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Li L, Fei X, Wang H, Chen S, Xu X, Ke H, Zhou Y, Hu Y, He C, Xie C, Lu N, Liu J, Zhu Y, Li N. Genome-wide DNA methylation profiling reveals a novel hypermethylated biomarker PRKCB in gastric cancer. Sci Rep 2024; 14:26605. [PMID: 39496833 PMCID: PMC11535215 DOI: 10.1038/s41598-024-78135-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/29/2024] [Indexed: 11/06/2024] Open
Abstract
Globally, gastric cancer (GC) ranks among the most prevalent forms of malignancy, posing a significant health burden. Epigenetic modifications, predominantly characterized by alterations in DNA methylation patterns, have been linked to a diverse array of neoplastic processes. Here, we undertake a comprehensive analysis of the DNA methylation signature in GC, with the aim to discover the potential diagnostic epigenetic biomarkers. Utilizing the Illumina 935 K BeadChip, we conducted a genome-wide exploration of DNA methylation patterns in four paired samples of GC tissues and adjacent non-cancerous counterparts. The bisulfite-pyrosequencing (n = 7) was employed to the quantification for methylated gene. The pubic databases including GWAS Catalog, TCGA and GEO were used. The immunohistochemistry and qRT-PCR analysis were performed. In contrast to adjacent tissues, GC tissues manifested pronounced hypermethylation patterns specifically within the promoter cytosine-phosphate-guanine (CpG) islands, indicating localized epigenetic alterations. DNA methylome analysis further revealed 4432 differentially-methylated probes (DMPs), with the gene PRKCB exhibited the most prominent average DNA methylation disparity (mean Δβ = 0.353). Pyrosequencing validation confirmed three DMPs within the PRKCB promoter (cg08406370, cg00735962, and cg18526361). Notably, the mean methylation levels of PRKCB were inversely correlated with mRNA expression levels in the GWAS Catalog. Furthermore, both mRNA and protein expression levels of PRKCB were significantly reduced in GCs when compared to their adjacent non-cancerous counterparts, verified by TCGA and GEO database. Our study reveals significant DNA methylation alterations in GC and emphasizes the pivotal role of PRKCB gene hypermethylation in conferring GC risk, which offers fresh perspectives for advancing diagnostic approaches and therapeutic strategies for GC.
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Affiliation(s)
- Leyan Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Fei
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huan Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Sihai Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huajing Ke
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yanan Zhou
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Hu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
| | - Nianshuang Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Christodoulidis G, Koumarelas KE, Kouliou MN, Thodou E, Samara M. Gastric Cancer in the Era of Epigenetics. Int J Mol Sci 2024; 25:3381. [PMID: 38542354 PMCID: PMC10970362 DOI: 10.3390/ijms25063381] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 11/11/2024] Open
Abstract
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
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Affiliation(s)
- Grigorios Christodoulidis
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Konstantinos-Eleftherios Koumarelas
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Marina-Nektaria Kouliou
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Eleni Thodou
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
| | - Maria Samara
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
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Cai HQ, Zhang LY, Fu LM, Xu B, Jiao Y. Mutational landscape of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg 2024; 16:276-283. [PMID: 38463349 PMCID: PMC10921187 DOI: 10.4240/wjgs.v16.i2.276] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 12/26/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg. A common gene mutation in gastric cancer (GC) is the TP53 mutation. As a tumor suppressor gene, TP53 is implicated in more than half of all tumor occurrences. TP53 gene mutations in GC tissue may be related with clinical pathological aspects. The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy. CDH1 encodes E-cadherin, which is involved in cell-to-cell adhesion, epithelial structure maintenance, cell polarity, differentiation, and intracellular signaling pathway modulation. CDH1 mutations and functional loss can result in diffuse GC, and CDH1 mutations can serve as independent prognostic indicators for poor prognosis. GC patients can benefit from genetic counseling and testing for CDH1 mutations. Demethylation therapy may assist to postpone the onset and progression of GC. The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations, as well as providing some basis for evaluating the prognosis of GC patients.
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Affiliation(s)
- Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Yue Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Ming Fu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bin Xu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Yang R, Xiang Z, Yan R, Kwan W, Zang L, Zhu Z, Qi Y, Xu Y, Zhang X, Gao H, Yu Y. Benchmark for establishment of organoids from gastrointestinal epithelium and cancer based on available consumables and reagents. Chin J Cancer Res 2023; 35:636-644. [PMID: 38204440 PMCID: PMC10774133 DOI: 10.21147/j.issn.1000-9604.2023.06.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Gastrointestinal cancers are a public health problem that threatens the lives of human being. A good experimental model is a powerful tool to promote the uncovering pathogenesis and establish novel treatment methods. High-quality biomedical research requires experimental models to recapitulate the physiological and pathological states of their parental tissues as much as possible. Organoids are such experimental models. Organoids refer to small organ-like cellular clusters formed by the expansion and passaging of living tissues in 3D culture medium in vitro. Organoids are highly similar to the original tissues in terms of cellular composition, cell functions, and genomic profiling. Organoids have many advantages, such as short preparation cycles, long-term storage based on cryopreservation, and reusability. In recent years, researchers carried out the establishment of organoids from gastrointestinal mucosa and cancer tissues, and accumulated valuable experiences. In order to promote effective usage and further development of organoid-related technologies in the research of gastrointestinal diseases, this study proposes a benchmark based on utilization of available experimental consumables and reagents, which are involved in the key steps such as collection and pretreatment of biospecimen, organoid construction, organoid cryopreservation and recovery, growth status evaluation, and organoid quality control. We believe that the standard for the construction and preservation of organoids derived from human gastrointestinal epithelium and cancer tissues can provide an important reference for the majority of scientific researchers.
