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de Melo Viana TC, Nakamura ET, Park A, Filardi KFXC, de Almeida Leite RM, Baltazar LFSR, Usón Junior PLS, Tustumi F. Molecular Abnormalities and Carcinogenesis in Barrett's Esophagus: Implications for Cancer Treatment and Prevention. Genes (Basel) 2025; 16:270. [PMID: 40149421 PMCID: PMC11942460 DOI: 10.3390/genes16030270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Barrett's esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies. METHODS This narrative review examines the molecular abnormalities associated with the progression of BE to EAC. RESULTS This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments. CONCLUSIONS BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC.
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Affiliation(s)
| | | | - Amanda Park
- Department of Evidenced-Based Medicine, Centro Universitário Lusíada, Santos 11050-071, Brazil
| | | | | | | | | | - Francisco Tustumi
- Department of Gastroenterology, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil
- Department of Health Sciences, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil
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2
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Peña-Galo EM, Palacios-Navarro G, Pastora-Membreño J, Torres-Herman T, Norwood DA, Montalvan-Sanchez EE, Beasley T, Bravo LE, Morgan DR. High Gastric Cancer Mortality and Years of Life Lost in Nicaragua: A Population-Based Study 1997 to 2012. Cancer Epidemiol Biomarkers Prev 2024; 33:1564-1570. [PMID: 38884563 DOI: 10.1158/1055-9965.epi-23-1392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 04/30/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Gastric adenocarcinoma is the fourth leading cause of cancer-related mortality and leading infection-associated cancer. Gastric adenocarcinoma has striking geographic variability, with high incidence in East Asia and mountainous Latin America. Reliable cancer data and population-based cancer registries are lacking for the majority of low- and middle-income countries, including the Central American Four region (CA-4, Nicaragua, El Salvador, Honduras, and Guatemala). METHODS Mortality data for Nicaragua were obtained from the highly rated Ministry of Health death registry. All the patients were diagnosed with gastric cancer between 1997 and 2012 (ICD-10 codes, C16.0-C16.9) and death due to any cause were included in the study. Data on variables such as sex, age (stratified by 5-year age groups), municipality, urban/rural, altitude, and year of death were analyzed. RESULTS A total of 3,886 stomach cancer deaths were reported in Nicaragua between 1997 and 2012, of which 2,214 (56.9%) were male. The age-standardized mortality rates were 13.1 and 8.7 per 100,000 habitants for males and females, respectively, and without significant change during the study period (annual percentage change = -0.7, P = 0.2). An average of 17.9 years were lost per death, accounting for 67,964 years of life lost (YLL). CONCLUSIONS The burden of gastric cancer mortality is high in Nicaragua with a significantly elevated age-standardized mortality rate, YYL, and average YLL. IMPACT The projected increase in mortality portends the double cancer burden in northern Central America, with persistent infection-associated cancers and growing transition cancers (e.g., breast and colon cancers), which has implications for cancer control in Mesoamerica and US Latino populations. See related commentary by Riquelme and Abnet, p. 1550.
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Affiliation(s)
- Edgar M Peña-Galo
- Aragon Health Research Institute (IIS Aragon), Zaragoza, Spain
- Universidad Nacional Autónoma de Nicaragua, Leon (UNAN-Leon), León, Nicaragua
| | | | | | - Tatiana Torres-Herman
- UAB Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Dalton A Norwood
- Division of Preventive Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Timothy Beasley
- Department of Biostatistics, School of Public Health, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Luis E Bravo
- Registro Poblacional de Cáncer de Cali, Departamento de Patología, Facultad de Salud, Universidad del Valle, Cali, Colombia
| | - Douglas R Morgan
- UAB Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham, Birmingham, Alabama
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3
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Abbasnia S, Hashem Asnaashari AM, Sharebiani H, Soleimanpour S, Mosavat A, Rezaee SA. Mycobacterium tuberculosis and host interactions in the manifestation of tuberculosis. J Clin Tuberc Other Mycobact Dis 2024; 36:100458. [PMID: 38983441 PMCID: PMC11231606 DOI: 10.1016/j.jctube.2024.100458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2024] Open
Abstract
The final step of epigenetic processes is changing the gene expression in a new microenvironment in the body, such as neuroendocrine changes, active infections, oncogenes, or chemical agents. The case of tuberculosis (TB) is an outcome of Mycobacterium tuberculosis (M.tb) and host interaction in the manifestation of active and latent TB or clearance. This comprehensive review explains and interprets the epigenetics findings regarding gene expressions on the host-pathogen interactions in the development and progression of tuberculosis. This review introduces novel insights into the complicated host-pathogen interactions, discusses the challengeable results, and shows the gaps in the clear understanding of M.tb behavior. Focusing on the biological phenomena of host-pathogen interactions, the epigenetic changes, and their outcomes provides a promising future for developing effective TB immunotherapies when converting gene expression toward appropriate host immune responses gradually becomes attainable. Overall, this review may shed light on the dark sides of TB pathogenesis as a life-threatening disease. Therefore, it may support effective planning and implementation of epigenetics approaches for introducing proper therapies or effective vaccines.
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Affiliation(s)
- Shadi Abbasnia
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hiva Sharebiani
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arman Mosavat
- Blood Borne Infections Research Center, Academic Center for Education, Culture, and Research (ACECR), Razavi Khorasan, Mashhad, Iran
| | - Seyed Abdolrahim Rezaee
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
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Mohammed O, Gizaw ST, Degef M. Potential diagnostic, prognostic, and predictive biomarkers of gastric cancer. Health Sci Rep 2024; 7:e2261. [PMID: 39040881 PMCID: PMC11260885 DOI: 10.1002/hsr2.2261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/24/2024] Open
Abstract
Background Gastric cancer (GC), a malignant epithelial tumor, is the fourth leading cause of cancer-related death worldwide. Therapeutic strategies for GC, despite the biggest challenges, can significantly improve survival rates through early detection and effective screening methods. Aim To provide brief information on the necessity of multiple specific diagnostic, prognostic, and predictive markers for GC. Methods This review was conducted using a variety of search engines, including PubMed Central, Scopus, Web of Science, Google Scholar, and others. Results Some potential biomarkers that provide essential information include circulating tumor cells (CTCs), DNA methylation, claudin 18.2, fibroblast growth factor receptor 2 (FGFR2), long noncoding RNAs (lncRNAs), cell-free DNA (cfDNA), microRNAs, and serum pepsinogens. Conclusion Multiple tumor markers are essential for screening, tumor identification, staging, prognostic assessment, and monitoring recurrence after therapy due to the absence of a single tumor indicator for diagnosing, prognosticating, and predicting GC.
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Affiliation(s)
- Ousman Mohammed
- Department of Medical Laboratory SciencesCollege of Medicine and Health Sciences, Wollo UniversityDessieEthiopia
| | - Solomon Tebeje Gizaw
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
| | - Maria Degef
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
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Liang X, Li X, Wu R, He T, Liu F, Li L, Zhang Y, Gong S, Zhang M, Kou X, Chen T, You Y, Shen M, Wu Q, Gong C. Breaking the Tumor Chronic Inflammation Balance with a Programmable Release and Multi-Stimulation Engineering Scaffold for Potent Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401377. [PMID: 38760901 PMCID: PMC11267263 DOI: 10.1002/advs.202401377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/26/2024] [Indexed: 05/20/2024]
Abstract
Tumor-associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel-based engineering scaffold with multi-stimulation and reactive oxygen species (ROS)-response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti-OX40 under ROS. Resiquimod is first released, leading to antigen-presenting cell maturation and the transformation of myeloid-derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti-OX40 is transported into the tumor microenvironment, leading to effector T-cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple-negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long-term antigen-specific immune response. An excellent inhibition and prolonged survival in PHOENIX-treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors.
