescence. Helicobacter 2023; 28:e12944. [PMID: 36539375 DOI: 10.1111/hel.12944] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 12/03/2022] [Accepted: 12/05/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Chronic atrophic gastritis (CAG) is a pathological stage in the Correa's cascade, whereby Helicobacter pylori (H. pylori) infection is the primary cause. Cellular senescence is an inducing factor for cancer occurrence and cellular senescence is an obvious phenomenon in gastric mucosal tissues of H. pylori-positive CAG patients. METHODS In this review, we collated the information on cellular senescence and H. pylori-positive CAG. RESULTS At present, only a few studies have observed the effect of cellular senescence on precancerous lesions. In combination with the latest research, this review has collated the information on cellular senescence and H. pylori-positive CAG from four aspects- telomere shortening, DNA methylation, increased reacive oxygen species (ROS) production, and failure of autophagy. CONCLUSION This is expected to be helpful for exploring the relevant mechanisms underlying inflammatory cancerous transformation and formulating appropriate treatment strategies.
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Affiliation(s)
- Shi-Yu Zheng
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Zhu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu-Yi Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui-Rong Liu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Peng Ma
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng-Die Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Jia Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huan-Gan Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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3
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Wang X, Liu Y. Offense and Defense in Granulomatous Inflammation Disease. Front Cell Infect Microbiol 2022; 12:797749. [PMID: 35846773 PMCID: PMC9277142 DOI: 10.3389/fcimb.2022.797749] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Granulomatous inflammation (GI) diseases are a group of chronic inflammation disorders characterized by focal collections of multinucleated giant cells, epithelioid cells and macrophages, with or without necrosis. GI diseases are closely related to microbes, especially virulent intracellular bacterial infections are important factors in the progression of these diseases. They employ a range of strategies to survive the stresses imposed upon them and persist in host cells, becoming the initiator of the fighting. Microbe-host communication is essential to maintain functions of a healthy host, so defense capacity of hosts is another influence factor, which is thought to combine to determine the result of the fighting. With the development of gene research technology, many human genetic loci were identified to be involved in GI diseases susceptibility, providing more insights into and knowledge about GI diseases. The current review aims to provide an update on the most recent progress in the identification and characterization of bacteria in GI diseases in a variety of organ systems and clinical conditions, and examine the invasion and escape mechanisms of pathogens that have been demonstrated in previous studies, we also review the existing data on the predictive factors of the host, mainly on genetic findings. These strategies may improve our understanding of the mechanisms underlying GI diseases, and open new avenues for the study of the associated conditions in the future.
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Affiliation(s)
- Xinwen Wang
- Shaanxi Clinical Research Center for Oral Diseases, National Clinical Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Oral Medicine, School of Stomatology, The Fourth Military Medical University, Xi’an, China
| | - Yuan Liu
- Shaanxi International Joint Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Department of Histology and Pathology, School of Stomatology, The Fourth Military Medical University, Xi’an, China
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Abstract
Tuberculosis (TB) remains the leading cause of bacterial disease-related death and is among the top 10 overall causes of death worldwide. The complex nature of this infectious lung disease has proven difficult to treat, and significant research efforts are now evaluating the feasibility of host-directed, adjunctive therapies. An attractive approach in host-directed therapy targets host epigenetics, or gene regulation, to redirect the immune response in a host-beneficial manner. Substantial evidence exists demonstrating that host epigenetics are dysregulated during TB and that epigenetic-based therapies may be highly effective to treat TB. However, the caveat is that much of the knowledge that exists on the modulation of the host epigenome during TB has been gained using in vitro, small-animal, or blood-derived cell models, which do not accurately reflect the pulmonary nature of the disease. In humans, the first and major target cells of Mycobacterium tuberculosis are alveolar macrophages (AM). As such, their response to infection and treatment is clinically relevant and ultimately drives the outcome of disease. In this review, we compare the fundamental differences between AM and circulating monocyte-derived macrophages in the context of TB and summarize the recent advances in elucidating the epigenomes of these cells, including changes to the transcriptome, DNA methylome, and chromatin architecture. We will also discuss trained immunity in AM as a new and emerging field in TB research and provide some perspectives for the translational potential of targeting host epigenetics as an alternative TB therapy.
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5
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Liu P, Liu JP, Sun SJ, Gao Y, Ai Y, Chen X, Sun Y, Zhou M, Liu Y, Xiong Y, Yuan HX. CBFB-MYH11 Fusion Sequesters RUNX1 in Cytoplasm to Prevent DNMT3A Recruitment to Target Genes in AML. Front Cell Dev Biol 2021; 9:675424. [PMID: 34336831 PMCID: PMC8321512 DOI: 10.3389/fcell.2021.675424] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
A growing number of human diseases have been found to be associated with aberrant DNA methylation, including cancer. Mutations targeting genes encoding DNA methyltransferase (DNMT), TET family of DNA demethylases, and isocitrate dehydrogenase (IDH1, IDH2) that produce TET inhibitory metabolite, 2-hyoxyglutarate (2-HG), are found in more than half of acute myeloid leukemia (AML). To gain new insights into the regulation of DNA de/methylation and consequence of its alteration in cancer development, we searched for genes which are mutated in a manner that is linked with gene mutations involved in DNA de/methylation in multiple cancer types. We found that recurrent CBFB-MYH11 fusions, which result in the expression of fusion protein comprising core-binding factor β (CBFB) and myosin heavy chain 11 (MYH11) and are found in 6∼8% of AML patients, occur mutually exclusively with DNMT3A mutations. Tumors bearing CBFB-MYH11 fusion show DNA hypomethylation patterns similar to those with loss-of-function mutation of DNMT3A. Expression of CBFB-MYH11 fusion or inhibition of DNMT3A similarly impairs the methylation and expression of target genes of Runt related transcription factor 1 (RUNX1), a functional partner of CBFB. We demonstrate that RUNX1 directly interacts with DNMT3A and that CBFB-MYH11 fusion protein sequesters RUNX1 in the cytoplasm, thereby preventing RUNX1 from interacting with and recruiting DNMT3A to its target genes. Our results identify a novel regulation of DNA methylation and provide a molecular basis how CBFB-MYH11 fusion contributes to leukemogenesis.