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Affiliation(s)
- Ruixin Yang
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhen Xiang
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ranlin Yan
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wingyan Kwan
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lu Zang
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhenggang Zhu
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yao Qi
- Shanghai Engineering Center for Molecular Medicine, Shanghai 200120, China
| | - Yanping Xu
- Shanghai Engineering Center for Molecular Medicine, Shanghai 200120, China
| | - Xiaoyan Zhang
- Shanghai Engineering Center for Molecular Medicine, Shanghai 200120, China
| | - Hengjun Gao
- Shanghai Engineering Center for Molecular Medicine, Shanghai 200120, China
| | - Yingyan Yu
- Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Xu W, Jiang T, Shen K, Zhao D, Zhang M, Zhu W, Liu Y, Xu C. GADD45B regulates the carcinogenesis process of chronic atrophic gastritis and the metabolic pathways of gastric cancer. Front Endocrinol (Lausanne) 2023; 14:1224832. [PMID: 37608794 PMCID: PMC10441793 DOI: 10.3389/fendo.2023.1224832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/18/2023] [Indexed: 08/24/2023] Open
Abstract
Background Gastric cancer continues to be a significant global healthcare challenge, and its burden remains substantial. The development of gastric cancer (GC) is closely linked to chronic atrophic gastritis (CAG), yet there is a scarcity of research exploring the underlying mechanisms of CAG-induced carcinogenesis. Methods In this study, we conducted a comprehensive investigation into the oncogenes involved in CAG using both bulk transcriptome and single-cell transcriptome data. Our approach employed hdWGCNA to identify pathogenic genes specific to CAG, with non-atrophic gastritis (NAG) serving as the control group. Additionally, we compared CAG with GC, using normal gastric tissue as the control group in the single-cell transcriptome analysis. By intersecting the identified pathogenic genes, we pinpointed key network molecules through protein interaction network analysis. To further refine the gene selection, we applied LASSO, SVM-RFE, and RF techniques, which resulted in a set of cancer-related genes (CRGs) associated with CAG. To identify CRGs potentially linked to gastric cancer progression, we performed a univariate COX regression analysis on the gene set. Subsequently, we explored the relationship between CRGs and immune infiltration, drug sensitivity, and clinical characteristics in gastric cancer patients. We employed GSVA to investigate how CRGs regulated signaling pathways in gastric cancer cells, while an analysis of cell communication shed light on the impact of CRGs on signal transmission within the gastric cancer tumor microenvironment. Lastly, we analyzed changes in metabolic pathways throughout the progression of gastric cancer. Results Using hdWGCNA, we have identified a total of 143 pathogenic genes that were shared by CAG and GC. To further investigate the underlying mechanisms, we conducted protein interaction network analysis and employed machine learning screening techniques. As a result, we have identified 15 oncogenes that are specifically associated with chronic atrophic gastritis. By performing ROC reanalysis and prognostic analysis, we have determined that GADD45B is the most significant gene involved in the carcinogenesis of CAG. Immunohistochemical staining and differential analysis have revealed that GADD45B expression was low in GC tissues while high in normal gastric tissues. Moreover, based on prognostic analysis, high expression of GADD45B has been correlated with poor prognosis in GC patients. Additionally, an analysis of immune infiltration has shown a relationship between GADD45B and the infiltration of various immune cells. By correlating GADD45B with clinical characteristics, we have found that it primarily affects the depth of invasion in GC. Through cell communication analysis, we have discovered that the CD99 signaling pathway network and the CDH signaling pathway network are the main communication pathways that significantly alter the microenvironment of gastric tissue during the development of chronic atrophic gastritis. Specifically, GADD45B-low GC cells were predominantly involved in the network communication of the CDH signaling pathway, while GADD45B-high GC cells played a crucial role in both signaling pathways. Furthermore, we have identified several metabolic pathways, including D-Glutamine and D-glutamate metabolism and N-Glycan biosynthesis, among others, that played important roles in the occurrence and progression of GC, in addition to the six other metabolic pathways. In summary, our study highlighted the discovery of 143 pathogenic genes shared by CAG and GC, with a specific focus on 15 oncogenes associated with CAG. We have identified GADD45B as the most important gene in the carcinogenesis of CAG, which exhibited differential expression in GC tissues compared to normal gastric tissues. Moreover, GADD45B expression was correlated with patient prognosis and is associated with immune cell infiltration. Our findings also emphasized the impact of the CD99 and CDH signaling pathway networks on the microenvironment of gastric tissue during the development of CAG. Additionally, we have identified key metabolic pathways involved in GC progression. Conclusion GADD45B, an oncogene implicated in chronic atrophic gastritis, played a critical role in GC development. Decreased expression of GADD45B was associated with the onset of GC. Moreover, GADD45B expression levels were closely tied to poor prognosis in GC patients, influencing the infiltration patterns of various cells within the tumor microenvironment, as well as impacting the metabolic pathways involved in GC progression.
