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Fujiwara-Tani R, Takagi T, Mori S, Kishi S, Nishiguchi Y, Sasaki T, Ikeda M, Nagai K, Bhawal UK, Ohmori H, Fujii K, Kuniyasu H. Short Telomere Lesions with Dysplastic Metaplasia Histology May Represent Precancerous Lesions of Helicobacter pylori-Positive Gastric Mucosa. Int J Mol Sci 2023; 24:3182. [PMID: 36834592 PMCID: PMC9958872 DOI: 10.3390/ijms24043182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Gastric cancers are strongly associated with Helicobacter pylori infection, with intestinal metaplasia characterizing the background mucosa in most cases. However, only a subset of intestinal metaplasia cases proceed to carcinogenesis, and the characteristics of high-risk intestinal metaplasia that link it with gastric cancer are still unclear. We examined telomere reduction in five gastrectomy specimens using fluorescence in situ hybridization, and identified areas with localized telomere loss (outside of cancerous lesions), which were designated as short telomere lesions (STLs). Histological analyses indicated that STLs were characteristic of intestinal metaplasia accompanied by nuclear enlargement but lacking structural atypia, which we termed dysplastic metaplasia (DM). A review of gastric biopsy specimens from 587 H. pylori-positive patients revealed 32 cases of DM, 13 of which were classified as high-grade based on the degree of nuclear enlargement. All high-grade DM cases exhibited a telomere volume reduced to less than 60% of that of lymphocytes, increased stemness, and telomerase reverse transcriptase (TERT) expression. Two patients (15%) exhibited low levels of p53 nuclear retention. After a 10-year follow-up, 7 (54%) of the high-grade DM cases had progressed to gastric cancer. These results suggest that DM is characterized by telomere shortening, TERT expression, and stem cell proliferation, and high-grade DM is a high-grade intestinal metaplasia that likely represents a precancerous lesion of gastric cancer. High-grade DM is expected to effectively prevent progression to gastric cancer in H. pylori-positive patients.
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Grants
- 19K16564 Ministry of Education, Culture, Sports, Science and Technology
- 20K21659 Ministry of Education, Culture, Sports, Science and Technology
- 20K18007 Ministry of Education, Culture, Sports, Science and Technology
- 21K10143 Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Tadataka Takagi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Yukiko Nishiguchi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Takamitsu Sasaki
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Masayuki Ikeda
- Miyoshi Central Hospital, 10531 Higashi-Sakaya-cho, Miyoshi 728-8502, Japan
| | - Kenta Nagai
- Miyoshi Central Hospital, 10531 Higashi-Sakaya-cho, Miyoshi 728-8502, Japan
| | - Ujjal Kumar Bhawal
- Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Matsudo 271-8587, Japan
- Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College, Chennai 600077, India
| | - Hitoshi Ohmori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Kiyomu Fujii
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
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BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer. Int J Mol Sci 2021; 22:ijms222312724. [PMID: 34884530 PMCID: PMC8657452 DOI: 10.3390/ijms222312724] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 low-grade atypical GHPs (19.6%), 7 high-grade atypical GHPs (6.9%), and 5 intramucosal cancer samples (4.9%). GHP atypia was more common in the elderly and increased with increasing polyp size. In particular, polyps larger than 1 cm were associated with a higher grade and cancer. Furthermore, mucus production decreased with increasing atypia. Although no correlation was found between atypia and Helicobacter pylori infection or intestinal metaplasia, enhanced proliferative ability (Ki-67) did correlate with atypia, as did nuclear 8-hydroxy-2'-deoxyguanosine levels. Interestingly, 4-hydroxynonenal levels in granulation tissue and the area ratio of granulation tissue within polyps also correlated with GHP atypia. In five cases of HPAGC, three cases exhibited caudal type homeobox transcription factor (CDX2)-positive cells and a mixed mucin phenotype, which is considered to be related to H. pylori infection. By contrast, two cases were CDX2 negative, with a gastric mucin phenotype, and H. pylori infection was not observed in the tumor or the surrounding mucosa. In these cases, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (V600E) was detected. All cancer samples showed high stemness and p53 protein accumulation, but no KRAS mutations. The molecular and phenotypic characteristics of the cases characterized by BRAF mutations may represent a novel subtype of HPAGC, reflecting a conserved pathway to oncogenesis that does not involve H. pylori infection. These findings are worthy of further investigation in a large-scale study with a substantial cohort of HPAGC patients to establish their clinical significance.