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Affiliation(s)
- Peng Liu
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jin-Pin Liu
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Si-Jia Sun
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yun Gao
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yingjie Ai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xiufei Chen
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yiping Sun
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Mengyu Zhou
- Ministry of Education (MOE) Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yun Liu
- Ministry of Education (MOE) Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yue Xiong
- Cullgen Inc., San Diego, CA, United States
| | - Hai-Xin Yuan
- The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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6
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Purkait S, Patra S, Mitra S, Behera MM, Panigrahi MK, Kumar P, Kar M, Hallur V, Chandra Samal S. Elevated Expression of DNA Methyltransferases and Enhancer of Zeste Homolog 2 in Helicobacter pylori - Gastritis and Gastric Carcinoma. Dig Dis 2021; 40:156-167. [PMID: 33895728 DOI: 10.1159/000516478] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/08/2021] [Indexed: 02/02/2023]
Abstract
AIM The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in Helicobacter pylori (HP)-associated gastritis and gastric carcinogenesis. METHODS The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (n = 104), mucosa adjacent to carcinoma (n = 104), HP-associated gastritis (n = 95), and histologically normal mucosa (n = 31) was assessed by immunohistochemistry and qRT-PCR. RESULTS The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome. CONCLUSION This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.
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Affiliation(s)
- Suvendu Purkait
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Susama Patra
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Suvradeep Mitra
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Minakshi M Behera
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Manas Kumar Panigrahi
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Pankaj Kumar
- Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Madhabananda Kar
- Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Vinaykumar Hallur
- Department of Microbiology, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Subash Chandra Samal
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India
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7
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Epstein-Barr Virus Promotes B Cell Lymphomas by Manipulating the Host Epigenetic Machinery. Cancers (Basel) 2020; 12:cancers12103037. [PMID: 33086505 PMCID: PMC7603164 DOI: 10.3390/cancers12103037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/28/2022] Open
Abstract
Simple Summary Epstein-Barr Virus (EBV)-induced lymphomas have a significant global incidence, given the widespread infection to the human population. EBV adopts several mechanisms to replicate and persist in the host, by hijacking its epigenetic machinery. The main topic of this review details the current insights of EBV interactions with the host epigenetic system, and it will be discussed the potential relationship between the EBV-induced chronic inflammation and the dysregulation of epigenetic modifiers that might lead to tumorigenesis. Promising novel therapies against several types of cancer involve the use of epigenetic modifier inhibitors. To design new therapeutical strategies targeting lymphomas, it is crucial to conduct exhaustive reaserch on the regulation of these enzymes. Abstract During the past decade, the rapid development of high-throughput next-generation sequencing technologies has significantly reinforced our understanding of the role of epigenetics in health and disease. Altered functions of epigenetic modifiers lead to the disruption of the host epigenome, ultimately inducing carcinogenesis and disease progression. Epstein–Barr virus (EBV) is an endemic herpesvirus that is associated with several malignant tumours, including B-cell related lymphomas. In EBV-infected cells, the epigenomic landscape is extensively reshaped by viral oncoproteins, which directly interact with epigenetic modifiers and modulate their function. This process is fundamental for the EBV life cycle, particularly for the establishment and maintenance of latency in B cells; however, the alteration of the host epigenetic machinery also contributes to the dysregulated expression of several cellular genes, including tumour suppressor genes, which can drive lymphoma development. This review outlines the molecular mechanisms underlying the epigenetic manipulation induced by EBV that lead to transformed B cells, as well as novel therapeutic interventions to target EBV-associated B-cell lymphomas.
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8
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Gao J, Yu T, Xuan Y, Zhu Z. High expression of GNB4 predicts poor prognosis in patients with Helicobacter pylori-positive advanced gastric cancer. Transl Cancer Res 2020; 9:4224-4238. [PMID: 35117790 PMCID: PMC8798254 DOI: 10.21037/tcr-19-2914] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 06/03/2020] [Indexed: 12/16/2022]
Abstract
Background Helicobacter pylori (H. pylori) is recognized as the most evident etiologic factor of infection-related gastric cancer (GC) and its involvement in GC initiation and progression has been well investigated. However, only a limited number of studies were performed to identify prognostic biomarkers and evaluate their clinical significance in GC patients infected with H. pylori. This study was conducted to investigate the clinical significance as well as its potential prognostic value of GNB4 in H. pylori-positive GC patients receiving standard treatment. Methods Retrospective statistical analysis was performed on 448 H. pylori-positive GC patients, with 137 early gastric cancer (EGC) patients undergoing radical gastrectomy alone and 311 advanced gastric cancer (AGC) patients receiving the same surgical procedure followed by fluorouracil-based chemotherapy. GNB4 expression was detected by immunohistochemistry staining on patient samples. H. pylori infection was routinely examined on endoscopic biopsy and/or surgical specimen of GC patients. Results High expression of GNB4 was 65.7% (90/137) in EGC and 62.7% (195/311) in AGC patients infected with H. pylori, respectively. In EGC patients, GNB4 expression was not associated with either clinicopathological parameters or 5-year overall survival (OS). In AGC patients however, high expression of GNB4 was significantly associated with patient’s pathological stage (P=0.047). Univariate analysis showed that tumor invasion depth (P=0.001), lymph node metastasis (P<0.001), pathological stage (P<0.001) as well as high expression of GNB4 (P=0.002) were significantly associated with 5-year OS. Multivariate analysis further identified lymph node metastasis (P=0.013) and GNB4 high expression (P=0.020) as independent prognostic factors for long-term outcome of H. pylori-positive AGC patients. Conclusions This study demonstrates that high expression of GNB4 is significantly associated with pathological stage of AGC patients with H. pylori infection. GNB4 expression independently predicts the 5-year OS of H. pylori-positive AGC patients undergoing radical gastrectomy and adjuvant chemotherapy.