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Affiliation(s)
- Wei Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tianxiao Jiang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kanger Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dongxu Zhao
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Man Zhang
- Department of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenxin Zhu
- Department of Gastroenterology, Kunshan Third People’s Hospital, Suzhou, Jiangsu, China
| | - Yunfei Liu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Fan Z, Chen R, Li M, Gu J, Li X, Wei W. Association between CDH1 methylation and esophageal cancer risk: a meta-analysis and bioinformatics study. Expert Rev Mol Diagn 2022; 22:895-903. [PMID: 36254608 DOI: 10.1080/14737159.2022.2132853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The aim is to evaluate the association of CDH1 methylation with esophageal cancer (EC) risk. METHODS The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched to identify relevant articles. Pooled odds ratios (ORs) with 95% confidence interval (CI) were estimated using the fixed- or random-effects models. The pooled sensitivity and specificity were calculated to assess the diagnostic value of CDH1 methylation for EC. The results of the meta-analysis were validated using The Cancer Genome Atlas and Gene Expression Omnibus databases. RESULTS Thirteen studies consisting of 1,633 samples were included. A high CDH1 methylation was significantly associated with an increased risk of EC (OR = 10.40, 95% CI = 6.29-17.18). Furthermore, CDH1 methylation status was related to tumor status, lymph node status, and metastasis. For the diagnosis of EC, the pooled sensitivity and specificity of CDH1 methylation were 0.57 (95% CI = 0.39-0.74) and 0.89 (95% CI = 0.81-0.94), respectively. Bioinformatics analysis showed that CDH1 methylation occurred more frequently in EC tissues than in normal controls, in good agreement with the results of the meta-analysis. CONCLUSION A significant association was found between CDH1 methylation and EC risk. We therefore suggest that CDH1 methylation can serve as a promising diagnostic marker for EC.
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Affiliation(s)
- Zhiyuan Fan
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peking, China
| | - Ru Chen
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peking, China
| | - Minjuan Li
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peking, China
| | - Jianhua Gu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, Peking, China
| | - Xinqing Li
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peking, China
| | - Wenqiang Wei
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peking, China
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Kang D, Kim IH. Molecular Mechanisms and Potential Rationale of Immunotherapy in Peritoneal Metastasis of Advanced Gastric Cancer. Biomedicines 2022; 10:biomedicines10061376. [PMID: 35740397 PMCID: PMC9220323 DOI: 10.3390/biomedicines10061376] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 11/16/2022] Open
Abstract
Peritoneal metastasis (PM) is one of the most frequent metastasis patterns of gastric cancer (GC), and the prognosis of patients with PM is very dismal. According to Paget’s theory, disseminated free cancer cells are seeded and survive in the abdominal cavity, adhere to the peritoneum, invade the subperitoneal tissue, and proliferate through angiogenesis. In these sequential processes, several key molecules are involved. From a therapeutic point of view, immunotherapy with chemotherapy combination has become the standard of care for advanced GC. Several clinical trials of newer immunotherapy agents are ongoing. Understanding of the molecular process of PM and the potential rationale of immunotherapy for PM treatment is necessary. Beyond understanding of the molecular aspect of PM, many studies have been conducted on the modality of treatment of PM. Notably, intraperitoneal approaches, including chemotherapy or immunotherapy, have been conducted, because systemic treatment of PM has limitations. In this study, we reviewed the molecular mechanisms and immunologic aspects of PM, and intraperitoneal approaches under investigation for treating PM.
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Affiliation(s)
- Donghoon Kang
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea;
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
- Correspondence:
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Liu S, Ni C, Li Y, Yin H, Xing C, Yuan Y, Gong Y. The Involvement of TRIB3 and FABP1 and Their Potential Functions in the Dynamic Process of Gastric Cancer. Front Mol Biosci 2021; 8:790433. [PMID: 34957220 PMCID: PMC8696077 DOI: 10.3389/fmolb.2021.790433] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/18/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Dysregulated expression of TRIB3 and FABP1 have been previously observed in human cancer tissues. However, there are little information as to their expression change in dynamic gastric diseases and the functional roles. Methods: Tissues from a total of 479 patients, including 89 GS, 102 IM-GA, 144 EGC, and 144 AGC were collected. The protein expressions of TRIB3 and FABP1 were detected by immunohistochemical staining. Meanwhile, the potential functions of TRIB3 and FABP1 in GC were further analyzed by R software and some internet public databases, such as TCGA and DAVID. Results: During this multi-stage process that go through GS to EGC, the expression trend of TRIB3 and FABP1 protein was GS > IM-GA > EGC. Besides, the expression of TRIB3 protein continued to decrease in AGC, while the expression of FABP1 was abnormally increased. Hp infection was significantly associated with the decreased expression of TRIB3 and FABP1. In addition, the diagnostic efficiency of the combination of these two indicators to diagnose EGC was higher than that of a single indicator. Survival analysis showed that higher expression of TRIB3 or FABP1 could indicate a better prognosis of GC. The protein expressions of TRIB3 and FABP1 were significantly positively correlated. Moreover, CEACAM5 and PRAP1 were positively correlated with both TRIB3 and FABP1 expressions, while GABRP and THBS4 were negatively correlated. The macrophages M0 infiltration was positively correlated with both TRIB3 and FABP1 expressions. Conclusion: The protein expressions of TRIB3 and FABP1 gradually decreased with the gastric disease progress, and was positively correlated. Hp infection may reduce the protein expression of TRIB3 and FABP1. Combing TRIB3 and FABP1 expressions can improve the diagnostic efficiency for EGC. Either a high expression of TRIB3 or FABP1 indicates a better prognosis for GC. TRIB3 and FABP1 may interact with CEACAM5, PRAP1, GABRP and THBS4, and affect tumor immune microenvironment by regulating immune cells, and participate in the development and progression of GC.