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Affiliation(s)
- Xiuqi Liang
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Xinchao Li
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Rui Wu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Tao He
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Furong Liu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Lu Li
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Yi Zhang
- Department of AnesthesiologyShengjing Hospital of China Medical UniversityShenyangChina
| | - Songlin Gong
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Miaomiao Zhang
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Xiaorong Kou
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Tao Chen
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Yanjie You
- Department of GastroenterologyPeople's Hospital of Ningxia Hui Autonomous RegionYinchuan750002China
| | - Meiling Shen
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Qinjie Wu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Changyang Gong
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
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Nieto Dominguez AJ, Eichinger SE, Guifarro D, Pan CW, Attar B. Modifiable Risk Factors in Hispanic Adults With Gastric Cancer in the United States. Cureus 2024; 16:e61920. [PMID: 38978891 PMCID: PMC11228387 DOI: 10.7759/cureus.61920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND Hispanics make up 19% of the U.S. population and are experiencing rising rates of cancer, primarily due to an increase in infection-related cancers (gastric, hepatic, cervical) and advanced cancers secondary to delayed screening (colorectal, cervical, breast). There is an increased incidence of gastric cancer (associated with infection, obesity, alcohol, and tobacco use) in Hispanics, especially at a young age, highlighting the need to consider ethnicity as a risk factor. METHODS This study utilized the 2016-2019 National Inpatient Sample database to examine all patients admitted with gastric cancer. Individuals were stratified by race, age, and comorbidities, including modifiable risk factors that are associated with gastric cancer. RESULTS There were 5,785 (7.44%) patients aged 18-44, 28,370 (36.49%) aged 45-64, and 43,590 (56.07%) over 65 years of age. Notably, 34.3% of the youngest group were Hispanic, contrasted with 19.7% and 12.9% in the older groups, respectively. Younger Hispanic patients showed a higher prevalence of H. pylori infection (8.6%) compared with older Hispanics (3.6% in the middle age group and 2.1% in the oldest, p<0.01). There was a high prevalence of obesity, tobacco use, and gastric ulcers in this cohort. Other risk factors such as alcohol use and gastric polyps were present at a lesser prevalence. CONCLUSIONS This study reveals that Hispanic patients tend to have a younger age of onset of gastric cancer, coupled with an increased incidence of H. pylori infection at a younger age. This finding underscores the potential benefit of H. pylori screening among asymptomatic young Hispanics with the aim of reducing gastric cancer morbidity and mortality in this population.
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Affiliation(s)
| | - Sarah E Eichinger
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Daniel Guifarro
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Chun-Wei Pan
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Bashar Attar
- Gastroenterology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
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7
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Zhu T, Tong H, Du Z, Beck S, Teschendorff AE. An improved epigenetic counter to track mitotic age in normal and precancerous tissues. Nat Commun 2024; 15:4211. [PMID: 38760334 PMCID: PMC11101651 DOI: 10.1038/s41467-024-48649-8] [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: 09/24/2023] [Accepted: 05/09/2024] [Indexed: 05/19/2024] Open
Abstract
The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC's mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.
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Affiliation(s)
- Tianyu Zhu
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Huige Tong
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Zhaozhen Du
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Stephan Beck
- Medical Genomics Group, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT, London, UK
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
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8
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Teschendorff AE. On epigenetic stochasticity, entropy and cancer risk. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230054. [PMID: 38432318 PMCID: PMC10909509 DOI: 10.1098/rstb.2023.0054] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/26/2023] [Indexed: 03/05/2024] Open
Abstract
Epigenetic changes are known to accrue in normal cells as a result of ageing and cumulative exposure to cancer risk factors. Increasing evidence points towards age-related epigenetic changes being acquired in a quasi-stochastic manner, and that they may play a causal role in cancer development. Here, I describe the quasi-stochastic nature of DNA methylation (DNAm) changes in ageing cells as well as in normal cells at risk of neoplastic transformation, discussing the implications of this stochasticity for developing cancer risk prediction strategies, and in particular, how it may require a conceptual paradigm shift in how we select cancer risk markers. I also describe the mounting evidence that a significant proportion of DNAm changes in ageing and cancer development are related to cell proliferation, reflecting tissue-turnover and the opportunity this offers for predicting cancer risk via the development of epigenetic mitotic-like clocks. Finally, I describe how age-associated DNAm changes may be causally implicated in cancer development via an irreversible suppression of tissue-specific transcription factors that increases epigenetic and transcriptomic entropy, promoting a more plastic yet aberrant cancer stem-cell state. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
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Affiliation(s)
- Andrew E. Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People's Republic of China
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Kim JL, Kim SG, Natsagdorj E, Chung H, Cho SJ. Helicobacter pylori Eradication Can Reverse Rho GTPase Expression in Gastric Carcinogenesis. Gut Liver 2023; 17:741-752. [PMID: 36718103 PMCID: PMC10502497 DOI: 10.5009/gnl220301] [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: 07/08/2022] [Revised: 11/13/2022] [Accepted: 11/23/2022] [Indexed: 02/01/2023] Open
Abstract
Background/Aims Altered DNA methylation is a key mechanism of epigenetic modification in gastric cancer (GC). This study aimed to evaluate the changes in epigenetic and genetic expression of multiple Rho GTPases in Helicobacter pylori-related gastric carcinogenesis by comparing H. pylori-positive GCs and negative controls. Methods The messenger RNA expression and methylation of Rho GTPases (RhoA, Rac1, DOCK180, ELMO1, and CDC42) were evaluated in H. pylori-negative (control) human gastric tissues and H. pylori-positive GCs by using real-time reverse transcription-polymerase chain reaction and the quantitative MethyLight assay, respectively. Changes in expression and methylation levels of the genes were also compared between H. pylori-eradicated and -persistent GCs at 1-year follow-up. Results In GCs, the methylation and expression levels of DOCK180 and ELMO1 were higher than in controls, while RhoA and Rac1 had lower levels than controls. CDC42 had the same expression pattern as DOCK180 and ELMO1 without DNA methylation. Although methylation levels of DOCK180 and ELMO1 had no difference between H. pylori-eradicated and -persistent GCs at the index endoscopic resection, those of H. pylori-persistent GCs increased and H. pylori-eradicated GCs decreased for 1 year. The expression levels of DOCK180, ELMO1, and CDC42 in H. pylori-persistent GCs were higher than those in H. pylori-eradicated GCs over 1 year, unlike those of RhoA and Rac1. The methylation levels at index and the degrees of change over time of RhoA and Rac1 had no difference between H. pylori-persistent and -eradicated GCs. Conclusions Epigenetic alterations of DOCK180 and ELMO1 are involved in H. pylori-related gastric carcinogenesis. This epigenetic field could be improved by H. pylori eradication.
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Affiliation(s)
- Jue Lie Kim
- Department of Internal Medicine, Health Promotion Center, Seoul National University Hospital, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Enerelt Natsagdorj
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunsoo Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Soo-Jeong Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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10
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Vlasac IM, Christensen BC, Salas LA. Normal gastric tissue Helicobacter pylori infection is associated with epigenetic age acceleration, increased mitotic tick rate, tissue cell composition, and Natural Killer cell methylation alterations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.28.546926. [PMID: 37425894 PMCID: PMC10327075 DOI: 10.1101/2023.06.28.546926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Background Gastric adenocarcinomas are a leading cause of global mortality, associated with chronic infection with Helicobacter pylori. The mechanisms by which infection with H. pylori contributes to carcinogenesis are not well understood. Recent studies from subjects with and without gastric cancer have identified significant DNA methylation alterations in normal gastric mucosa associated with H. pylori infection and gastric cancer risk. Here we further investigated DNA methylation alterations in normal gastric mucosa in gastric cancer cases (n = 42) and control subjects (n = 42) with H. pylori infection data. We assessed tissue cell type composition, DNA methylation alterations within cell populations, epigenetic aging, and repetitive element methylation. Results In normal gastric mucosa of both gastric cancer cases and control subjects, we observed increased epigenetic age acceleration associated with H. pylori infection. We also observed an increased mitotic tick rate associated with H. pylori infection in both gastric cancer cases and controls. Significant differences in immune cell populations associated with H. pylori infection in normal tissue from cancer cases and controls were identified using DNA methylation cell type deconvolution. We also found natural killer cell-specific methylation alterations in normal mucosa from gastric cancer patients with H. pylori infection. Conclusions Our findings from normal gastric mucosa provide insight into underlying cellular composition and epigenetic aspects of H. pylori associated gastric cancer etiology.