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Sasaki T, Yamashita Y, Kuniyasu H. AKT plays a crucial role in gastric cancer. Oncol Lett 2015; 10:607-611. [PMID: 26622541 DOI: 10.3892/ol.2015.3260] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 04/29/2015] [Indexed: 02/07/2023] Open
Abstract
The AKT protein is involved in the phosphatidylinositol-3 kinase signaling pathway and is a vital regulator of survival, proliferation and differentiation in various types of cells. Helicobacter pylori infection induces epithelial cell proliferation and oxidative stress in chronic gastritis. These alterations lead to telomere shortening, resulting in the activation of telomerase. AKT, in particular, is activated by H. pylori-induced inflammation. AKT then promotes the expression of human telomerase reverse transcriptase, which encodes a catalytic subunit of telomerase, and induces telomerase activity, an essential component of the process of carcinogenesis. AKT activation is increased in gastric mucosa with carcinogenic properties and is associated with the low survival of patients with gastric cancer. The findings of the present study suggest that AKT is pivotal in gastric carcinogenesis and progression.
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Affiliation(s)
- Takamitsu Sasaki
- Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Fukuoka 812-8582, Japan
| | - Yuichi Yamashita
- Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Fukuoka 812-8582, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
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Wada T, Ishimoto T, Seishima R, Tsuchihashi K, Yoshikawa M, Oshima H, Oshima M, Masuko T, Wright NA, Furuhashi S, Hirashima K, Baba H, Kitagawa Y, Saya H, Nagano O. Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia. Cancer Sci 2013; 104:1323-9. [PMID: 23848514 PMCID: PMC7656553 DOI: 10.1111/cas.12236] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 07/04/2013] [Accepted: 07/11/2013] [Indexed: 12/20/2022] Open
Abstract
Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia-carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(-), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v(+) metaplastic cells manifested upregulation of xCT expression compared with CD44v(-) cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v-xCT could thus prove effective for prevention or attenuation of the CD44v-dependent development of preneoplastic lesions and cancer.
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Affiliation(s)
- Takeyuki Wada
- Division of Gene Regulation, Institute for Advanced Medical Research, Tokyo, Japan; Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
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Himaya SWA, Dewapriya P, Kim SK. EGFR tyrosine kinase inhibitory peptide attenuates Helicobacter pylori-mediated hyper-proliferation in AGS enteric epithelial cells. Toxicol Appl Pharmacol 2013; 269:205-14. [PMID: 23566958 DOI: 10.1016/j.taap.2013.03.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 03/11/2013] [Accepted: 03/25/2013] [Indexed: 12/21/2022]
Abstract
Helicobacter pylori infection is one of the most critical causes of stomach cancer. The current study was conducted to explore the protective effects of an isolated active peptide H-P-6 (Pro-Gln-Pro-Lys-Val-Leu-Asp-Ser) from microbial hydrolysates of Chlamydomonas sp. against H. pylori-induced carcinogenesis. The peptide H-P-6 has effectively suppressed H. pylori-induced hyper-proliferation and migration of gastric epithelial cells (AGS). However, the peptide did not inhibit the viability of the bacteria or invasion into AGS cells. Therefore, the effect of the peptide on regulating H. pylori-induced molecular signaling was investigated. The results indicated that H. pylori activates the EGFR tyrosine kinase signaling and nuclear translocation of the β-catenin. The EGFR activation has led to the up-regulation of PI3K/Akt signaling pathway. Moreover, the nuclear translocation levels of β-catenin were significantly increased as a result of Akt mediated down-regulation of GSK3/β protein levels in the cytoplasm. Both of these consequences have resulted in increased expression of cell survival and migration related genes such as c-Myc, cyclin-D, MMP-2 and matrilysin. Interestingly, the isolated peptide potently inhibited H. pylori-mediated EGFR activation and thereby down-regulated the subsequent P13K/Akt signaling leading to β-catenin nuclear translocation. The effect of the peptide was confirmed with the use of EGFR tyrosine kinase inhibitor AG1487 and molecular docking studies. Collectively this study identifies a potent peptide which regulates the H. pylori-induced hyper-proliferation and migration of AGS cells at molecular level.