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Affiliation(s)
- Jianpeng Gao
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Yu
- Department of Pathology, Ruijin hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi Xuan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhenglun Zhu
- Department of Gastrointestinal Surgery, Ruijin hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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Ye DM, Xu G, Ma W, Li Y, Luo W, Xiao Y, Liu Y, Zhang Z. Significant function and research progress of biomarkers in gastric cancer. Oncol Lett 2020; 19:17-29. [PMID: 31897111 PMCID: PMC6924079 DOI: 10.3892/ol.2019.11078] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 09/26/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is one of the most common gastrointestinal tumor types, and the incidence and mortality rates are higher in men compared with women. Various studies have revealed that gastric cancer is a spectrum of tumor types, which have biological and genetic diversity. It has proven to be difficult to improve the overall survival and disease-free survival of patients with gastric cancer through the use of traditional surgery and chemoradiation, as gastric cancer is usually identified at an advanced stage. In consequence, the outcome is frequently poor. Thus, novel biomarkers and anticancer targets are required to improve the outcome. As the identification of biomarkers has increased due to advances in research and the greater availability of bioinformatics and functional genomics, the potential therapeutic regimens available have also increased concurrently. These advances have also improved the ability to predict responses to chemotherapy, targeted therapy and immunotherapy, whilst other biomarkers predict post-treatment survival and recurrence based on their expression. This review focuses closely on the important functions of biomarkers in the timely diagnosis and treatment of gastric cancer, in addition to the advances in the study of certain novel markers in gastric cancer.
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Affiliation(s)
- Dong Mei Ye
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Gaosheng Xu
- Department of Surgery, Yueyang Maternal and Child Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Wei Ma
- Department of Surgery, Yueyang Maternal and Child Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Yuxuan Li
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Weiru Luo
- Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yiyang Xiao
- Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yong Liu
- Department of Pathology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiwei Zhang
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
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Ding L, Tian Y, Wang L, Bi M, Teng D, Hong S. Hypermethylated long noncoding RNA MEG3 promotes the progression of gastric cancer. Aging (Albany NY) 2019; 11:8139-8155. [PMID: 31584879 PMCID: PMC6814614 DOI: 10.18632/aging.102309] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 09/21/2019] [Indexed: 12/16/2022]
Abstract
This study aims to explore the expression and degree of methylation of lncRNA MEG3 in gastric cancer tissues and to analyze its effect on the migration and proliferation of gastric cancer patients and the mechanism by which this occurs. The targeting relationship between MEG3, miR-181a-5p and ATP4B was detected through molecular biology experiments. Wound healing, transwell, colony formation and flow cytometry assays were used to analyze the effects of lncRNA MEG3 and methylation on tumor cell migration, invasion, proliferation and apoptosis. In addition, a tumor xenotransplantation model was established to study the influence of MEG3 on tumor growth in vivo. Bioinformatics analysis showed that lncRNA MEG3 and ATP4B were downregulated in gastric cancer tissues compared with normal tissues. Bioinformatics predicted that ATP4B might be regulated by targeting miR-181a-5p. The overexpression of MEG3 and the application of 5-Aza treatment inhibited the migration, invasion and proliferation of MGC-803 cells and promoted apoptosis. In gastric cancer tissues, MEG3 is hypermethylated to decrease expression. Once the expression of MEG3 is restored or methylation is inhibited, tumor growth can be inhibited both in vivo and in vitro. This finding could be utilized as a clinical reference for gastric cancer treatment in the future.
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Affiliation(s)
- Lei Ding
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130022, Jilin, China
| | - Yuan Tian
- Department of Medical Examination, China-Japan Union Hospital of Jilin University, Changchun 130022, Jilin,China
| | - Ling Wang
- Department of Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China
| | - Miaomiao Bi
- Department of Ophthalmology, China-Japan Union Hospital of Jilin University, Changchun, 130022, Jilin, China
| | - Dengke Teng
- Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun 130022, Jilin, China
| | - Sen Hong
- Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun 130000, Jilin, China
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11
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Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas. Melanoma Res 2018; 27:85-96. [PMID: 27997431 DOI: 10.1097/cmr.0000000000000315] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Epigenetic modification of DNA, namely covalent changes of cytosine residues, plays a key role in the maintenance of inactive chromatin regions, both in health and in disease. In the vast majority of malignant melanomas, the most notable known epigenetic abnormality is the attenuation of 5-hydroxymethylcytosine (5-hmC) residues. However, it remains unknown whether a decrease in 5-hmC represents a primary defect of melanoma cancer epigenome or whether it is secondary to the loss of 5-methylcytosine (5-mC), a chemical substrate for 5-hmC. Here, we evaluated 5-mC levels in a spectrum of melanocytic proliferations. To study the epigenetic features of melanocytic nuclei, we began by measuring 5-mC levels in histologic specimens semiquantitatively by immunohistochemistry. We next treated established melanoma cell lines with S-adenosyl methionine (SAM), a universal methyl group donor, in an effort to cause changes in 5-mC levels. We detected a marked reduction in 5-mC levels in both primary and metastatic melanomas compared with 5-mC levels in benign melanocytic nevi. We also empirically induced changes in 5-mC in melanoma cell lines by incubation with SAM. To our surprise, we observed a significant cytoreductive effect of SAM on all melanoma cell lines examined. At subcytotoxic levels, SAM treatment is accompanied by a genome-wide increase in 5-mC. Moreover, we recorded a dose-dependent increase in genome-wide 5-mC levels in melanoma cell lines following SAM treatment. Taken together, we report that genome-wide attenuation of 5-mC is a hallmark of malignant melanomas. We propose that genome-wide attenuation of 5-mC is not merely an epiphenomenon as it is required for melanoma cell growth, albeit by an as of yet undetermined mechanism. Given its potential benefit in slowing down the growth of melanoma cells, SAM should be studied further to determine its role in epigenome modulation.