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Affiliation(s)
- Irma M. Vlasac
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Brock C. Christensen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Lucas A. Salas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
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11
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Chen L, Deng J. Role of non-coding RNA in immune microenvironment and anticancer therapy of gastric cancer. J Mol Med (Berl) 2022; 100:1703-1719. [PMID: 36329206 DOI: 10.1007/s00109-022-02264-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
Abstract
Gastric cancer remains one of the cancers with the highest mortality in the world; therefore, it is very important to investigate its pathogenesis to improve the prognosis of gastric cancer patients. Recently, noncoding RNAs have become a research hotspot in the field of oncology. These RNA molecules play complex roles in the regulation of tumor cells, immune cells, and the tumor microenvironment. Therefore, studying their ability to regulate the gastric cancer immune microenvironment will provide us with a better perspective to understand their potential role in anticancer therapy. In this review, we discuss the regulatory effects of several common noncoding RNAs on the immune microenvironment of gastric cancer and their prospects in anticancer therapy to provide some novel insight into the identification of valuable diagnostic markers and improving the prognosis of gastric cancer patients.
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Affiliation(s)
- Liqiao Chen
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
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12
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Kim HN, Kim MJ, Jacobs JP, Yang HJ. Altered Gastric Microbiota and Inflammatory Cytokine Responses in Patients with Helicobacter pylori-Negative Gastric Cancer. Nutrients 2022; 14:nu14234981. [PMID: 36501012 PMCID: PMC9740132 DOI: 10.3390/nu14234981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022] Open
Abstract
The role of the gastric mucosal microbiome in Helicobacter pylori-negative gastric cancer (GC) remains unclear. Therefore, we aimed to characterize the microbial alterations and host inflammatory cytokine responses in H. pylori-negative GC. Gastric mucosal samples were obtained from 137 H. pylori-negative patients with GC (n = 45) and controls (chronic gastritis or intestinal metaplasia, n = 92). We performed 16S rRNA gene sequencing (n = 67), a quantitative reverse transcription-polymerase chain reaction to determine the relative mRNA expression levels of TNF (tumor necrosis factor), IL1B (interleukin 1 beta), IL6 (interleukin 6), CXCL8 (C-X-C motif chemokine ligand 8), IL10 (interleukin 10), IL17A (interleukin 17A), TGFB1 (transforming growth factor beta 1) (n = 113), and the correlation analysis between sequencing and expression data (n = 47). Gastric mucosal microbiota in patients with GC showed reduced diversity and a significantly different composition compared to that of the controls. Lacticaseibacillus was significantly enriched, while Haemophilus and Campylobacter were depleted in the cancer group compared to the control group. These taxa could distinguish the two groups in a random forest algorithm. Moreover, the combined relative abundance of these taxa, a GC microbiome index, significantly correlated with gastric mucosal IL1B expression, which was elevated in the cancer group. Overall, altered gastric mucosal microbiota was found to be associated with increased mucosal IL1B expression in H. pylori-negative GC.
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Affiliation(s)
- Han-Na Kim
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul 06355, Republic of Korea
| | - Min-Jeong Kim
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Jonathan P. Jacobs
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Hyo-Joon Yang
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
- Correspondence:
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13
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Feunteun J, Ostyn P, Delaloge S. TUMOR CELL MALIGNANCY: A COMPLEX TRAIT BUILT THROUGH RECIPROCAL INTERACTIONS BETWEEN TUMORS AND TISSUE-BODY SYSTEM. iScience 2022; 25:104217. [PMID: 35494254 PMCID: PMC9044163 DOI: 10.1016/j.isci.2022.104217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Since the discovery of oncogenes and tumor suppressor genes in the late past century, cancer research has been overwhelmingly focused on the genetics and biology of tumor cells and hence has addressed mostly cell-autonomous processes with emphasis on traditional driver/passenger genetic models. Nevertheless, over that same period, multiple seminal observations have accumulated highlighting the role of non-cell autonomous effectors in tumor growth and metastasis. However, given that cell autonomous and non-autonomous events are observed together at the time of diagnosis, it is in fact impossible to know whether the malignant transformation is initiated by cell autonomous oncogenic events or by non-cell autonomous conditions generated by alterations of the tissue-body ecosystem. This review aims at addressing this issue by taking the option of defining malignancy as a complex genetic trait incorporating genetically determined reciprocal interactions between tumor cells and tissue-body ecosystem.
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Affiliation(s)
- Jean Feunteun
- INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Corresponding author
| | - Pauline Ostyn
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Suzette Delaloge
- Breast Cancer Group, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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14
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Abstract
Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. Pioneering genomic studies, focusing largely on primary GCs, revealed driver alterations in genes such as ERBB2, FGFR2, TP53 and ARID1A as well as multiple molecular subtypes. However, clinical efforts targeting these alterations have produced variable results, hampered by complex co-alteration patterns in molecular profiles and intra-patient genomic heterogeneity. In this Review, we highlight foundational and translational advances in dissecting the genomic cartography of GC, including non-coding variants, epigenomic aberrations and transcriptomic alterations, and describe how these alterations interplay with environmental influences, germline factors and the tumour microenvironment. Mapping of these alterations over the GC life cycle in normal gastric tissues, metaplasia, primary carcinoma and distant metastasis will improve our understanding of biological mechanisms driving GC development and promoting cancer hallmarks. On the translational front, integrative genomic approaches are identifying diverse mechanisms of GC therapy resistance and emerging preclinical targets, enabled by technologies such as single-cell sequencing and liquid biopsies. Validating these insights will require specifically designed GC cohorts, converging multi-modal genomic data with longitudinal data on therapeutic challenges and patient outcomes. Genomic findings from these studies will facilitate 'next-generation' clinical initiatives in GC precision oncology and prevention.
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Affiliation(s)
- Khay Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
| | - Patrick Tan
- Singapore Gastric Cancer Consortium, Singapore, Singapore.
- Cancer and Stem Cell Biology, Duke-NUS Medical School Singapore, Singapore, Singapore.
- Genome Institute of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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15
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Gastric Xanthelasma, Microsatellite Instability and Methylation of Tumor Suppressor Genes in the Gastric Mucosa: Correlation and Comparison as a Predictive Marker for the Development of Synchronous/Metachronous Gastric Cancer. J Clin Med 2021; 11:jcm11010009. [PMID: 35011751 PMCID: PMC8745081 DOI: 10.3390/jcm11010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 11/23/2022] Open
Abstract
A predictive marker for the development of synchronous/metachronous gastric cancer (GC) would be highly desirable in order to establish an effective strategy for endoscopic surveillance. Herein, we examine the significance of gastric xanthelasma (GX) and molecular abnormalities for the prediction of synchronous/metachronous GC. Patients (n = 115) were followed up (range, 12–122; median, 55 months) in whom the presence of GX and molecular alterations, including microsatellite instability (MSI) and methylation of human mutL homolog 1 (hMLH1), cyclin-dependent kinase inhibitor 2A (CDKN2A) and adenomatous polyposis coli (APC) genes, had been confirmed in non-neoplastic gastric mucosa when undergoing endoscopic submucosal dissection (ESD) for early GC. At the start of surveillance, the numbers of positive subjects were as follows: GX, 59 (51.3%); MSI, 48 (41.7%); hMLH1, 37 (32.2%); CDKN2A, 7 (6.1%); APC, 18 (15.7%). After ESD treatment, synchronous/metachronous GCs occurred in patients with the following positive factors: GX, 16 (27.1%); MSI, 7 (14.6%); hMLH1, 6 (16.2%); CDKN2A, 3 (42.9%); APC, 3 (16.7%). The presence of GX had no significant relationship to positivity for MSI or methylation of hMLH1, CDKN2A or APC. GX was significantly (p = 0.0059) and independently (hazard ratio, 3.275; 95% confidence interval, 1.134–9.346) predictive for the development of synchronous/metachronous GC, whereas those genetic alterations were not predictive. GX is a simple and powerful marker for predicting the development of synchronous or metachronous GC.