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Affiliation(s)
- Songyi Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Chuxuan Ni
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yizhi Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Honghao Yin
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Chengzhong Xing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuehua Gong
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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The utility of high-mobility group A2 overexpression for predicting the prognosis of gastric cancer patients and its contribution to poor prognosis via chemoresistance and the propensity for the occurrence of carcinomatosis peritonei. Surgery 2020; 169:1213-1220. [PMID: 33376002 DOI: 10.1016/j.surg.2020.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/22/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to elucidate the correlation of high-mobility group protein A2 overexpression with gastric cancer prognosis and compare its prognostic power with that of pre-existing markers. METHODS Malignant tissues from 396 patients with gastric cancer who underwent gastrectomy from 2008 to 2012 were examined. High-mobility group protein A2 expression was assessed by immunohistochemistry and the sensitivity and specificity for predicting disease progression and overall survival of high-mobility group protein A2 and the prognostic biomarkers p53, Ki-67, human epidermal growth factor receptor 2, cyclooxygenase-2, and epidermal growth factor receptor were compared. RESULTS A total of 95 samples (24.1%) showed high-mobility group protein A2 overexpression, which was related to advanced stage, undifferentiated histology, and lymphatic and perineural invasion. Additionally, high-mobility group protein A2 overexpression was an independent prognostic factor in multivariate analysis for disease progression and overall survival. Based on Kaplan-Meier survival analysis disease progression and overall survival, the high-mobility group protein A2-overexpressing patients showed worse survival. The recurrence pattern of peritoneal dissemination was more frequently observed in high-mobility group protein A2-positive group. Moreover, chemoresistance was more frequently observed in the high-mobility group protein A2-positive group. High-mobility group protein A2 exhibited a better ability for predicting disease progression and overall survival than other markers, and the prognostic power was enhanced when high-mobility group protein A2 was used with these markers. CONCLUSION High-mobility group protein A2 overexpression is associated with chemoresistance and a propensity for carcinomatosis peritonei after surgery in patients with gastric cancer. The power to predict the prognosis of patients with gastric cancer can be enhanced with the use of preexisting biomarkers and high-mobility group protein A2.
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10
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Yao X, Ajani JA, Song S. Molecular biology and immunology of gastric cancer peritoneal metastasis. Transl Gastroenterol Hepatol 2020; 5:57. [PMID: 33073052 DOI: 10.21037/tgh.2020.02.08] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/03/2020] [Indexed: 12/24/2022] Open
Abstract
Peritoneal metastases occur in 55-60% of patients with gastric cancer (GC) and are associated with a 2% 5-year overall survival rate. There are limited treatment options for these patients, and no targeted therapy or immunotherapy is available. Rational therapeutic targets remain to be found. In this review, we present the published literature and our own recent experience in molecular biology to identify important molecules and signaling pathways as well as cellular immunity involved in the peritoneal metastasis of GC. We also suggest potential novel strategies for improving the outcomes of GC patients with peritoneal metastasis.
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Affiliation(s)
- Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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11
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Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini PL, Fernández-Barrena MG, Avila MA. Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities. Int J Mol Sci 2020; 21:E5500. [PMID: 32752096 PMCID: PMC7432799 DOI: 10.3390/ijms21155500] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Pier-Luigi Lollini
- Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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12
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CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer. Genes (Basel) 2020; 11:genes11040391. [PMID: 32260281 PMCID: PMC7231129 DOI: 10.3390/genes11040391] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/16/2023] Open
Abstract
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.
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Li X, Liu J, Wang K, Zhou J, Zhang H, Zhang M, Shi Y. Polymorphisms and rare variants identified by next-generation sequencing confer risk for lung cancer in han Chinese population. Pathol Res Pract 2020; 216:152873. [PMID: 32107087 DOI: 10.1016/j.prp.2020.152873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 01/16/2020] [Accepted: 02/11/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Lung cancer is one of the leading causes of cancer death worldwide, and genetic risk factors account for a large part of its carcinogenesis. The low economic requirements and high efficiency of next-generation sequencing (NGS) make it widely used in detecting genetic alterations in pathogenesis. METHODS We performed targeted panel sequencing in 780 Han Chinese lung cancer patients using a commercial probe, and the correlations between dozens of susceptible sites were verified in 1113 healthy controls. This study used Fisher's exact test and Benjamini-Hochberg FDR correction to analyze the mutual exclusion between mutated genes, and Pearson's p was used to verify the correlations between mutations and lung cancer susceptibility. RESULTS Our results determined the mutation spectrum and showed that each lung cancer patient carried at least one DNA mutation. The most frequently mutated gene was BRCA2 (mutation rate,10.6 %.). The co-occurrence and mutual exclusion analysis of DNA damage related genes showed that gene ATM was mutually exclusive from MSH6. We conducted a further case-control study in different subtypes of lung cancer and the results described 14 mutations associated with adenocarcinoma, 9 with squamous cell carcinoma, and 4 with small cell lung cancer. These variants were novel de-novo germline mutations in lung cancer. Particularly, rs3864017 in FANCD2 showed a protective effect of lung adenocarcinoma for carriers (OR = 0.146, 95 % CI = 0.052∼0.405, Padjusted = 3.37 × 10-4). CONCLUSIONS 18 candidate mutations might alter the risk of lung cancer in the Han Chinese population, including polymorphisms rs3864017(FANCD2), rs55740729(MSH6) and 16 rare variants. The underlying mechanisms of candidate genes in lung cancer remain unclear and we suggest more functional studies on exploring how these genes affect the risk of lung cancer.