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Affiliation(s)
- S W A Himaya
- Marine Bio-Process Research Center, Pukyong National University, Nam-Gu, Busan, 608-737, Republic of Korea
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Long XD, Ma Y, Huang YZ, Yi Y, Liang QX, Ma AM, Zeng LP, Fu GH. Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility to Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi population, China. Mol Carcinog 2010; 49:611-8. [PMID: 20232359 DOI: 10.1002/mc.20630] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of gastric antrum adenocarcinoma (GAA) related to Helicobacter pylori infection. This study, including 361 GAAs and 616 controls without any evidence of tumors, was designed to evaluate the association between the polymorphisms of DNA repair genes XPC Ala499Val (RS#2228000) and Lys939Gln (RS#2228001), XPD Lys751Gln (RS#13181), and XRCC4 Ala247Ser (RS#3734091) and Ser298Asn (RS#1805377), and GAA risk for Guangxi population by means of TaqMan-PCR analysis. Increased risks of GAA were found for individuals with H. pylori positive [odds ratio (OR), 2.48; 95% confidence interval (CI), 1.84-3.33] or cagA positive (OR, 7.34; 95% CI, 5.46-9.87). No differences were observed among the studied groups with regard to the genotype distribution of XPC codons 499 and 939 and of XRCC4 codon 247; but XPD codon 751 genotypes with Gln [ORs (95% CI) were 2.67 (1.98-3.58) and 3.97 (2.64-5.99) for Lys/Gln and Gln/Gln, respectively] and XRCC4 codon 298 genotypes with Asn [ORs (95% CI) were 3.01 (2.21-4.10) and 4.78 (3.24-7.05) for Ser/Asn and Asn/Asn, respectively] increased the risk of GAA. Interestingly, there was an interactive effect between the risk genotypes of these two genes and cagA-positive status in the GAA risk (OR(interact) = 2.05 and 2.08, respectively). However, we did not find the gene-H. pylori-status interaction effects on the risk of GAA (P(interact) > 0.05). The results suggested that the polymorphisms of XPD codon 751 and XRCC4 codon 298 are associated with an increased risk of developing H. pylori-related GAA among Guangxi population.
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Affiliation(s)
- Xi-Dai Long
- Department of Pathology, Shanghai Jiao Tong University School of Medicine, No. 280 South Chongqing Road, Shanghai, PR China
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Kabir S. Effect of Helicobacter pylori eradication on incidence of gastric cancer in human and animal models: underlying biochemical and molecular events. Helicobacter 2009; 14:159-71. [PMID: 19702845 DOI: 10.1111/j.1523-5378.2009.00677.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer remains one of the most common cancers worldwide. A strong association exists between Helicobacter pylori infection and the risk of developing noncardia gastric cancer. H. pylori eradication by antibiotic treatment is regarded as a primary chemoprevention strategy to reduce gastric cancer incidence. AIM To analyze the efficacy of H. pylori eradication in preventing gastric cancer in human and animal models, and to discuss whether biochemical, genetic, and epigenetic changes associated with H. pylori infection are reversible after curing the infection. RESULTS Several intervention trials have indicated that in some patients, H. pylori eradication leads to regression and prevents the progression of precancerous lesions. The eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. A few recent intervention studies in Japan have demonstrated significant prophylactic effects of eradication therapy on the development of gastric cancer, suggesting the use of eradication therapy in high-risk populations as a gastric cancer reduction strategy. However, gastric cancer may still develop despite successful eradication therapy. Studies in animal models have confirmed the use of eradication therapy at an early point of infection to prevent gastric cancer development. CONCLUSION H. pylori eradication may not completely abolish the risk of gastric cancer. However, eradication therapy may be used in high-risk populations to reduce gastric cancer incidence. It can reverse many biochemical, genetic, and epigenetic changes that H. pylori infection induces in the stomach.