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16
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Tsuyuki S, Takeshima H, Sekine S, Yamagata Y, Ando T, Yamashita S, Maeda S, Yoshikawa T, Ushijima T. Comparable genetic alteration profiles between gastric cancers with current and past Helicobacter pylori infection. Sci Rep 2021; 11:23443. [PMID: 34873204 PMCID: PMC8648804 DOI: 10.1038/s41598-021-02761-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/23/2021] [Indexed: 11/09/2022] Open
Abstract
Gastric cancers can develop even after Helicobacter pylori (H. pylori) eradication in 0.2-2.9% cases per year. Since H. pylori is reported to directly activate or inactivate cancer-related pathways, molecular profiles of gastric cancers with current and past H. pylori infection may be different. Here, we aimed to analyze whether profiles of point mutation and gene amplification are different between the two groups. Current or past infection by H. pylori was determined by positive or negative amplification of H. pylori jhpr3 gene by PCR, and past infection was established by the presence of endoscopic atrophy. Among the 90 gastric cancers analyzed, 55 were with current infection, and 35 were with past infection. Target sequencing of 46 cancer-related genes revealed that 47 gastric cancers had 68 point mutations of 15 different genes, such as TP53 (36%), KRAS (4%), and PIK3CA (4%) and that gene amplification was present for ERBB2, KRAS, PIK3CA, and MET among the 26 genes assessed for copy number alterations. Gastric cancers with current and past infection had similar frequencies of TP53 mutations (38% and 31%, respectively; p = 0.652) and oncogene activation (20% and 29%, respectively; p = 0.444). Gastric cancers with current and past infection had comparable profiles of genetic alterations.
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Affiliation(s)
- Sho Tsuyuki
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shigeki Sekine
- Division of Molecular Pathology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yukinori Yamagata
- Department of Gastric Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, 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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17
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18
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Qin W, Scicluna BP, van der Poll T. The Role of Host Cell DNA Methylation in the Immune Response to Bacterial Infection. Front Immunol 2021; 12:696280. [PMID: 34394088 PMCID: PMC8358789 DOI: 10.3389/fimmu.2021.696280] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
Host cells undergo complex transcriptional reprogramming upon infection. Epigenetic changes play a key role in the immune response to bacteria, among which DNA modifications that include methylation have received much attention in recent years. The extent of DNA methylation is well known to regulate gene expression. Whilst historically DNA methylation was considered to be a stable epigenetic modification, accumulating evidence indicates that DNA methylation patterns can be altered rapidly upon exposure of cells to changing environments and pathogens. Furthermore, the action of proteins regulating DNA methylation, particularly DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases, may be modulated, at least in part, by bacteria. This review discusses the principles of DNA methylation, and recent insights about the regulation of host DNA methylation during bacterial infection.
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Affiliation(s)
- Wanhai Qin
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Brendon P Scicluna
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Tom van der Poll
- Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Division of Infectious Diseases, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Hibino S, Kawazoe T, Kasahara H, Itoh S, Ishimoto T, Sakata-Yanagimoto M, Taniguchi K. Inflammation-Induced Tumorigenesis and Metastasis. Int J Mol Sci 2021; 22:ijms22115421. [PMID: 34063828 PMCID: PMC8196678 DOI: 10.3390/ijms22115421] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
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Affiliation(s)
- Sana Hibino
- Research Center for Advanced Science and Technology, Department of Inflammology, The University of Tokyo, Tokyo 153-0041, Japan;
| | - Tetsuro Kawazoe
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Hidenori Kasahara
- National Center for Global Health and Medicine, Department of Stem Cell Biology, Research Institute, Tokyo 162-8655, Japan;
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Takatsugu Ishimoto
- Gastrointestinal Cancer Biology, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan;
| | | | - Koji Taniguchi
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan;
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Correspondence: ; Tel.: +81-11-706-5050
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20
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Watari J, Tomita T, Tozawa K, Oshima T, Fukui H, Miwa H. Preventing Metachronous Gastric Cancer after the Endoscopic Resection of Gastric Epithelial Neoplasia: Roles of Helicobacter pylori Eradication and Aspirin. Gut Liver 2021; 14:281-290. [PMID: 31547640 PMCID: PMC7234884 DOI: 10.5009/gnl19079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/11/2019] [Accepted: 06/06/2019] [Indexed: 12/13/2022] Open
Abstract
Whether Helicobacter pylori eradication actually reduces the risk of metachronous gastric cancer (MGC) development remains a controversial question. In this review, we addressed this topic by reviewing the results of clinical investigations and molecular pathological analyses of the roles of H. pylori eradication and aspirin administration in the prevention of MGC. In regard to the clinical studies, the results of meta-analyses and randomized control trials differ from those of retrospective studies: the former trials show that H. pylori eradication has a preventive effect on MGC, while the latter studies do not. This discrepancy may be at least partly attributable to differences in the follow-up periods: H. pylori eradication is more likely to prevent MGC over a long-term follow-up period (≥5 years) than over a short-term follow-up period. In addition, many studies have shown that aspirin may have an additive effect on MGC-risk reduction after H. pylori eradication has been achieved. Both H. pylori eradication and aspirin use induce molecular alterations in the atrophic gastritis mucosa but not in the intestinal metaplasia. Unfortunately, the molecular pathological analyses of these interventions have been limited by short follow-up periods. Therefore, a long-term prospective cohort is needed to clarify the changes in molecular events caused by these interventions.
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Affiliation(s)
- Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Katsuyuki Tozawa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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21
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Obayashi Y, Kawano S, Sakae H, Abe M, Kono Y, Kanzaki H, Iwamuro M, Kawahara Y, Tanaka T, Yanai H, Okada H. Risk Factors for Gastric Cancer after the Eradication of Helicobacter pylori Evaluated Based on the Background Gastric Mucosa: A Propensity Score-matched Case-control Study. Intern Med 2021; 60:969-976. [PMID: 33162475 PMCID: PMC8079910 DOI: 10.2169/internalmedicine.5486-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Objective The eradication of Helicobacter pylori (H. pylori) reduces the risk for gastric cancer (GC) development, but it cannot prevent GC completely. We investigated the risk factors of early GC development after the eradication of H. pylori, based on the histological characteristics of gastric mucosa. Methods Sixty-one patients who underwent endoscopic submucosal dissection for early GC after successful H. pylori eradication (Group A) and 122 patients without developing a gastric neoplasm over 3 years after successful H. pylori eradication (Group B) were analyzed. We compared the histological findings of the patients enrolled in Group A and Group B before and after the propensity score-matching. Results Comparing the characteristics of two the groups, Group A consisted predominantly of males, had significantly more elderly patients, and the years after successful eradication tended to be longer. We performed score matching for these three factors to reduce the influence of any confounding factors. After matching, the scores of inflammation for Group A (n=54) was significantly higher than those of Group B (n=54) at the greater curvature of the antrum, the lesser curvature of the corpus, and the greater curvature of the corpus. According to a multivariate analysis, inflammation of the greater curvature of the antrum and lesser curvature of the corpus were found to be independent risk factors. The risk ratio and 95% CI were 5.92 (2.11-16.6) (p<0.01), and 3.56 (1.05-13.2) (p=0.04), respectively. Conclusion A continuous high level of inflammation of the background gastric mucosa may be a risk factor for gastric cancer onset after H. pylori eradication.
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Affiliation(s)
- Yuka Obayashi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Seiji Kawano
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Hiroyuki Sakae
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Makoto Abe
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Yoshiyasu Kono
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Hiromitsu Kanzaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Yoshiro Kawahara
- Department of Practical Gastrointestinal Endoscopy, Okayama University Hospital, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Hiroyuki Yanai
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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22
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Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T. Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination. Cell Rep 2021; 34:108779. [PMID: 33626356 DOI: 10.1016/j.celrep.2021.108779] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 12/08/2020] [Accepted: 02/02/2021] [Indexed: 01/08/2023] Open
Abstract
In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.