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Affiliation(s)
- Xiaoqi Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jinsheng Liu
- Shanghai Jiao Tong University Hospital, Shanghai 200030, China
| | - Ke Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Juan Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Hang Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Mancang Zhang
- DYnastyGene Biotech Co. Ltd., Building 25, No.10688 Bei Qing Road, Qingpu District, Shanghai 201700, PR China
| | - Yongyong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
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Bouras E, Karakioulaki M, Bougioukas KI, Aivaliotis M, Tzimagiorgis G, Chourdakis M. Gene promoter methylation and cancer: An umbrella review. Gene 2019; 710:333-340. [PMID: 31202904 DOI: 10.1016/j.gene.2019.06.023] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/05/2019] [Accepted: 06/11/2019] [Indexed: 12/11/2022]
Abstract
Gene promoter methylation is a common epigenetic event, taking place in the early phase of tumorigenesis, which has a great potential as a diagnostic and prognostic cancer biomarker. In this umbrella review, we provide an overview on the association between gene-promoter methylation of protein-coding genes and cancer risk based on currently available meta-analyses data on gene promoter methylation. We searched MEDLINE via PubMed and the Cochrane Database of Systematic Reviews for meta-analyses that examine the association between gene-promoter methylation and cancer, published until January 2019 in English. We used AMSTAR to assess the quality of the included studies and applied a set of pre-specified criteria to evaluate the magnitude of each association. We provide a comprehensive overview of 80 unique combinations between 22 different genes and 18 cancer outcomes, all of which indicated a positive association between promoter hypermethylation and cancer. In total, the 70 meta-analyses produced significant results under a random-effects model with odds ratios that ranged from 1.94 to 26.60, with the summary effect being in favor of the unmethylated group in all cases. Three of the strong evidence associations involve RASSF1 methylation on bladder cancer risk (OR = 18.46; 95% CI: 12.69-26.85; I2 = 0%), MGMT methylation on NSCLC (OR = 4.25; 95% CI: 2.83-6.38; I2 = 22.4%) and RARB methylation on prostate cancer (OR = 6.87; 95% CI: 4.68-10.08; I2 = 0%). Meta-analyses showed a moderate quality, AMSTAR score ranging from 4 to 9 (Mdn = 8; IQR: 7.0 to 8.0). As primary studies and meta-analyses on the subject accumulate, more genetic loci may be found to be highly associated with specific cancer types and hence the biomarker sets will become wider.
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Affiliation(s)
- Emmanouil Bouras
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Meropi Karakioulaki
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Konstantinos I Bougioukas
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
| | - Michalis Aivaliotis
- Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece; Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Thessaloniki, Greece; Genomics and Epigenomics Translational Research (GENeTres), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Thessaloniki, Greece
| | - Georgios Tzimagiorgis
- Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece; Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Thessaloniki, Greece; Genomics and Epigenomics Translational Research (GENeTres), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Thessaloniki, Greece
| | - Michael Chourdakis
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece.
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15
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Xie ZC, Huang JC, Zhang LJ, Gan BL, Wen DY, Chen G, Li SH, Yan HB. Exploration of the diagnostic value and molecular mechanism of miR‑1 in prostate cancer: A study based on meta‑analyses and bioinformatics. Mol Med Rep 2018; 18:5630-5646. [PMID: 30365107 PMCID: PMC6236292 DOI: 10.3892/mmr.2018.9598] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Accepted: 09/24/2018] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) remains a principal issue to be addressed in male cancer-associated mortality. Therefore, the present study aimed to examine the clinical value and associated molecular mechanism of microRNA (miR)-1 in PCa. A meta-analysis was conducted to evaluate the diagnosis of miR-1 in PCa via Gene Expression Omnibus and ArrayExpress datasets, The Cancer Genome Atlas miR-1 expression data and published literature. It was identified that expression of miR-1 was significantly downregulated in PCa. Decreased miR-1 expression possessed moderate diagnostic value, with area under the curve, sensitivity, specificity and odds ratio values at 0.73, 0.77, 0.57 and 4.60, respectively. Using bioinformatics methods, it was revealed that a number of pathways, including the ‘androgen receptor signaling pathway’, ‘androgen receptor activity’, ‘transcription factor binding’ and ‘protein processing in the endoplasmic reticulum’, were important in PCa. A total of seven hub genes, including phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccin ocarboxamide synthase (PAICS), cadherin 1 (CDH1), SRC proto-oncogene, non-receptor tyrosine kinase, twist family bHLH transcription factor 1 (TWIST1), ZW10 interacting kinetochore protein (ZWINT), PCNA clamp associated factor (KIAA0101) and androgen receptor, among which, five (PAICS, CDH1, TWIST1, ZWINT and KIAA0101) were significantly upregulated and negatively correlated with miR-1, were identified as key miR-1 target genes in PCa. Additionally, it was investigated whether miR-1 and its hub genes were associated with clinical features, including age, tumor status, residual tumor, lymph node metastasis, pathological T stage and prostate specific antigen level. Collectively the results suggest that miR-1 may be involved in the progression of PCa, and consequently be a promising diagnostic marker. The ‘androgen receptor signaling pathway’, ‘androgen receptor activity’, ‘transcription factor binding’ and ‘protein processing in the endoplasmic reticulum’ may be crucial interactive pathways in PCa. Furthermore, PAICS, CDH1, TWIST1, ZWINT and KIAA0101 may serve as crucial miR-1 target genes in PCa.