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Affiliation(s)
- Shahjahan Kabir
- Academic Research and Information Management, Uppsala, Sweden.
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Tahara E. Abnormal growth factor/cytokine network in gastric cancer. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2008; 1:85-91. [PMID: 19308687 PMCID: PMC2654359 DOI: 10.1007/s12307-008-0008-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2007] [Accepted: 02/18/2008] [Indexed: 12/11/2022]
Abstract
Gastric cancer cells express a broad spectrum of the growth factor/cytokine receptor systems that organize the complex interaction between cancer cells and stromal cells in tumor microenvironment, which confers cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. However, these abnormal growth factor/cytokine networks differ in the two histological types of gastric cancer. Importantly, activation of nuclear factor-kB pathway by Helicobacter pylori infection may act as a key player for induction of growth factor/cytokine networks in gastritis and pathogenesis of gastric cancer. Better understanding of these events will no doubt provide new approaches for biomarkers of diagnosis and effective therapeutic targeting of gastric cancer.
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Affiliation(s)
- Eiichi Tahara
- Hiroshima University, Hiroshima Cancer Seminar Foundation, Naka-ku, Hiroshima, Japan.
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9
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Zhu Y, Shu X, Chen J, Xie Y, Xu P, Huang DQ, Lu NH. Effect of Helicobacter pylori eradication on oncogenes and cell proliferation. Eur J Clin Invest 2008; 38:628-33. [PMID: 18837738 DOI: 10.1111/j.1365-2362.2008.01987.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Helicobacter pylori , the main cause of chronic gastritis, is a class 1 gastric carcinogen. However, it remains unclear whether H. pylori affects molecular alterations in chronic gastritis. Thus, this study was designed to investigate the effect of H. pylori eradication on the expression of human telomerase RNA (hTR), human telomerase reverse transcriptase (hTERT), c-myc and proliferation nuclear cell antigen (PCNA) in H. pylori associated chronic gastritis. MATERIALS AND METHODS hTR was determined by in situ hybridization, hTERT, c-myc and PCNA were detected by immunohistochemistry using stomach tissues obtained from 39 H. pylori-infected and 21 H. pylori-negative patients with chronic gastritis before and after H. pylori eradication therapy or treatment for symptom relief only. RESULTS Levels of hTR, hTERT, c-myc and PCNA were significantly higher in H. pylori-infected mucosa (51.3%, 53.8%, 53.8% and 16.8 +/- 5.8, respectively) when compared to H. pylori-negative mucosa before therapy (19.0%, 23.8%, 28.6%, 8.8 +/- 3.4, respectively; P < 0.05 in all cases). In patients with successful eradication of H. pylori the levels of hTR, hTERT, c-myc and PCNA (55.5%, 59.3%, 59.3%, 16.8 +/- 5.8, respectively) were significantly reduced after the therapy (22.2%, 22.2%, 14.8%, 7.0 +/- 5.0, respectively; P < 0.05 in all cases). In the H. pylori failed eradication and H. pylori-negative groups, there was no statistical difference in all four measurements. CONCLUSIONS H. pylori infection may induce the overexpression of hTR, hTERT, c-myc and stimulate cell proliferation. Eradication of H. pylori may reverse the aberrant expression of these oncoproteins and thus correct the abnormal cell proliferation.