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Affiliation(s)
- Tadahito Yasuda
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Mayu Koiwa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Atsuko Yonemura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Keisuke Miyake
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Sho Kubota
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Takako Yokomizo-Nakano
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Noriko Yasuda-Yoshihara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tomoyuki Uchihara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Rumi Itoyama
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Luke Bu
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Lingfeng Fu
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Kota Arima
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Daisuke Izumi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shiro Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kojiro Eto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroto Ohguchi
- Division of Disease Epigenetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | | | - Goro Sashida
- Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Akiko Takahashi
- The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
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Takeshima H, Niwa T, Yamashita S, Takamura-Enya T, Iida N, Wakabayashi M, Nanjo S, Abe M, Sugiyama T, Kim YJ, Ushijima T. TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest 2021; 130:5370-5379. [PMID: 32663196 DOI: 10.1172/jci124070] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 07/07/2020] [Indexed: 01/15/2023] Open
Abstract
Chronic inflammation is deeply involved in various human disorders, such as cancer, neurodegenerative disorders, and metabolic disorders. Induction of epigenetic alterations, especially aberrant DNA methylation, is one of the major mechanisms, but how it is induced is still unclear. Here, we found that expression of TET genes, methylation erasers, was downregulated in inflamed mouse and human tissues, and that this was caused by upregulation of TET-targeting miRNAs such as MIR20A, MIR26B, and MIR29C, likely due to activation of NF-κB signaling downstream of IL-1β and TNF-α. However, TET knockdown induced only mild aberrant methylation. Nitric oxide (NO), produced by NOS2, enhanced enzymatic activity of DNA methyltransferases (DNMTs), methylation writers, and NO exposure induced minimal aberrant methylation. In contrast, a combination of TET knockdown and NO exposure synergistically induced aberrant methylation, involving genomic regions not methylated by either alone. The results showed that a vicious combination of TET repression, due to NF-κB activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.
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Affiliation(s)
- Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tohru Niwa
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeji Takamura-Enya
- Department of Applied Chemistry, Kanagawa Institute of Technology, Kanagawa, Japan
| | - Naoko Iida
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Mika Wakabayashi
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Sohachi Nanjo
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Masanobu Abe
- Department of Oral and Maxillofacial Surgery, University of Tokyo Hospital, Tokyo, Japan.,Division for Health Service Promotion, University of Tokyo, Tokyo, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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24
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Tian YM, He HL, Cheng YT, Yi L, Yang Y, Yang P. A Combined Phytochemical and Network Pharmacology Approach to Reveal the Effective Substances and Mechanism of Eomecon chionantha Hance for the Treatment of Ulcerative Colitis. Nat Prod Commun 2021; 16. [DOI: 10.1177/1934578x21992966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Eomecon chionantha Hance (ECH), a traditional Chinese herbal medicine, has been reported for the treatment of traumatic injuries and colitis. The current treatments for ulcerative colitis (UC) are unstable and have side effects, so ECH is potentially useful for treating this condition. However, the active ingredients and pharmacological mechanisms of ECH in treating UC remain unclear. In this study, 21 alkaloids were extracted and purified from the roots of ECH, among which 13 were extracted from this herb for the first time. Our results showed that 12 ingredients may have effective pharmacological effects after absorption, distribution, metabolism, and excretion (ADME) screening. Network pharmacological analysis revealed that the active ingredients may have positive effects on 19 significant signaling pathways, such as on small cell lung cancer, serotonergic synapses, the IL-17 signaling pathway, Th17 cell differentiation, the estrogen signaling pathway, transcriptional misregulation in cancer, the PI3K-Akt signaling pathway, and others by targeting 23 proteins, including MAPK14, RXRA, GSK3B, CDK2, RXRB, HSP90AA1, PTGS2, and ESR1. It is of great benefit to use separation, purification, and network pharmacology together to screen active natural products. This study indicated potential anti-UC mechanisms of the active ingredients of ECH and provides theoretical support for the treatment of UC using ECH.
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Affiliation(s)
- Yu-mei Tian
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
| | - Hai-lang He
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
| | - Ya-ting Cheng
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
| | - Li Yi
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
| | - Yuan Yang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
- Dong Medicine Key Laboratory of Hunan Province, Department of Laboratory Medicine, Hunan University of Medicine, Huaihua 418000, China
- Hunan Provincial Key Laboratory for Synthetic Biology of Traditional Chinese Medicine, Hunan University of Medicine, Huaihua 418000, China
| | - Peng Yang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery System, School of Pharmaceutical Sciences, School of Nursing, Hunan University of Medicine, Huaihua 418000, China
- Hunan Provincial Key Laboratory for Synthetic Biology of Traditional Chinese Medicine, Hunan University of Medicine, Huaihua 418000, China
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25
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Kubota Y, Tanabe S, Azuma M, Horio K, Fujiyama Y, Soeno T, Furue Y, Wada T, Watanabe A, Ishido K, Katada C, Yamashita K, Koizumi W, Kusano C. Predictive Significance of Promoter DNA Methylation of Cysteine Dioxygenase Type 1 (CDO1) in Metachronous Gastric Cancer. J Gastric Cancer 2021; 21:379-391. [PMID: 35079440 PMCID: PMC8753284 DOI: 10.5230/jgc.2021.21.e35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/06/2021] [Accepted: 11/15/2021] [Indexed: 11/20/2022] Open
Abstract
Purpose Promoter DNA methylation of various genes has been associated with metachronous gastric cancer (MGC). The cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), has been implicated in the occurrence of residual gastric cancer. We evaluated whether DNA methylation of CDO1 could be a predictive biomarker of MGC using specimens of MGC developing on scars after endoscopic submucosal dissection (ESD). Materials and Methods CDO1 methylation values (TaqMeth values) were compared between 33 patients with early gastric cancer (EGC) with no confirmed metachronous lesions at >3 years after ESD (non-MGC: nMGC group) and 11 patients with MGC developing on scars after ESD (MGCSE groups: EGC at the first ESD [MGCSE-1 group], EGC at the second ESD for treating MGC developing on scars after ESD [MGCSE-2 group]). Each EGC specimen was measured at five locations (at tumor [T] and the 4-point tumor-adjacent noncancerous mucosa [TAM]). Results In the nMGC group, the TaqMeth values for T were significantly higher than that for TAM (P=0.0006). In the MGCSE groups, TAM (MGCSE-1) exhibited significantly higher TaqMeth values than TAM (nMGC) (P<0.0001) and TAM (MGCSE-2) (P=0.0041), suggesting that TAM (MGCSE-1) exhibited CDO1 hypermethylation similar to T (P=0.3638). The area under the curve for discriminating the highest TaqMeth value of TAM (MGCSE-1) from that of TAM (nMGC) was 0.81, and using the cut-off value of 43.4, CDO1 hypermethylation effectively enriched the MGCSE groups (P<0.0001). Conclusions CDO1 hypermethylation has been implicated in the occurrence of MGC, suggesting its potential as a promising MGC predictor.
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Affiliation(s)
- Yo Kubota
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Satoshi Tanabe
- Division of Therapeutic Endoscopy, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kazue Horio
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yoshiki Fujiyama
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takafumi Soeno
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasuaki Furue
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takuya Wada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akinori Watanabe
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kenji Ishido
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikatoshi Katada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Keishi Yamashita
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chika Kusano
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
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26
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Bertolini I, Ghosh JC, Kossenkov AV, Mulugu S, Krishn SR, Vaira V, Qin J, Plow EF, Languino LR, Altieri DC. Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment. Dev Cell 2020; 55:163-177.e6. [PMID: 32780991 DOI: 10.1016/j.devcel.2020.07.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/30/2020] [Accepted: 07/16/2020] [Indexed: 01/05/2023]
Abstract
The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked kinase (ILK) as the most upregulated pathway in sEV-treated epithelial cells, and genetic or pharmacologic targeting of ILK reversed mitochondrial reprogramming and suppressed sEV-induced cell movements. In a three-dimensional (3D) model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death and/or cell proliferation, loss of apical-basal polarity, and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEVs released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium.