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Affiliation(s)
- Zu-Cheng Xie
- Department of Urological Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jia-Cheng Huang
- Department of Urological Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Li-Jie Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Bin-Liang Gan
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dong-Yue Wen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Sheng-Hua Li
- Department of Urological Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hai-Biao Yan
- Department of Urological Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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16
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Zhang Y, Li D, Dai Y, Li R, Gao Y, Hu L. The Role of E-cadherin in Helicobacter pylori-Related Gastric Diseases. Curr Drug Metab 2018; 20:23-28. [PMID: 29938616 DOI: 10.2174/1389200219666180625113010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 04/09/2018] [Accepted: 04/17/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori)-related gastric diseases are a series of gastric mucosal disorders associated with H. pylori infection. Gastric cancer (GC) is widely believed to evolve from gastritis and gastric ulcer. As an important adhesion molecule of epithelial cells, E-cadherin plays a key role in the development of gastric diseases. In this review, we aim to seek the characteristic of E-cadherin expression at different stages of gastric diseases. METHODS We searched plenty of databases for research literature about E-cadherin expression in H. pylori-related gastric diseases, and reviewed the relationship of E-cadherin and H. pylori, and the role of E-cadherin at different stages of gastric diseases. RESULTS H. pylori was shown to decrease E-cadherin expression by various ways in vitro, while most of clinical studies have not found the relationship between H. pylori and E-cadherin expression. It is defined that poor outcome of GC is related to loss expression of E-cadherin, but it is still unclear when qualitative change of E-cadherin expression in gastric mucosa emerges. CONCLUSION Expression level of E-cadherin in gastric cells may be a consequence of injury factors and body's selfrepairing ability. More studies on E-cadherin expression in gastric mucosa with precancerous lesions need to be performed, which may be potential and useful for early detection, prevention and treatment of GC.
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Affiliation(s)
- Yunzhan Zhang
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Danyan Li
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Yunkai Dai
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Ruliu Li
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Yong Gao
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
| | - Ling Hu
- Piwei Institute, Guangzhou University of Chinese Medicine, Guangdong, China
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17
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Kiyozumi Y, Iwatsuki M, Kurashige J, Ogata Y, Yamashita K, Koga Y, Toihata T, Hiyoshi Y, Ishimoto T, Baba Y, Miyamoto Y, Yoshida N, Yanagihara K, Mimori K, Baba H. PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer. Int J Cancer 2018; 143:1202-1211. [PMID: 29603227 DOI: 10.1002/ijc.31410] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/09/2018] [Accepted: 03/20/2018] [Indexed: 12/16/2022]
Abstract
Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.
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Affiliation(s)
- Yuki Kiyozumi
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Junji Kurashige
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kohei Yamashita
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuki Koga
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kazuyoshi Yanagihara
- Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, 874-0838, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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18
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Lee JY, Lee KM, Lee DH, Kim DS. Association of low-dose exposure to persistent organic pollutants withE-cadherinpromoter methylation in healthy Koreans. Biomarkers 2018; 23:293-298. [DOI: 10.1080/1354750x.2017.1417482] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Ji Yun Lee
- Department of Anatomy, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Kyung Min Lee
- Department of Anatomy, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Duk Hee Lee
- Preventive Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Dong Sun Kim
- Department of Anatomy, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea
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Petrelli F, Ghidini M, Barni S, Steccanella F, Sgroi G, Passalacqua R, Tomasello G. Prognostic Role of Primary Tumor Location in Non-Metastatic Gastric Cancer: A Systematic Review and Meta-Analysis of 50 Studies. Ann Surg Oncol 2017; 24:2655-2668. [DOI: 10.1245/s10434-017-5832-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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20
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Zhou S, Zhang Z, Zheng P, Zhao W, Han N. MicroRNA-1285-5p influences the proliferation and metastasis of non-small-cell lung carcinoma cells via downregulating CDH1 and Smad4. Tumour Biol 2017. [PMID: 28631567 DOI: 10.1177/1010428317705513] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Abnormal expression of microRNAs has been reported to regulate gene expression and cancer cell growth, invasion, and migration. Recently, upregulation of hsa-miR-1285 was demonstrated in bronchoalveolar lavage fluid samples from patients with lung cancer and downregulation in plasma level of stage-I lung cancer patients. However, the function and the underlying mechanism of miR-1285 in non-small-cell lung carcinoma have not been elucidated. In this study, we found that miR-1285-5p, the mature form of miR-1285, was significantly upregulated in human non-small-cell lung carcinoma cell lines A549 and SK-MES-1. Additionally, cells transfected with the miR-1285-5p inhibitor LV-anti-miR-1285-5p demonstrated significantly inhibited proliferation and invasion and depressed migration. Further analysis demonstrated that the miR-1285-5p precursor LV-miR-1285-5p attenuated the expression of Smad4 and cadherin-1 (CDH1) but that LV-anti-miR-1285-5p showed opposite results. A luciferase reporter assay confirmed that miR-1285-5p targeted Smad4 and CDH1. Mechanism analyses revealed that silence of Smad4 and CDH1 significantly attenuated the inhibitory effects of LV-anti-miR-1285-5p on non-small-cell lung carcinoma growth and invasion. Taken together, our data suggest that miR-1285-5p functions as a tumor promoter in the development of non-small-cell lung carcinoma by targeting Smad4 and CDH1, indicating a novel therapeutic strategy for non-small-cell lung carcinoma patients.