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Affiliation(s)
- Y Zhu
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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Mihara M, Yoshida Y, Tsukamoto T, Inada KI, Nakanishi Y, Yagi Y, Imai K, Sugimura T, Tatematsu M, Ushijima T. Methylation of multiple genes in gastric glands with intestinal metaplasia: A disorder with polyclonal origins. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:1643-51. [PMID: 17071588 PMCID: PMC1780214 DOI: 10.2353/ajpath.2006.060552] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2'-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.
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Affiliation(s)
- Mami Mihara
- Carcinogenesis Division, National Cancer Center Research Institute, Tsukiji 5-chome, Tokyo 104, Japan
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Abstract
Gastric cancer remains a global killer with a shifting burden from the developed to the developing world. The cancer develops along a multistage process that is defined by distinct histological and pathophysiological phases. Several genetic and epigenetic alterations mediate the transition from one stage to another and these include mutations in oncogenes, tumour suppressor genes and cell cycle and mismatch repair genes. The most significant advance in the fight against gastric caner came with the recognition of the role of Helicobacter pylori (H pylori) as the most important acquired aetiological agent for this cancer. Recent work has focussed on elucidating the complex host/microbial interactions that underlie the neoplastic process. There is now considerable insight into the pathogenesis of this cancer and the prospect of preventing and eradicating the disease has become a reality. Perhaps more importantly, the study of H pylori-induced gastric carcinogenesis offers a paradigm for understanding more complex human cancers. In this review, we examine the molecular and cellular events that underlie H pylori-induced gastric cancer.
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Affiliation(s)
- Malcolm-G Smith
- Department of Medicine and Therapeutics, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom
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Matysiak-Budnik T, Mégraud F. Helicobacter pylori infection and gastric cancer. Eur J Cancer 2006; 42:708-16. [PMID: 16556496 DOI: 10.1016/j.ejca.2006.01.020] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Accepted: 01/13/2006] [Indexed: 02/06/2023]
Abstract
The pathogenesis of gastric cancer (GC) includes a sequence of events that begins with Helicobacter pylori-induced chronic superficial gastritis, progressing towards atrophic gastritis, intestinal metaplasia, dysplasia and eventually GC. The association between H. pylori and GC is supported by experimental data showing a capacity of H. pylori to induce GC in animals, and the results of interventional studies showing that H. pylori eradication can lower the risk of GC and prevent development of pre-cancerous lesions in humans and in experimental animals. The "driving force" of gastric carcinogenesis is a chronic gastric inflammation, whose intensity and localisation depending on bacterial, host and environmental factors, determines the risk of GC. The mechanisms by which chronic inflammation lead to epithelial and pre-cancerous lesions include induction of oxidative stress, perturbation of the epithelial cells proliferation/apoptosis ratio, and cytokine secretion. Several molecular alterations associated with gastric carcinogenesis have also been described.
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Nardone G, Rocco A, Malfertheiner P. Review article: helicobacter pylori and molecular events in precancerous gastric lesions. Aliment Pharmacol Ther 2004; 20:261-70. [PMID: 15274662 DOI: 10.1111/j.1365-2036.2004.02075.x] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric cancer can be divided into intestinal type and diffuse type that differ substantially in epidemiology and pathogenesis. The most important aetiological factor associated both with intestinal and diffuse gastric cancer, is Helicobacter pylori. Exposure of gastric epithelial cells to H. pylori results in an inflammatory reaction with the production of reactive oxygen species and nitric oxide that, in turn, deaminates DNA causing mutations. The complex interplay between H. pylori strain, inflammation and host characteristics may directly promote diffuse type gastric cancer or induce a cascade of morphological events, i.e. atrophy, intestinal metaplasia and dysplasia, finally leading to intestinal type gastric cancer. Two mechanisms, genetic and epigenetic have been held to play a role in the molecular alterations underlying gastric carcinogenesis. The former, comprising changes in the DNA sequence, is irreversible; the latter, involving DNA methylation, is potentially reversible by eliminating the triggering agents. If H. pylori is eradicated before development of stable mutations, the risk of gastric cancer will likely be prevented. Thus, eradication of H. pylori might immediately reduce the risk of diffuse type gastric cancer, whereas prevention of intestinal type gastric cancer may be less effective if patients are treated later in the evolution of the carcinogenic process.