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Affiliation(s)
- Irene Bertolini
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Jagadish C Ghosh
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Andrew V Kossenkov
- Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Sudheer Mulugu
- Electron Microscopy Resource Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shiv Ram Krishn
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA; Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Valentina Vaira
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Jun Qin
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Edward F Plow
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Lucia R Languino
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA; Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Dario C Altieri
- Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
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27
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Teschendorff AE. A comparison of epigenetic mitotic-like clocks for cancer risk prediction. Genome Med 2020; 12:56. [PMID: 32580750 PMCID: PMC7315560 DOI: 10.1186/s13073-020-00752-3] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/10/2020] [Indexed: 12/19/2022] Open
Abstract
Background DNA methylation changes that accrue in the stem cell pool of an adult tissue in line with the cumulative number of cell divisions may contribute to the observed variation in cancer risk among tissues and individuals. Thus, the construction of epigenetic “mitotic” clocks that can measure the lifetime number of stem cell divisions is of paramount interest. Methods Building upon a dynamic model of DNA methylation gain in unmethylated CpG-rich regions, we here derive a novel mitotic clock (“epiTOC2”) that can directly estimate the cumulative number of stem cell divisions in a tissue. We compare epiTOC2 to a different mitotic model, based on hypomethylation at solo-WCGW sites (“HypoClock”), in terms of their ability to measure mitotic age of normal adult tissues and predict cancer risk. Results Using epiTOC2, we estimate the intrinsic stem cell division rate for different normal tissue types, demonstrating excellent agreement (Pearson correlation = 0.92, R2 = 0.85, P = 3e−6) with those derived from experiment. In contrast, HypoClock’s estimates do not (Pearson correlation = 0.30, R2 = 0.09, P = 0.29). We validate these results in independent datasets profiling normal adult tissue types. While both epiTOC2 and HypoClock correctly predict an increased mitotic rate in cancer, epiTOC2 is more robust and significantly better at discriminating preneoplastic lesions characterized by chronic inflammation, a major driver of tissue turnover and cancer risk. Our data suggest that DNA methylation loss at solo-WCGWs is significant only when cells are under high replicative stress and that epiTOC2 is a better mitotic age and cancer risk prediction model for normal adult tissues. Conclusions These results have profound implications for our understanding of epigenetic clocks and for developing cancer risk prediction or early detection assays. We propose that measurement of DNAm at the 163 epiTOC2 CpGs in adult pre-neoplastic lesions, and potentially in serum cell-free DNA, could provide the basis for building feasible pre-diagnostic or cancer risk assays. epiTOC2 is freely available from 10.5281/zenodo.2632938
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Affiliation(s)
- Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China. .,UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
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28
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Maeda M, Takeshima H, Iida N, Hattori N, Yamashita S, Moro H, Yasukawa Y, Nishiyama K, Hashimoto T, Sekine S, Ishii G, Ochiai A, Fukagawa T, Katai H, Sakai Y, Ushijima T. Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3. Gut 2020; 69:243-251. [PMID: 31085554 DOI: 10.1136/gutjnl-2018-317645] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 03/25/2019] [Accepted: 04/21/2019] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. DESIGN Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. RESULTS CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal-epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. CONCLUSIONS H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.
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Affiliation(s)
- Masahiro Maeda
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.,Department of Gastrointestinal Surgery, Faculty of Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Naoko Iida
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Naoko Hattori
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroshi Moro
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshimi Yasukawa
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuhiro Nishiyama
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Taiki Hashimoto
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Shigeki Sekine
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Genichiro Ishii
- Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Chiba, Japan
| | - Atsushi Ochiai
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Takeo Fukagawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiharu Sakai
- Department of Gastrointestinal Surgery, Faculty of Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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29
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Hsu CH, Hsiao CW, Sun CA, Wu WC, Yang T, Hu JM, Liao YC, Huang CH, Chen CY, Lin FH, Chou YC. Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan. Sci Rep 2020; 10:145. [PMID: 31924802 PMCID: PMC6954240 DOI: 10.1038/s41598-019-56691-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/16/2019] [Indexed: 12/16/2022] Open
Abstract
This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80–23.1; P for trend <0.01) and 8.01 (95% CI, 1.92–33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.
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Affiliation(s)
- Chih-Hsiung Hsu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Teaching Office, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Cheng-Wen Hsiao
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, Republic of China.,Big Data Research Center, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, Republic of China
| | - Wen-Chih Wu
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Department of Surgery, Suao and Yuanshan branches of Taipei Veterans General Hospital, Yilan County, Taiwan, Republic of China
| | - Tsan Yang
- Department of Health Business Administration, Meiho University, Pingtung County, Taiwan, Republic of China
| | - Je-Ming Hu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Adjunct Instructor, School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yu-Chan Liao
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chi-Hua Huang
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chao-Yang Chen
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Adjunct Instructor, School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yu-Ching Chou
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China. .,School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China.
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30
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Sugimoto K, Ito T, Hulbert A, Chen C, Orita H, Maeda M, Moro H, Fukagawa T, Ushijima T, Katai H, Wada R, Sato K, Sakamoto K, Yu W, Considine M, Cope L, Brock MV. DNA methylation genome-wide analysis in remnant and primary gastric cancers. Gastric Cancer 2019; 22:1109-1120. [PMID: 30863929 DOI: 10.1007/s10120-019-00949-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although primary (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. We hypothesized that there would be distinct differences in DNA methylation patterns that would occur during carcinogenesis of RGC and PGC, and that the differences in methylation patterns may help identify the primary factor contributing to chronic inflammation in patients with RGC. METHODS We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients using the Infinium HumanMethylation450 Beadchip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. RESULTS We found that in our training cohort of 48 patients, the most variable genes from the gastric cancer tissues identified by the Infinium HumanMethylation450 Beadchip clustered the resultant heatmap into high and low methylation groups. On multivariate analysis, PGCs contributed significantly to the high methylation group (p = 0.004, OR 12.33), which suggested that the promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the EPB41L3 gene, chosen because of its high β value on microarray analysis in the gastric cancer tissues, had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. CONCLUSIONS This study demonstrated that promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of the absence of Helicobacter pylori on the reduced DNA methylation in the remnant stomach.
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Affiliation(s)
- Kiichi Sugimoto
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA. .,Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan.
| | - Tomoaki Ito
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA.,Department of Surgery, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Alicia Hulbert
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA
| | - Chen Chen
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA
| | - Hajime Orita
- Department of Surgery, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Masahiro Maeda
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroshi Moro
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeo Fukagawa
- Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hitoshi Katai
- Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Ryo Wada
- Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Koichi Sato
- Department of Surgery, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Wayne Yu
- Microarray Core Facility, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Michael Considine
- Experimental and Computational Genomics Core, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Leslie Cope
- Experimental and Computational Genomics Core, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Malcolm V Brock
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA
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31
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Sokolova O, Naumann M. Crosstalk Between DNA Damage and Inflammation in the Multiple Steps of Gastric Carcinogenesis. Curr Top Microbiol Immunol 2019; 421:107-137. [PMID: 31123887 DOI: 10.1007/978-3-030-15138-6_5] [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] [Indexed: 01/10/2023]
Abstract
Over the last years, intensive investigations in molecular biology and cell physiology extended tremendously the knowledge about the association of inflammation and cancer. In frame of this paradigm, the human pathogen Helicobacter pylori triggers gastritis and gastric ulcer disease, and contributes to the development of gastric cancer. Mechanisms, by which the bacteria-induced inflammation in gastric mucosa leads to intestinal metaplasia and carcinoma, are represented in this review. An altered cell-signaling response and increased production of free radicals by epithelial and immune cells account for the accumulation of DNA damage in gastric mucosa, if infection stays untreated. Host genetics and environmental factors, especially diet, can accelerate the process, which offers the opportunity of intervention based on a balanced nutrition. It is supposed that inflammation might influence stem- or progenitor cells in gastric tissue predisposing for metaplasia or tumor relapse. Herein, DNA is strongly mutated and labile, which restricts therapy options. Thus, the understanding of the mechanisms that underlie gastric carcinogenesis will be of preeminent importance for the development of strategies for screening and early detection. As most gastric cancer patients face late-stage disease with a poor overall survival, the development of multi-targeted therapeutic intervention strategies is a major challenge for the future.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany
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Kuo HY, Chang WL, Yeh YC, Cheng HC, Tsai YC, Wu CT, Lin SH, Yang HB, Lu CC, Sheu BS. Spasmolytic polypeptide-expressing metaplasia associated with higher expressions of miR-21, 155, and 223 can be regressed by Helicobacter pylori eradication in the gastric cancer familial relatives. Helicobacter 2019; 24:e12578. [PMID: 30990573 DOI: 10.1111/hel.12578] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 01/19/2019] [Accepted: 02/07/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. METHODS We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication. RESULTS GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR-21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR-21, 155, and 223 decreased after H pylori eradication (P < 0.05). CONCLUSION The H pylori-infected GCF subjects were prone to have SPEM with higher tissues miR-21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR-21, 155, and 233 expression levels.