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12
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Abbas M, Habib M, Naveed M, Karthik K, Dhama K, Shi M, Dingding C. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice. Biomed Pharmacother 2017; 95:1082-1090. [PMID: 28922727 DOI: 10.1016/j.biopha.2017.09.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 09/07/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023] Open
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13
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Zeng XQ, Wang J, Chen SY. Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review). Int J Oncol 2017; 50:1921-1933. [DOI: 10.3892/ijo.2017.3981] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 03/22/2017] [Indexed: 11/06/2022] Open
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Abstract
We propose here a hypothesis of the cause of cancer that brings together fundamental changes in methyl-group metabolism resulting in methionine dependence and global DNA hypomethylation which destabilizes the genome leading to aneuploid karyotypes which evolve and stabilize into autonomous cancer. Experimental support for this hypothesis is that methioine dependence is a general metabolic defect in caner. Methionine dependence is due to excess use of methionene for aberrant transmethylation reactions that apparently divert methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomena in cancer. Global hypomethylation leads to an unstable genomes and aneuploid karyotypes, another general phenomena in cancer. The excessive and aberrant use of methionine in cancer is strongly observed in [11C]methionine PET imaging, where high uptake of [11C]methionine results in a very strong and selective tumor signal compared with normal tissue background. [11C]methionine is superior to [18C] fluorodeoxyglucose (FDG)-PET for PET imaging, suggesting methionine dependence is more tumor-specific than glucose dependence.
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Affiliation(s)
- Robert M Hoffman
- a AntiCancer Inc. , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA , USA
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15
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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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16
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Procainamide Inhibits DNA Methylation and Alleviates Multiple Organ Dysfunction in Rats with Endotoxic Shock. PLoS One 2016; 11:e0163690. [PMID: 27661616 PMCID: PMC5035080 DOI: 10.1371/journal.pone.0163690] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Accepted: 09/13/2016] [Indexed: 12/22/2022] Open
Abstract
Excessive inflammatory and oxidative stress lead to circulatory failure, multiple organ dysfunction, and high mortality in patients with sepsis. Microbial infection-induced DNA hypermethylation is associated with the augmentation of inflammation and oxidative stress. In our previous study, the antiarrhythmic drug procainamide inhibits the expression of DNA methyltransferase 1 (DNMT1) and diminishes IL-6 levels in rats with rhabdomyolysis. Thus, we further evaluated the effects of procainamide on the development of circulatory failure and multiple organ dysfunction in rats with endotoxic shock. Male Wistar rats were intravenously infused with saline or lipopolysaccharide (LPS) followed by procainamide administration. The changes of hemodynamics, blood glucose, biochemical variables, and plasma nitric oxide (NO) levels were analyzed during the experimental period. At the end of experiments, animal organs were also obtained for examining superoxide production, neutrophil infiltration, and DNA methylation status. Our results showed that LPS induced circulatory failure, multiple organ dysfunction, and high mortality rate in endotoxemic rats. Overt neutrophil infiltration and superoxide production, accompanied by the elevations of DNMT1 and 5-methylcytosine levels in the lung of endotoxemic rats were also observed. Treatment of endotoxemic animals with procainamide not only inhibited the increased levels of DNMT1 and 5-methylcytosine but also ameliorated neutrophil infiltration and superoxide production in the lung. In addition, the anti-inflammatory gene, IL27RA, was down-regulated in the LPS group and up-regulated in the LPS + Procainamide group. Procainamide also diminished IL27RA methylation in the lung of endotoxemic rat. Moreover, both DNMT inhibitors procainamide and hydralazine improved hypotension, hypoglycemia, and multiple organ dysfunction of LPS-treated rats. Thus, we suggest that the beneficial effects of procainamide could be attributed to the suppression of DNA methylation, neutrophil infiltration, superoxide production, and NO formation. It seems that this old drug may have new potential uses in infectious diseases, in particular, associated with endotoxemia.
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17
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Eftang LL, Klajic J, Kristensen VN, Tost J, Esbensen QY, Blom GP, Bukholm IRK, Bukholm G. GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer. BMC Cancer 2016; 16:225. [PMID: 26984265 PMCID: PMC4794813 DOI: 10.1186/s12885-016-2247-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 03/02/2016] [Indexed: 12/31/2022] Open
Abstract
Background A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Methods Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Results Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. Conclusions The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2247-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lars Lohne Eftang
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway. .,Department of Gastrointestinal Surgery, Akershus University Hospital, N-1478, Nordbyhagen, Lørenskog, Norway.