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Affiliation(s)
- G Nardone
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, Federico II University, Naples, Italy.
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Kuniyasu H, Kitadai Y, Mieno H, Yasui W. Helicobactor pylori infection is closely associated with telomere reduction in gastric mucosa. Oncology 2004; 65:275-82. [PMID: 14657602 DOI: 10.1159/000074481] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To investigate differential reduction in telomere DNA in tissue components of gastric mucosa with respect to Helicobactor pylori infection. MATERIALS AND METHODS The telomere content was examined by fluorescent in situ hybridization with the (TTAGGG)(4) probe. To compare the signal intensities from the probe (telomere volume) with telomere length, five gastric carcinoma cell lines were used. Telomere volumes were examined in 9 healthy persons, 124 non-cancer patients, and 86 gastric cancer patients. RESULTS Telomere volume showed a linear correlation with telomere length measured by Southern blotting in gastric carcinoma cells. In healthy persons without H. pylori infection, the telomere volumes of gastric epithelial tissues were 70-79% that of intramucosal lymphocytes (internal control). In 124 patients without gastric cancer, telomere volume of H.-PYLORI-infected mucosa was significantly less than that of H.-pylori-negative mucosa in both metaplastic and non- metaplastic tissues (p < 0.0001). In 86 gastric cancer patients, telomere volumes in intestinal metaplasia adjacent to cancer were 75% that of intestinal metaplasia of non-cancer patients (p = 0.0001). hTERT expression was detected in 6 cancer-associated and 2 cancer-negative intestinal metaplasia specimens, in which telomere volume was markedly reduced. CONCLUSION H. pylori infection is closely associated with telomere reduction in gastric epithelium.
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Affiliation(s)
- Hiroki Kuniyasu
- Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan.
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Wang KX, Wang XF, Peng JL, Cui YB, Wang J, Li CP. Detection of serum anti- Helicobacter pylori immunoglobulin G in patients with different digestive malignant tumors. World J Gastroenterol 2003; 9:2501-4. [PMID: 14606084 PMCID: PMC4656528 DOI: 10.3748/wjg.v9.i11.2501] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the seroprevalence of Helicobacter pylori infection in patients with different digestive malignant tumors.
METHODS: Enzyme linked immunosorbent assay (ELISA) was used to detect serum anti-Helicobacter pylori IgG antibody in 374 patients with different digestive malignant tumors and 310 healthy subjects (normal control group).
RESULTS: The seroprevalence of Helicobacter pylori infection was 61.50% (230/374) and 46.77% (145/310), respectively, in patients with digestive tumors and normal controls (P < 0.05). The seroprevalence was 52.38% (33/63), 86.60% (84/97), 83.14% (84/101), 45.24 (19/42), 51.13% (18/35) and 44.44% (16/36), respectively in patients with carcinomas of esophagus, stomach, duodenum, rectum, colon and liver (P < 0.01). In patients with intestinal and diffuse type gastric cancers, the seroprevalence was 93.75% (60/64) and 72.73% (24/33), respectively (P < 0.05). In patients with gastric antral and cardiac cancers, the seroprevalence was 96.43% (54/56) and 73.17% (30/41), respectively (P < 0.05). In patients with ulcerous and proliferous type duodenal cancers, the seroprevalence of H. pylori infection was 91.04% (61/67) and 52.27% (23/44), respectively (P < 0.05). In patients with duodenal bulb and descending cancers, the seroprevalence was 94.20% (65/69) and 45.20% (19/42), respectively (P < 0.05).