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Affiliation(s)
- Hsin-Yu Kuo
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Lun Chang
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chun Yeh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Hsiu-Chi Cheng
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ching Tsai
- Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Tainan Hospital, Department of Health, Ministry of Welfare and Health, Tainan, Taiwan
| | - Chung-Tai Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Hsiang Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Hsiao-Bai Yang
- Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Pathology, Ton-Yen General Hospital, Hsin-chu, Taiwan
| | - Cheng-Chang Lu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Bor-Shyang Sheu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Tainan Hospital, Department of Health, Ministry of Welfare and Health, Tainan, Taiwan
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Hoffman RM. Is the Hoffman Effect for Methionine Overuse Analogous to the Warburg Effect for Glucose Overuse in Cancer? Methods Mol Biol 2019; 1866:273-278. [PMID: 30725423 DOI: 10.1007/978-1-4939-8796-2_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
The general cancer-specific metabolic defect of methionine (MET) dependence is due to MET overuse for aberrant transmethylation reactions. The excess use of MET for aberrant transmethylation reactions apparently diverts methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomenon in cancer and leads to unstable genomes and aneuploid karyotypes. The excessive and aberrant use of MET in cancer is readily observed in [11C]-MET-PET imaging, where high uptake of [11C]-MET results in a very strong and selective tumor signal compared to normal tissue background for brain cancer and possibly other cancers. [11C]-MET is superior to [18C]-fluorodeoxyglucose (FDG) for PET imaging, suggesting that MET overuse in cancer ("Hoffman effect") is greater than glucose overuse in cancer ("Warburg effect").
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Affiliation(s)
- Robert M Hoffman
- AntiCancer, Inc., San Diego, CA, USA.
- Department of Surgery, University of California, San Diego, CA, USA.
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Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. Gastric Cancer 2018; 21:745-755. [PMID: 29427040 DOI: 10.1007/s10120-018-0803-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 01/27/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The risk stratification of healthy individuals after Helicobacter pylori eradication is an urgent issue. The assessment of aberrant DNA methylation accumulated in gastric tissues with normal appearance, which can reflect overall epigenomic damage, is a promising strategy. We aimed to establish novel epigenetic cancer risk markers for H. pylori-eradicated individuals. METHODS Gastric mucosa was collected from eight healthy volunteers without H. pylori infection (G1), 75 healthy individuals with gastric atrophy (G2), and 94 gastric cancer patients (G3) after H. pylori eradication. Genome-wide analysis was conducted using Infinium 450 K and differentially methylated probes were screened using large difference and iEVORA-based methods. Bisulfite pyrosequencing was used for validation. RESULTS Screening, using 8 G1, 12 G2, and 12 G3 samples, isolated 57 candidates unmethylated in G1 and differentially methylated in G3 compared with G2. Validation for nine candidate markers (FLT3, LINC00643, RPRM, JAM2, ELMO1, BHLHE22, RIMS1, GUSBP5, and ZNF3) in 63 G2 and 82 G3 samples showed that all of them had significantly higher methylation levels in G3 than in G2 (P < 0.0001). Their methylation levels were highly correlated, which indicated that they reflect overall epigenomic damage. The candidates had sufficient performance (AUC: 0.70-0. 80) and high odds ratios (5.43-23.41), some of which were superior to a previous marker, miR-124a-3. The methylation levels of our novel markers were not associated with gastric atrophy, gender, or age. CONCLUSIONS Novel epigenetic markers for gastric cancer risk optimized for H. pylori-eradicated individuals were established.
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Lahner E, Carabotti M, Annibale B. Treatment of Helicobacter pylori infection in atrophic gastritis. World J Gastroenterol 2018; 24:2373-2380. [PMID: 29904244 PMCID: PMC6000293 DOI: 10.3748/wjg.v24.i22.2373] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 05/16/2018] [Accepted: 05/28/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (Hp) is a major human pathogen causing chronic, progressive gastric mucosal damage and is linked to gastric atrophy and cancer. Hp-positive individuals constitute the major reservoir for transmission of infection. There is no ideal treatment for Hp. Hp infection is not cured by a single antibiotic, and sometimes, a combined treatment with three or more antibiotics is ineffective. Atrophic gastritis (AG) is a chronic disease whose main features are atrophy and/or intestinal metaplasia of the gastric glands, which arise from long-standing Hp infection. AG is reportedly linked to an increased risk for gastric cancer, particularly when extensive intestinal metaplasia is present. Active or past Hp infection may be detected by conventional methods in about two-thirds of AG patients. By immunoblotting of sera against Hp whole-cell protein lysates, a previous exposure to Hp infection is detected in all AG patients. According to guidelines, AG patients with Hp positivity should receive eradication treatment. The goals of treatment are as follows: (1) Cure of infection, resolution of inflammation and normalization of gastric functions; (2) possible reversal of atrophic and metaplastic changes of the gastric mucosa; and (3) prevention of gastric cancer. An ideal antibiotic regimen for Hp should achieve eradication rates of approximately 90%, and complex multidrug regimens are required to reach this goal. Amongst the factors associated with treatment failure are high bacterial load, high gastric acidity, Hp strain, smoking, low compliance, overweight, and increasing antibiotic resistance. AG, when involving the corporal mucosa, is linked to reduced gastric acid secretion. At a non-acidic intra-gastric pH, the efficacy of the common treatment regimens combining proton pump inhibitors with one or more antibiotics may not be the same as that observed in patients with Hp gastritis in an acid-producing stomach. Although the efficacy of these therapeutic regimens has been thoroughly tested in subjects with Hp infection, there is a paucity of evidence in the subgroup of patients with AG. Bismuth-based therapy may be an attractive treatment in the specific setting of AG, and specific studies on the efficacy of bismuth-based therapies are needed in patients with AG.
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Affiliation(s)
- Edith Lahner
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, Sant’Andrea Hospital, University Sapienza, Rome 00189, Italy
| | - Marilia Carabotti
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, Sant’Andrea Hospital, University Sapienza, Rome 00189, Italy
| | - Bruno Annibale
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, Sant’Andrea Hospital, University Sapienza, Rome 00189, Italy
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Gao Y, Widschwendter M, Teschendorff AE. DNA Methylation Patterns in Normal Tissue Correlate more Strongly with Breast Cancer Status than Copy-Number Variants. EBioMedicine 2018; 31:243-252. [PMID: 29735413 PMCID: PMC6013931 DOI: 10.1016/j.ebiom.2018.04.025] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/25/2018] [Accepted: 04/27/2018] [Indexed: 02/07/2023] Open
Abstract
Normal tissue at risk of neoplastic transformation is characterized by somatic mutations, copy-number variation and DNA methylation changes. It is unclear however, which type of alteration may be more informative of cancer risk. We analyzed genome-wide DNA methylation and copy-number calls from the same DNA assay in a cohort of healthy breast samples and age-matched normal samples collected adjacent to breast cancer. Using statistical methods to adjust for cell type heterogeneity, we show that DNA methylation changes can discriminate normal-adjacent from normal samples better than somatic copy-number variants. We validate this important finding in an independent dataset. These results suggest that DNA methylation alterations in the normal cell of origin may offer better cancer risk prediction and early detection markers than copy-number changes.
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Affiliation(s)
- Yang Gao
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Martin Widschwendter
- Department of Women's Cancer, University College London, 74 Huntley Street, London WC1E 6AU, United Kingdom
| | - Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Department of Women's Cancer, University College London, 74 Huntley Street, London WC1E 6AU, United Kingdom; UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London WC1E 6BT, United Kingdom.
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Garcia-Gomez A, Rodríguez-Ubreva J, Ballestar E. Epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment. Clin Immunol 2018; 196:64-71. [PMID: 29501540 DOI: 10.1016/j.clim.2018.02.013] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 02/26/2018] [Indexed: 12/14/2022]
Abstract
Compelling evidences highlight the critical role of the tumor microenvironment as mediator of tumor progression and immunosuppression in several types of cancer. The reciprocal interplay between neoplastic and non-tumoral host cells is mediated by direct cell-to-cell contact, soluble factors and exosomes that result in differential gene expression patterns that are driven by epigenetic mechanisms. In this regard, extensive literature has described the abnormalities in the DNA methylation status and histone modification profiles in tumor cells. However, little is known about the mechanisms of epigenetic dysregulation that participate as a consequence of the intricate crosstalk among the cells within the tumor niche. This review summarizes the current knowledge on epigenetic changes that result from the interactions between myeloid, stromal and cancer cells in the tumor microenvironment and its functional impact in both tumorigenesis and tumor progression. We also discuss potential niche-specific epigenetic biomarkers to improve the prognosis and clinical treatment of cancer patients.