| | - Jovana Klajic
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Vessela N Kristensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Jörg Tost
- Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France
| | - Qin Ying Esbensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway
| | - Gustav Peter Blom
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | - Ida Rashida Khan Bukholm
- Institute of Clinical Medicine, Akershus University Hospital and University of Oslo, Lørenskog, Norway
| | - Geir Bukholm
- Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.,Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
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18
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Uno K, Iijima K, Shimosegawa T. Gastric cancer development after the successful eradication of Helicobacter pylori. World J Gastrointest Oncol 2016; 8:271-281. [PMID: 26989462 PMCID: PMC4789612 DOI: 10.4251/wjgo.v8.i3.271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 09/11/2015] [Accepted: 12/15/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) develops as a result of inflammation-associated carcinogenesis due to Helicobacter pylori (H. pylori) infection and subsequent defects in genetic/epigenetic events. Although the indication for eradication therapy has become widespread, clinical studies have revealed its limited effects in decreasing the incidence of GC. Moreover, research on biopsy specimens obtained by conventional endoscopy has demonstrated the feasibility of the restoration of some genetic/epigenetic alterations in the gastric mucosa. Practically, the number of sporadic cases of primary/metachronous GC that emerge after successful eradication has increased, while on-going guidelines recommend eradication therapy for patients with chronic gastritis and those with background mucosa after endoscopic resection for GC. Accordingly, regular surveillance of numerous individuals who have received eradication therapy is recommended despite the lack of biomarkers. Recently, the focus has been on functional reversibility after successful eradication as another cue to elucidate the mechanisms of restoration as well as those of carcinogenesis in the gastric mucosa after H. pylori eradication. We demonstrated that Congo-red chromoendoscopy enabled the identification of the multi-focal distribution of functionally irreversible mucosa compared with that of restored mucosa after successful eradication in individuals at extremely high risk for GC. Further research that uses functional imaging may provide new insights into the mechanisms of regeneration and carcinogenesis in the gastric mucosa post-eradication and may allow for the development of useful biomarkers.
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Huang Q, Wen J, Chen G, Ge M, Gao Y, Ye X, Liu C, Cai C. Omega-3 Polyunsaturated Fatty Acids Inhibited Tumor Growth via Preventing the Decrease of Genomic DNA Methylation in Colorectal Cancer Rats. Nutr Cancer 2016; 68:113-9. [DOI: 10.1080/01635581.2016.1115526] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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20
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Tsai KW, Li GC, Chen CH, Yeh MH, Huang JS, Tseng HH, Fu TY, Liou HH, Pan HW, Huang SF, Chen CC, Chang HY, Ger LP, Chang HT. Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype. Breast Cancer Res Treat 2015; 153:219-34. [PMID: 26253945 DOI: 10.1007/s10549-015-3525-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 07/29/2015] [Indexed: 11/28/2022]
Abstract
DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.
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Affiliation(s)
- Kuo-Wang Tsai
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, 81362, Kaohsiung, Taiwan
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21
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Peczek L, Zuk K, Stec-Michalska K, Medrek M, Nawrot B. The influence of Helicobacter pylori eradication on the expression and methylation status of the FHIT gene in non-cancerous gastric mucosa of dyspeptic patients. J Dig Dis 2015; 16:385-94. [PMID: 25943773 DOI: 10.1111/1751-2980.12252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effect of Helicobacter pylori (H. pylori) eradication on the expression level of the FHIT gene and its methylation status in the gastric mucosa of dyspeptic patients with or without a family history of gastric cancer (FHGC). METHODS In all, 31 patients with H. pylori infection including 13 with FHGC were enrolled in the study. The effectiveness of H. pylori eradication were confirmed by UBT, RUT and multiplex PCR (the presence of selected H. pylori strains) for biopsy samples from the antrum and corpus. Histopathological assessment was also performed. The expression of FHIT mRNA was determined by quantitative reverse transcription-polymerase chain reaction and the methylation status of the FHIT promoter was assessed by methylation-specific polymerase chain reaction. RESULTS After H. pylori eradication, the improvement of inflammation from superficial gastritis to normal mucosa (G → N) was observed in 39% of the patients without FHGC and in 54% of those with FHGC. FHIT mRNA expression was increased in patients without FHGC after H. pylori eradication (P < 0.05), while there was no statistically significant change in gene methylation status after H. pylori eradication (P > 0.05). For the samples from those with FHGC, the FHIT mRNA expression was not significantly changed and the methylation status fluctuated evenly. CONCLUSIONS H. pylori eradication results in the improvement of gastric mucosal inflammation and histopathological non-atrophic changes. The FHIT gene expression is increased in patients without FHGC, which may contribute to the prevention of GC development.
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Affiliation(s)
- Lukasz Peczek
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
| | - Karolina Zuk
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
| | | | - Marta Medrek
- Department of Gastroenterology, Medical University of Lodz, Lodz, Poland
| | - Barbara Nawrot
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
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22
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Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer. Clin Transl Gastroenterol 2015; 6:e85. [PMID: 25928808 PMCID: PMC4459532 DOI: 10.1038/ctg.2015.14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 03/10/2015] [Accepted: 03/19/2015] [Indexed: 01/06/2023] Open
Abstract
Objectives: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk. Methods: We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method. Results: GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10−12), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10−5) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC. Conclusions: Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes.
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23
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Relationship between LINE-1 hypomethylation and Helicobacter pylori infection in gastric mucosae. Med Oncol 2015; 32:117. [DOI: 10.1007/s12032-015-0571-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 03/13/2015] [Indexed: 12/30/2022]
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24
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Jin Z, Jiang W, Wang L. Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). Oncol Lett 2015; 9:1502-1508. [PMID: 25788990 PMCID: PMC4356326 DOI: 10.3892/ol.2015.2959] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 01/08/2015] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of leading causes of cancer-related mortality worldwide and is a notable disease due to its heterogeneity. Recently, numerous studies have investigated the molecular basis of gastric cancer, involving the alteration of pathogenesis, and invasion and metastasis. With the development of modern technologies, various novel biomarkers had been identified that appear to possess diagnostic and prognostic value; therefore, the present review describes our current knowledge of biomarkers for the early diagnosis and prognosis of gastric cancer. Classic biomarkers for gastric cancer diagnosis include carcinoembryonic antigen and cancer antigen 19-9, while microRNA and DNA hypomethylation are proposed as novel biomarkers. Excluding classical biomarkers, biomarkers for determining the progression and prognosis of gastric cancer focus on targeting microRNAs, epigenetic alterations and genetic polymorphisms.