CONCLUSION: H. pylori infection is associated with occurrence and development of gastric and duodenal carcinomas. Furthermore, it is also associated with histological type and locations of gastric and duodenal carcinomas.
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Affiliation(s)
- Ke-Xia Wang
- School of Medicine, Anhui University of Science and Technology, Huainan, 232001, Anhui Province, China
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16
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Abstract
Gastric cancer is one of the world's most common cancers. Its carcinogenic pathway is mainly associated with Helicobacter pylori infection, subsequent inflammation and tissue regeneration. During the regeneration process, cells deviate from the normal pathway of gastric differentiation to an 'intestinal phenotype', which is thought to be precancerous and associated with the intestinal type of gastric cancer. Inappropriate activation of intestine-specific transcription factors could contribute to the occurrence of the intestinal-type cancer of the stomach.
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Affiliation(s)
- Yasuhito Yuasa
- Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
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18
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Unger Z, Molnár B, Prónai L, Szaleczky E, Zágoni T, Tulassay Z. Mutant p53 expression and apoptotic activity of Helicobacter pylori positive and negative gastritis in correlation with the presence of intestinal metaplasia. Eur J Gastroenterol Hepatol 2003; 15:389-93. [PMID: 12655259 DOI: 10.1097/00042737-200304000-00009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Mutation of the p53 gene is detectable in most cases of gastric cancer, as it is the most common genetic alteration in human malignancies. It is also well documented that Helicobacter pylori infection plays an important role in gastric carcinogenesis. There is still no clarification, however, concerning how genetic instability influences the homeostasis of gastric epithelium. We have studied the effect of H. pylori infection on apoptosis of the antral epithelium in the presence/absence of intestinal metaplasia and the expression of the p53 oncoprotein. The relationship between these two processes is analysed. METHODS Antral biopsies were taken from 36 patients who underwent routine upper endoscopy (17 men, 19 women, mean age 61.0 years). The biopsies were fixed in formalin and embedded in paraffin. Patients were classified into two histological groups: (1) as chronic gastritis without intestinal metaplasia (n = 19), and (2) chronic gastritis with intestinal metaplasia (n = 17). An immunohistochemical method was used to detect the expression of p53 oncoprotein, and the terminal transferase mediated dUTP nick end-labelling (TUNEL) method was used to detect apoptotic cells. RESULTS In the absence of intestinal metaplasia, both the apoptotic index (0.0272 +/- 0.011 vs 0.0128 +/- 0.006) and expresssion of p53 (35.55 +/- 31.16 vs 18.33 +/- 19.65) were significantly higher in H. pylori positive cases compared to H. pylori negative cases. In the presence of intestinal metaplasia, p53 expression was further increased (P < 0.05), but apoptosis was similar to that observed in H. pylori negative gastritis without intestinal metaplasia. In the presence of intestinal metaplasia, H. pylori infection did not influence apoptosis (0.013 +/- 0.004 vs 0.011 +/- 0.004), or p53 ratio (70.16 +/- 22.54 vs 68.50 +/- 28.96). In the sequence of gastritis-intestinal metaplasia the two indices show a close negative correlation (P < 0.05). CONCLUSION In the absence of intestinal metaplasia H. pylori infection increases both apoptotic activity and expression of p53 oncoprotein in the gastric mucosa. The lack of increased apoptosis with a higher p53 expression in the presence of intestinal metaplasia suggests an increased genetic instability and also may suggest that mutation of the p53 gene is an early step in the multistep process of gastric carcinogenesis.