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Affiliation(s)
- Antonio Garcia-Gomez
- Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Javier Rodríguez-Ubreva
- Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Esteban Ballestar
- Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
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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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Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proc Natl Acad Sci U S A 2018; 115:1328-1333. [PMID: 29358395 DOI: 10.1073/pnas.1717340115] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69-89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52-23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis.
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Abstract
Tumorigenesis begins long before the growth of a clinically detectable lesion and, indeed, even before any of the usual morphological correlates of pre-malignancy are recognizable. Field cancerization, which is the replacement of the normal cell population by a cancer-primed cell population that may show no morphological change, is now recognized to underlie the development of many types of cancer, including the common carcinomas of the lung, colon, skin, prostate and bladder. Field cancerization is the consequence of the evolution of somatic cells in the body that results in cells that carry some but not all phenotypes required for malignancy. Here, we review the evidence of field cancerization across organs and examine the biological mechanisms that drive the evolutionary process that results in field creation. We discuss the clinical implications, principally, how measurements of the cancerized field could improve cancer risk prediction in patients with pre-malignant disease.
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Affiliation(s)
- Kit Curtius
- Centre for Tumour Biology, Barts Cancer Institute, EC1M 6BQ London, UK
| | - Nicholas A Wright
- Centre for Tumour Biology, Barts Cancer Institute, EC1M 6BQ London, UK
| | - Trevor A Graham
- Centre for Tumour Biology, Barts Cancer Institute, EC1M 6BQ London, UK
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Tomlinson MS, Bommarito PA, Martin EM, Smeester L, Fichorova RN, Onderdonk AB, Kuban KCK, O’Shea TM, Fry RC. Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes. PLoS One 2017; 12:e0188664. [PMID: 29240761 PMCID: PMC5730116 DOI: 10.1371/journal.pone.0188664] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 11/10/2017] [Indexed: 12/26/2022] Open
Abstract
Microorganisms in the placenta have been linked to adverse pregnancy outcomes as well as neonatal illness. Inflammation in the placenta has been identified as a contributing factor in this association, but the underlying biological mechanisms are not yet fully understood. The placental epigenome may serve as an intermediate between placental microbes and inflammation, contributing to adverse outcomes in the offspring. In the present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 84 placentas was analyzed in relation to 16 species of placental microorganisms using samples collected from the Extremely Low Gestation Age Newborns (ELGAN) cohort. A total of n = 1,789 CpG sites, corresponding to n = 1,079 genes, displayed differential methylation (q<0.1) in relation to microorganisms. The altered genes encode for proteins that are involved in immune/inflammatory responses, specifically the NF-κB signaling pathway. These data support bacteria-dependent epigenetic patterning in the placenta and provide potential insight into mechanisms that associate the presence of microorganisms in the placenta to pregnancy and neonatal outcomes. This study lays the foundation for investigations of the placental microbiome and its role in placental function.
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Affiliation(s)
- Martha Scott Tomlinson
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Paige A. Bommarito
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Elizabeth M. Martin
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Lisa Smeester
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Raina N. Fichorova
- Laboratory of Genital Tract Biology, Department of Obstetrics and Gynecology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
| | - Andrew B. Onderdonk
- Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
| | - Karl C. K. Kuban
- Division of Pediatric Neurology, Department of Pediatrics, Boston Medical Center, Boston, Massachusetts, United States of America
| | - T. Michael O’Shea
- Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Rebecca C. Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
- * E-mail:
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Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer. Oncogene 2017; 37:993-1004. [PMID: 29106391 DOI: 10.1038/onc.2017.397] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 08/08/2017] [Accepted: 09/15/2017] [Indexed: 02/07/2023]
Abstract
Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6. In gastric cancer cells that express high GATA6 levels, a GATA2 CpG island is hypermethylated, repressing expression in these cells. In contrast, GATA6 expression is undetectable in GATA2-overexpressing gastric cancer cells, which lack GATA2 DNA methylation. Furthermore, PRC2 complex-mediated transcriptional silencing of GATA6 was observed in the GATA2-overexpressing cells. We also show that the GATA2 and PRC2 complexes are enriched within the GATA6 locus, and that the recruitment of the PRC2 complex is impaired by disrupting GATA2 expression, resulting in GATA6 upregulation. In addition, ectopic GATA2 expression significantly downregulates GATA6 expression, suggesting GATA2 directly represses GATA6. Furthermore, GATA6 downregulation showed antitumor activity by inducing growth arrest. Finally, we show that aberrant GATA2 methylation occurs early during the multistep process of gastric carcinogenesis regardless of Helicobacter pylori infection. Taken together, GATA2 dysregulation by epigenetic modification is associated with unfavorable phenotypes in human gastric cancer cells by allowing GATA6 expression.
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Abstract
OBJECTIVES Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP. METHODS Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing. RESULTS Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP. CONCLUSIONS These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.
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Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:1359-1369. [PMID: 28460880 DOI: 10.1016/j.bbamcr.2017.04.017] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 04/24/2017] [Accepted: 04/26/2017] [Indexed: 12/24/2022]
Abstract
Reprogramming, or generation of induced pluripotent stem (iPS) cells (functionally similar to embryonic stem cells or ES cells) by the use of transcription factors (typically: Oct3/4, Sox2, c-Myc, Klf4) called "Yamanaka factors" (OSKM), has revolutionized regenerative medicine. However, factors used to induce stemness are also overexpressed in cancer. Both, ES cells and iPS cells cause teratoma formation when injected to tissues. This raises a safety concern for therapies based on iPS derivates. Transdifferentiation (lineage reprogramming, or -conversion), is a process in which one mature, specialized cell type changes into another without entering a pluripotent state. This process involves an ectopic expression of transcription factors and/or other stimuli. Unlike in the case of reprogramming, tissues obtained by this method do not carry the risk of subsequent teratomagenesis.
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Song Y, Wang Y, Tong C, Xi H, Zhao X, Wang Y, Chen L. A unified model of the hierarchical and stochastic theories of gastric cancer. Br J Cancer 2017; 116:973-989. [PMID: 28301871 PMCID: PMC5396111 DOI: 10.1038/bjc.2017.54] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 01/16/2017] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a life-threatening disease worldwide. Despite remarkable advances in treatments for GC, it is still fatal to many patients due to cancer progression, recurrence and metastasis. Regarding the development of novel therapeutic techniques, many studies have focused on the biological mechanisms that initiate tumours and cause treatment resistance. Tumours have traditionally been considered to result from somatic mutations, either via clonal evolution or through a stochastic model. However, emerging evidence has characterised tumours using a hierarchical organisational structure, with cancer stem cells (CSCs) at the apex. Both stochastic and hierarchical models are reasonable systems that have been hypothesised to describe tumour heterogeneity. Although each model alone inadequately explains tumour diversity, the two models can be integrated to provide a more comprehensive explanation. In this review, we discuss existing evidence supporting a unified model of gastric CSCs, including the regulatory mechanisms of this unified model in addition to the current status of stemness-related targeted therapy in GC patients.
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Affiliation(s)
- Yanjing Song
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yao Wang
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Chuan Tong
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Hongqing Xi
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xudong Zhao
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yi Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
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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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48
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CMTM3 decreases EGFR expression and EGF-mediated tumorigenicity by promoting Rab5 activity in gastric cancer. Cancer Lett 2017; 386:77-86. [DOI: 10.1016/j.canlet.2016.11.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/27/2016] [Accepted: 11/10/2016] [Indexed: 02/06/2023]
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Mahan MJ, Heithoff DM, Barnes V L, Sinsheimer RL. Epigenetic Programming by Microbial Pathogens and Impacts on Acute and Chronic Disease. EPIGENETICS AND HUMAN HEALTH 2017:89-112. [DOI: 10.1007/978-3-319-55021-3_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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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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