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Affiliation(s)
- Shixia Zhou
- 1 Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhongmian Zhang
- 1 Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengyuan Zheng
- 2 Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenchao Zhao
- 3 Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Na Han
- 1 Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Zhang J, Liu Y, Yu CJ, Dai F, Xiong J, Li HJ, Wu ZS, Ding R, Wang H. Role of ARPC2 in Human Gastric Cancer. Mediators Inflamm 2017; 2017:5432818. [PMID: 28694563 PMCID: PMC5485321 DOI: 10.1155/2017/5432818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/06/2017] [Indexed: 01/01/2023] Open
Abstract
Gastric cancer continues to be the second most frequent cause of cancer deaths worldwide. However, the exact molecular mechanisms are still unclear. Further research to find potential targets for therapy is critical and urgent. In this study, we found that ARPC2 promoted cell proliferation and invasion in the human cancer cell line MKN-28 using a cell total number assay, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, cell colony formation assay, migration assay, invasion assay, and wound healing assay. For downstream pathways, CTNND1, EZH2, BCL2L2, CDH2, VIM, and EGFR were upregulated by ARPC2, whereas PTEN, BAK, and CDH1 were downregulated by ARPC2. In a clinical study, we examined the expression of ARPC2 in 110 cases of normal human gastric tissues and 110 cases of human gastric cancer tissues. ARPC2 showed higher expression in gastric cancer tissues than in normal gastric tissues. In the association analysis of 110 gastric cancer tissues, ARPC2 showed significant associations with large tumor size, lymph node invasion, and high tumor stage. In addition, ARPC2-positive patients exhibited lower RFS and OS rates compared with ARPC2-negative patients. We thus identify that ARPC2 plays an aneretic role in human gastric cancer and provided a new target for gastric cancer therapy.
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Affiliation(s)
- Jun Zhang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Yi Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang-Jun Yu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fu Dai
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Jie Xiong
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong-Jun Li
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Zheng-Sheng Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Ding
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong Wang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
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22
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Lins RR, Oshima CTF, Oliveira LAD, Silva MS, Mader AMAA, Waisberg J. EXPRESSION OF E-CADHERIN AND WNT PATHWAY PROTEINS BETACATENIN, APC, TCF-4 AND SURVIVIN IN GASTRIC ADENOCARCINOMA: CLINICAL AND PATHOLOGICAL IMPLICATION. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2017; 29:227-231. [PMID: 28076475 PMCID: PMC5225860 DOI: 10.1590/0102-6720201600040004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 08/02/2016] [Indexed: 12/24/2022]
Abstract
Background Gastric cancer is the fifth most frequent cancer and the third most common cause of cancer-related deaths worldwide.It has been reported that Wnt/ betacatenin pathway is activated in 30-50% of these tumors. However,the deregulation of this pathway has not been fully elucidated. Aim To determine the expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins in gastric adenocarcinoma tissues and correlate with clinical and pathological parameters. Method Seventy-one patients with gastric adenocarcinoma undergoing gastrectomy were enrolled. The expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins was detected by immunohistochemistryand related to the clinical and pathological parameters. Results The expression rates of E-cadherin in the membrane was 3%; betacatenin in the cytoplasm and nucleus were 23,4% and 3,1% respectively; APC in the cytoplasm was 94,6%; TCF-4 in the nucleus was 19,4%; and survivin in the nucleus 93,9%. The expression rate of E-cadherin was correlated with older patients (p=0,007), while betacatenin with tumors <5 cm (p=0,041) and APC with proximal tumors (p=0,047). Moreover, the expression of TCF-4 was significantly higher in the diffuse type (p=0,017) and T4 tumors (p=0,002). Conclusion The Wnt/betacatenin is not involved in gastric carcinogenesis. However, the high frequency of survivin allows to suggest that other signaling pathways must be involved in the transformation of gastric tissue.
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Affiliation(s)
- Rodrigo Rego Lins
- Postgraduate Program in Interdisciplinary Surgical Science, Federal University of São Paulo - UNIFESP, São Paulo, SP; Brazil
| | | | - Levindo Alves de Oliveira
- Postgraduate Program in Interdisciplinary Surgical Science, Federal University of São Paulo - UNIFESP, São Paulo, SP; Brazil
| | | | | | - Jaques Waisberg
- Postgraduate Program in Interdisciplinary Surgical Science, Federal University of São Paulo - UNIFESP, São Paulo, SP; Brazil
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23
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Kanda M, Kodera Y. Molecular mechanisms of peritoneal dissemination in gastric cancer. World J Gastroenterol 2016; 22:6829-6840. [PMID: 27570420 PMCID: PMC4974582 DOI: 10.3748/wjg.v22.i30.6829] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets.
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24
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Liu D, Chen Y, Sun P, Bai W, Gao A. STAT3 methylation in white blood cells as a novel sensitive biomarker for the toxic effect of low-dose benzene exposure. Toxicol Res (Camb) 2016; 5:800-807. [PMID: 30090390 PMCID: PMC6061912 DOI: 10.1039/c5tx00445d] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 01/20/2016] [Indexed: 12/13/2022] Open
Abstract
Alterations in DNA methylation patterns play an essential role in disease process and are associated with cancer risk. To explore the toxic effect and early sensitive biomarker of the health effects of low-dose benzene exposure (LDBE), and investigate the correlation between DNA methylation and the toxic effect of LDBE, a cross-sectional study was conducted in a sample of 571 workers; 312 workers who were exposed to a 1.82 ± 1.16 mg m-3 air benzene concentration were assigned to the LDBE group, while 259 non-known benzene exposure (NBE) workers were assigned to the control group, with an air benzene concentration of 0.06 ± 0.01 mg m-3. Routine blood indexes, alanine transaminase (ALT), oxidative stress parameters and signal transducer and activator of transcription 3 (STAT3) methylation were detected. Compared with the NBE population, the STAT3 methylation level (P = 0.001), Platelets (PLTs) (P = 0.002) and 8-isoprostane-PGFs (8-iso-PGF2a) (P = 0.001) manifested a significant reduction, while ALT (P = 0.002) and 8-hydroxy-2 deoxyguanosine (8-OHdG) (P = 0.002) showed a significant rise in the LDBE population. In addition, a significant correlation was observed between STAT3 methylation and oxidative stress, namely 8-OhdG and 8-iso-PGF2a. Furthermore, a multivariate analysis showed that the STAT3 methylation (structure loadings = 0.909) was the most strongly correlated with the other set of variables, especially with white blood cells (WBCs) (structure loadings = 0.675). Taken together, STAT3 methylation may be the underlying mechanism involved in the early toxic effect of LDBE, therefore, STAT3 methylation can be a novel sensitive biomarker for the toxic effect of low-dose benzene exposure.