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Affiliation(s)
- Ziliang Jin
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
| | - Weihua Jiang
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
| | - Liwei Wang
- Department of Oncology, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
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25
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26
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Reduced 5-methylcytosine level as a potential progression predictor in patients with T1 or non-invasive urothelial carcinoma. Int J Mol Sci 2014; 16:677-90. [PMID: 25561224 PMCID: PMC4307268 DOI: 10.3390/ijms16010677] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/17/2014] [Indexed: 12/12/2022] Open
Abstract
This study aims to elucidate the level of DNA methylation in urothelial carcinomas (UCs) using 5-methylcytosine (5-MeC) immunohistochemistry (IHC). We examined the relationship among 5-MeC levels, DNA (cytosine-5)-methyltransferase 1 (DNMT1) immunostaining levels, and clinicopathologic features. Tissue samples included 23 normal urothelia and 150 urothelial neoplasia, which comprised 40 non-invasive and 110 invasive UCs. The levels of 5-MeC and DNMT1 were assessed based on their immunoreactivities and then divided into low and high levels. In addition, we collected information on clinical variables, pathologic features, and recurrent status from patient questionnaires and medical records. Chi-square test and multivariate logistic regression model were used for analyses. Results showed that 5-MeC levels were positively associated with DNMT1 levels in UC (p = 0.0288). Both 5-MeC and DNMT1 were low in approximately 50% (76/150) of UC. The percentage of low 5-MeC levels was higher in invasive UC (65/110; 59%) than in normal urothelia (2/23; 13%) and non-invasive UC (18/40; 45%). Clinical factors were independently associated with low 5-MeC levels after adjusting for age and sex, including cancer stages II-IV, presence of UC in situ, and marked inflammation. Low 5-MeC levels in stage I invasive UC were not significantly different from those of non-invasive tumors (p = 0.8478). Low DNMT1 levels were only associated with UC with squamous differentiation (p = 0.0365). Neither 5-MeC nor DNMT1 levels were associated with UC recurrence. In conclusion, a low 5-MeC level could predict the progression of UC invasion into muscle.
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27
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Rugge M, Capelle LG, Fassan M. Individual risk stratification of gastric cancer: evolving concepts and their impact on clinical practice. Best Pract Res Clin Gastroenterol 2014; 28:1043-1053. [PMID: 25439070 DOI: 10.1016/j.bpg.2014.09.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/02/2014] [Accepted: 09/15/2014] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide and it mostly develops in long-standing inflammatory conditions, and Helicobacter pylori-gastritis, in particular. Despite the increasing understanding of both the phenotypic alterations and the molecular mechanisms occurring during GC multi-step carcinogenesis, no reliable biomarker is available to be reliably implemented into GC secondary prevention strategies. Multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling currently appears as the most appropriate approach for patients' stratification into different GC risk classes.
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Affiliation(s)
- Massimo Rugge
- Department of Medicine, DIMED, Surgical Pathology and Cytopathology Unit, University of Padua, 35100 Padua, Italy.
| | - Lisette G Capelle
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
| | - Matteo Fassan
- Department of Medicine, DIMED, Surgical Pathology and Cytopathology Unit, University of Padua, 35100 Padua, Italy
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28
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Yang M, Kim HS, Cho MY. Different methylation profiles between intestinal and diffuse sporadic gastric carcinogenesis. Clin Res Hepatol Gastroenterol 2014; 38:613-20. [PMID: 24953529 DOI: 10.1016/j.clinre.2014.03.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 02/25/2014] [Accepted: 03/28/2014] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Gastric cancer (GC) is histologically classified into intestinal type and diffuse type, and diffuse type cancer can be further subdivided into poorly differentiated carcinoma (PDC) and signet ring cell carcinoma (SRCC). Recent evidence suggests that early SRCC is an initial, differentiated form of diffuse GC that may evolve into PDC. This study aimed at identifying the molecular features of epigenetic methylation changes in histologic differentiation status of GC. METHODS Included in this study are 149 samples of paraffin-embedded tissues and 115 fresh endoscopically biopsied tissues. Multiple paraffin tissues involving normal (n=22), dysplasias (GDs, n=39), differentiated cancers (DCs, n=35), PDCs (n=33) and SRCCs (n=20) were included as an experimental group. For the validation group, endoscopically biopsied tissues of DCs (n=50), PDCs (n=31), and SRCs (n=34) were analyzed. DNAs, isolated from each group were analyzed to determine the methylation status of 6 genes (GDNF, RORA, MINT25, KLF7, CDH1, LINE-1) using pyrosequencing. RESULTS LINE-1 was hypomethylated in GCs compared to normal and GD. GDNF, RORA and MINT25 were more hypermethylated in intestinal type GCs than those of diffuse type GCs, whereas CDH1 showed opposite patterns of methylation. Among diffuse type GCs, SRCCs showed lower level of methylation for GDNF, RORA, MINT25 and KLF7, and higher level for CDH1 compared to PDCs. CONCLUSIONS In conclusion, intestinal type of GCs shows different epigenetic methylation profiles compared to the diffuse one. Moreover, SRCCs have different methylation profiles compared with PDCs, suggesting a unique molecular pathway in the gastric carcinogenesis.