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Affiliation(s)
- Di Liu
- Department of Occupational Health and Environmental Health , School of Public Health , Capital Medical University , Beijing 100069 , China . ; ; Tel: +86-10-83911509
- Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing 100069 , China
| | - Yujiao Chen
- Department of Occupational Health and Environmental Health , School of Public Health , Capital Medical University , Beijing 100069 , China . ; ; Tel: +86-10-83911509
- Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing 100069 , China
| | - Pengling Sun
- Department of Occupational Health and Environmental Health , School of Public Health , Capital Medical University , Beijing 100069 , China . ; ; Tel: +86-10-83911509
- Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing 100069 , China
| | - Wenlin Bai
- Department of Occupational Health and Environmental Health , School of Public Health , Capital Medical University , Beijing 100069 , China . ; ; Tel: +86-10-83911509
- Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing 100069 , China
| | - Ai Gao
- Department of Occupational Health and Environmental Health , School of Public Health , Capital Medical University , Beijing 100069 , China . ; ; Tel: +86-10-83911509
- Beijing Key Laboratory of Environmental Toxicology , Capital Medical University , Beijing 100069 , China
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25
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Tu C, Yuan L, Zhou J. Comments on a meta-analysis and systematic review of the clinicopathological significance of CDH1 in gastric cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:1159-60. [PMID: 27042007 PMCID: PMC4801163 DOI: 10.2147/dddt.s103922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Chao Tu
- Department of Geriatric Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Lianwen Yuan
- Department of Geriatric Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Jianping Zhou
- Department of Geriatric Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
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26
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Yen CY, Huang HW, Shu CW, Hou MF, Yuan SSF, Wang HR, Chang YT, Farooqi AA, Tang JY, Chang HW. DNA methylation, histone acetylation and methylation of epigenetic modifications as a therapeutic approach for cancers. Cancer Lett 2016; 373:185-92. [DOI: 10.1016/j.canlet.2016.01.036] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/23/2015] [Accepted: 01/18/2016] [Indexed: 02/09/2023]
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27
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Wu CY, Lin JT. The changing epidemiology of Asian digestive cancers: From etiologies and incidences to preventive strategies. Best Pract Res Clin Gastroenterol 2015; 29:843-53. [PMID: 26651247 DOI: 10.1016/j.bpg.2015.09.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 09/02/2015] [Accepted: 09/17/2015] [Indexed: 02/06/2023]
Abstract
Digestive cancers are a major health burden in Asia. Due to the presence of similar "infection-inflammation-cancer" pathways in the carcinogenesis process, eradicating infective pathogens or attenuating relevant inflammatory signaling pathways may reduce digestive cancer incidences and improve patient outcomes. The aim of this paper is to review the recent evidence regarding the epidemiology of three major digestive cancers in Asia: stomach cancer, liver cancer, and colorectal cancer. We focused on the incidence trends, the major etiologies, and especially the potential preventive strategies.
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Affiliation(s)
- Chun-Ying Wu
- Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine and Graduate Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Public Health and Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, Taipei, Taiwan; Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
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28
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Brito LA, Yamamoto GL, Melo S, Malcher C, Ferreira SG, Figueiredo J, Alvizi L, Kobayashi GS, Naslavsky MS, Alonso N, Felix TM, Zatz M, Seruca R, Passos-Bueno MR. Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate. Hum Mutat 2015; 36:1029-33. [PMID: 26123647 DOI: 10.1002/humu.22827] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 06/17/2015] [Indexed: 12/12/2022]
Abstract
Nonsyndromic orofacial cleft (NSOFC) is a complex disease of still unclear genetic etiology. To investigate the contribution of rare epithelial cadherin (CDH1) gene variants to NSOFC, we target sequenced 221 probands. Candidate variants were evaluated via in vitro, in silico, or segregation analyses. Three probably pathogenic variants (c.760G>A [p.Asp254Asn], c.1023T>G [p.Tyr341*], and c.2351G>A [p.Arg784His]) segregated according to autosomal dominant inheritance in four nonsyndromic cleft lip with or without cleft palate (NSCL/P) families (Lod score: 5.8 at θ = 0; 47% penetrance). A fourth possibly pathogenic variant (c.387+5G>A) was also found, but further functional analyses are needed (overall prevalence of CDH1 candidate variants: 2%; 15.4% among familial cases). CDH1 mutational burden was higher among probands from familial cases when compared to that of controls (P = 0.002). We concluded that CDH1 contributes to NSCL/P with mainly rare, moderately penetrant variants, and CDH1 haploinsufficiency is the likely etiological mechanism.
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Affiliation(s)
- Luciano Abreu Brito
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Guilherme Lopes Yamamoto
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Soraia Melo
- IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Carolina Malcher
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Simone Gomes Ferreira
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Joana Figueiredo
- IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Lucas Alvizi
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Gerson Shigeru Kobayashi
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Michel Satya Naslavsky
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Nivaldo Alonso
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Temis Maria Felix
- Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil
| | - Mayana Zatz
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
| | - Raquel Seruca
- IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Maria Rita Passos-Bueno
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
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