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Affiliation(s)
- Misuk Yang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hyun-Soo Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
| | - Mee Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Wang Y, Huang LH, Xu CX, Xiao J, Zhou L, Cao D, Liu XM, Qi Y. Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis. World J Gastroenterol 2014; 20:11770-9. [PMID: 25206281 PMCID: PMC4155367 DOI: 10.3748/wjg.v20.i33.11770] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/11/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the mechanism of abnormal Connexin (Cx) 32 and Cx43 expression in the gastric mucosa after Helicobacter pylori (H. pylori) infection. METHODS Biopsy specimens of gastric mucosa in different gastric carcinogenesis stages with H. pylori infection, that is, non-atrophic gastritis (NAG; n = 24), chronic atrophic gastritis (CAG; n = 25), intestinal metaplasia (IM; n = 28), dysplasia (DYS; n = 24), and gastric cancer (GC; n = 30), as well as specimens of normal gastric mucosa without H. pylori infection (NGM; n = 25), were confirmed by endoscopy and pathological examination. Cx32 and Cx43 mRNA expression was detected by real-time polymerase chain reaction (PCR). Cx32 and Cx43 promoter CpG island methylation status was determined by methylation-specific PCR (MSP), bisulfite PCR sequencing (BSP) and MassArray methods. RESULTS The relative mRNA expression levels in the gastric mucosa of patients with NGM, NAG, CAG, IM, DYS and GC were 0.146 ± 0.011, 0.133 ± 0.026, 0.107 ± 0.035, 0.039 ± 0.032, 0.037 ± 0.01 and 0.03 ± 0.011 for Cx32; and 0.667 ± 0.057, 0.644 ± 0.051, 0.624 ± 0.049, 0.555 ± 0.067, 0.536 ± 0.058 and 0.245 ± 0.121 for Cx43, respectively, which were gradually decreasing and significantly different (GC vs NGM: P < 0.001 for Cx32, P < 0.001 for Cx43). The promoter methylation levels in the gastric mucosa from NGM to GC stages by MSP were 38.8% ± 9.0%, 43.1% ± 9.4%, 56.5% ± 3.1%, 64.4% ± 9.7%, 72.5% ± 4.2% and 79.6% ± 6.8% for Cx32; and 49.0% ± 3.9%, 58.1% ± 5.0%, 66.5% ± 7.9%, 74.0% ± 8.8%, 78.3% ± 3.6% and 88.7% ± 6.2% for Cx43, respectively, which were gradually increasing and significantly different (P = 0.039, P = 0.019). The promoter methylation levels by BSP and MassArray exhibited similar trends. Cx32 and Cx43 mRNA expression was negatively correlated with promoter methylation status and gastric carcinogenesis stages (P < 0.001, P = 0.016). CONCLUSION Cx32 and Cx43 mRNA expression decreased gradually during H. pylori infection-associated gastric carcinogenesis, and it is associated with hypermethylation of these genes' promoter.
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30
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Toiyama Y, Okugawa Y, Goel A. DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. Biochem Biophys Res Commun 2014; 455:43-57. [PMID: 25128828 DOI: 10.1016/j.bbrc.2014.08.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 07/22/2014] [Accepted: 08/01/2014] [Indexed: 02/06/2023]
Abstract
Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers - primarily DNA methylation and non-coding RNAs - as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients.
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Affiliation(s)
- Yuji Toiyama
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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Abstract
Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the 'point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.
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Affiliation(s)
- Jan Bornschein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University of Magdeburg, Magdeburg, Germany
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Kovalchuk I, Walz P, Thomas J, Kovalchuk O. The increased expression of proteins involved in proliferation, DNA repair and DNA methylation in spleen of mice exposed to E. coli O157:H7 lipopolysaccharide. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2013; 54:421-8. [PMID: 23813549 DOI: 10.1002/em.21787] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Revised: 04/21/2013] [Accepted: 04/22/2013] [Indexed: 06/02/2023]
Abstract
Previous research showed that the consumption of heat-killed E. coli O157:H7 bacteria resulted in an increase in the level of DNA damage in intestine, liver and spleen cells. We hypothesized that certain bacterial components released from heat-killed bacteria trigger this response. We analysed the possibility that bacterial components [such as lipopolysaccharides (LPS)] could induce changes in the level of proteins involved in cell proliferation, DNA repair and DNA methylation in distal spleen tissues of mice. Four-week-old male mice were provided water supplemented with whole heat-killed E. coli O157:H7 bacteria or components of bacteria (DNA, RNA, proteins and LPS). Spleen cells responded to exposure to whole heat-killed bacteria and LPS with an alteration in the level of PCNA proteins, DNA methylation proteins (DNMT1, DNMT3A, DNMT3B, and MeCP2) and DNA repair proteins (APE1 and KU70). Other bacterial components analysed in this study mostly did not alter protein expression. The data suggest that LPS is a bacterial component capable of inducing molecular changes in naïve spleen cells of hosts exposed to it.
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Affiliation(s)
- Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, T1K 3M4, Canada.
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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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Calcagno DQ, Gigek CO, Chen ES, Burbano RR, Smith MDAC. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol 2013; 19:1182-92. [PMID: 23482412 PMCID: PMC3587474 DOI: 10.3748/wjg.v19.i8.1182] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations contribute significantly to the development and progression of gastric cancer, one of the leading causes of cancer death worldwide. Epigenetics refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA, and these changes lead to transcriptional activation or silencing of the gene. Over the years, the study of epigenetic processes has increased, and novel therapeutic approaches that target DNA methylation and histone modifications have emerged. A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer treatment. Here, we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.
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Yang Q, Lu Z, Ramchandran R, Longo LD, Raj JU. Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation. Am J Physiol Lung Cell Mol Physiol 2012; 303:L1001-10. [PMID: 23043075 DOI: 10.1152/ajplung.00092.2012] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
High-altitude long-term hypoxia (LTH) is known to induce pulmonary arterial smooth muscle cell (PASMC) proliferation in the fetus, leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn. The mechanisms underlying these conditions remain enigmatic however. We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling. To test this hypothesis, we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [pregnant ewes were kept at 3,801 m altitude from ~40 to 145 days gestation] or to sea level atmosphere. Intrapulmonary arteries were isolated, and fetal PASMC were cultured from both control and LTH fetuses. Compared with controls, in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of the cyclin-dependent kinase inhibitor p21. Treatment of LTH fetal PASMCs with histone deacetylase (HDAC) inhibitor trichostatin A decreased their proliferation rate, in part because of altered expression of p21 at both RNA and protein level. In PASMC of LTH fetuses, HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. On the basis of these observations, we propose that epigenetic alterations (reduced histone acetylation and DNA methylation) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21.
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Affiliation(s)
- Qiwei Yang
- Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
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Li W, Wu P, Zhang H, Cai C. Signal Amplification of Graphene Oxide Combining with Restriction Endonuclease for Site-Specific Determination of DNA Methylation and Assay of Methyltransferase Activity. Anal Chem 2012; 84:7583-90. [DOI: 10.1021/ac301990f] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Wen Li
- Jiangsu Key Laboratory of New Power Batteries, College
of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210097, P. R. China
| | - Ping Wu
- Jiangsu Key Laboratory of New Power Batteries, College
of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210097, P. R. China
| | - Hui Zhang
- Jiangsu Key Laboratory of New Power Batteries, College
of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210097, P. R. China
| | - Chenxin Cai
- Jiangsu Key Laboratory of New Power Batteries, College
of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210097, P. R. China
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Lu XX, Yu JL, Ying LS, Han J, Wang S, Yu QM, Wang XB, Fang XH, Ling ZQ. Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression. Cancer 2012; 118:5507-17. [PMID: 22576578 DOI: 10.1002/cncr.27604] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 03/16/2012] [Accepted: 03/22/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Helicobacter pylori has been recognized as a definite carcinogen for gastric cancer (GC); however, the pathogenesis of H. pylori infection remains unclear. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to GC. However, in H. pylori infection-associated GC, the role of RUNX3 has not been studied. METHODS The authors used real-time methylation-specific polymerase chain reaction analysis to determine methylation status of the RUNX3 promoter in a spectrum of gastric lesions, including 220 samples of chronic atrophic gastritis, 196 samples of intestinal metaplasia, 134 samples of gastric adenoma, 102 samples of dysplasia, and 202 samples of GC with paired noncancerous mucosa tissues and corresponding blood specimens. The association of abnormal methylation with precancerous gastric lesions was evaluated along with the association between RUNX3 methylation and H. pylori infection, and the concordance of methylation levels was investigated between serum and tissues. RESULTS The results indicated that increasing RUNX3 promoter methylation was correlated with distinct stages of GC progression. GC tissues had the highest methylation proportion (75.2%) compared with precancerous gastric lesions, including chronic atrophic gastritis (15.9%), intestinal metaplasia (36.7%), gastric adenoma (41.8%), and dysplasia (54.9%). H. pylori infection, a major risk factor for GC, contributed to the inactivation of RUNX3 in gastric epithelial cells through promoter hypermethylation. The levels of RUNX3 methylation in serum were in significant concordance with the methylation levels observed in GC tissues (P = .887). CONCLUSIONS The current findings supported RUNX3 methylation as a risk factors for the carcinogenesis of chronic atrophic gastritis with H. pylori infection and indicated that circulating RUNX3 methylation is a valuable biomarker for the detection of early GC.
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Affiliation(s)
- Xiao-Xiao Lu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, People's Republic of China
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Can the battle against tuberculosis gain from epigenetic research? Trends Microbiol 2012; 20:220-6. [PMID: 22464289 DOI: 10.1016/j.tim.2012.03.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 12/24/2022]
Abstract
A healthy immune system needs to be highly plastic to cope with host defense and surveillance. What mechanisms provide this plasticity? Considering the threat of infectious diseases to a large part of the world's population, can these mechanisms possibly be of use in the ongoing battle against infectious diseases? Against the backdrop of the pandemic nature of tuberculosis, we discuss whether and how epigenetic mechanisms can shed light on our understanding of infectious disease, and if epigenetic marks can be employed to monitor latent infection, disease reactivation or treatment response.
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Niller HH, Banati F, Ay E, Minarovits J. Microbe-Induced Epigenetic Alterations. PATHO-EPIGENETICS OF DISEASE 2012:419-455. [DOI: 10.1007/978-1-4614-3345-3_14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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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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Torres AL, Barrientos EY, Wrobel K, Wrobel K. Selective derivatization of cytosine and methylcytosine moieties with 2-bromoacetophenone for submicrogram DNA methylation analysis by reversed phase HPLC with spectrofluorimetric detection. Anal Chem 2011; 83:7999-8005. [PMID: 21905673 DOI: 10.1021/ac2020799] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In eukaryotes, actual DNA methylation patterns provide biologically important information, for which both, genome-wide and locus-specific methylation at cytosine residues have been extensively studied. The original contribution of this work relies on the selective derivatization of cytosine moieties with 2-bromoacetophenone for the determination of global DNA methylation by reversed phase high performance liquid chromatography with spectrofluorimetric detection. The important features of the proposed procedure are as follows: (1) no need for the elimination of RNA, (2) detection limits for cytidine, 2'-deoxycytidine, 5-methylcytidine, and 5-methyl-2'-deoxycytidine in the range of 14.4-22.7 fmol, (3) feasibility for the detection of 0.06% of methylation in a low amount of DNA (80 ng), (4) potential viability for the evaluation of RNA methylation, and (5) relative simplicity in terms of analytical instrumentation and personnel training. The results obtained in the analysis of salmon testes DNA and nucleic acids from plant, human blood, and earthworms demonstrate the utility of the proposed procedure in biological studies and, in particular, for evaluation of the potential effect of environmental factors on actual DNA methylation in different types of living organisms.
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Affiliation(s)
- Adolfo Lopez Torres
- Department of Chemistry, University of Guanajuato, L de Retana No. 5, 36000 Guanajuato, Mexico
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