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Affiliation(s)
- Zsuzsa Unger
- Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, 1088 Budapest, Szentkirályi út 46, Hungary.
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Lan J, Xiong YY, Lin YX, Wang BC, Gong LL, Xu HS, Guo GS. Helicobacter pylori infection generated gastric cancer through p53-Rb tumor-suppressor system mutation and telomerase reactivation. World J Gastroenterol 2003; 9:54-8. [PMID: 12508351 PMCID: PMC4728249 DOI: 10.3748/wjg.v9.i1.54] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2002] [Revised: 03/23/2002] [Accepted: 04/20/2002] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between Helicobacter pylori (H.pylori) infection and the expressions of the p53, Rb, c-myc, bcl-2 and hTERT mRNA in a series of diseases from chronic gastritis (CG), intestinal metaplasia type I or II(IMI-II), intestinal metaplasia type III (IMIII), mild or modest dysplasia (DysI-II), severe dysplasia (DysIII) to gastric cancer(GC) and to elucidate the mechanism of gastric carcinogenesis relating to H.pylori infection. METHODS 272 cases between 1998 and 2001 were available for the study including 42 cases of CG, 46 cases of IMI-II, 25 cases of IMIII, 48 cases of DysI-II, 27 cases of DysIII, 84 cases of GC. H.pylori infection and the expressions of p53, Rb, c-myc, bcl-2 were detected by means of streptavidin-peroxidase (SP) immunohistochemical method. HTERT mRNA was detected by in situ hybridization (ISH). RESULTS The expressions of p53, Rb, c-myc, hTERT mRNA and bcl-2 were higher in the GC than in CG, IM, Dys. The expression of c-myc was higher in IMIII with H.pylori infection (10/16) than that without infection (1/9) and the positive rate in DysI-II and DysIII with H.pylori infection was 18/30 and 13/17, respectively, higher than that without infection (4/18 and 3/10, respectively). In our experiment mutated p53 had no association with H.pylori infection, the expression of Rb was associated with H.pylori infection in GC, but the p53-Rb tumor-suppressor system abnormal in DysI-II cases, DysIII and GC cases with H.pylori infection was 21/30, 15/17 and 48/48 respectively, higher than non-infection groups (4/18, 3/10, 28/36). Furthermore the level of hTERT mRNA in GC with H.pylori infection (47/48) was higher than that without infection (30/36), however the relationship between bcl-2 and H.pylori was only in IMIII. C-myc had a close association with hTERT mRNA in DysIII and GC (P=0.0 253,0.0 305 respectively). CONCLUSION In the gastric carcinogenesis, H.pylori might cause the severe imbalance of proliferation and apoptosis in the precancerous lesions (IMIII and GysIII) first, leading to p53-Rb tumor-suppressor system mutation and telomerase reactivation, and finally causes gastric cancer.
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Affiliation(s)
- Jing Lan
- Department of Pathology, Zhongnan Hospital, Wuhan University,Wuhan city 430071, Hubei Province, China.
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20
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Abstract
The RUNX family of transcription factors plays pivotal roles during normal development and in neoplasias. Recent data involve RUNX3 as an important tumor suppressor in gastric cancers and pose interesting questions about how perturbed levels and interspecific competition among RUNX family members may contribute to tumorigenesis.
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Affiliation(s)
- Anders H Lund
- Division of Molecular Genetics, The Netherlands Cancer Institute, Antoni van Leeuwenhoek ziekenhuis, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
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21
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Lancaster CRD, Simon J. Succinate:quinone oxidoreductases from epsilon-proteobacteria. BIOCHIMICA ET BIOPHYSICA ACTA 2002; 1553:84-101. [PMID: 11803019 DOI: 10.1016/s0005-2728(01)00230-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The epsilon-proteobacteria form a subdivision of the Proteobacteria including the genera Wolinella, Campylobacter, Helicobacter, Sulfurospirillum, Arcobacter and Dehalospirillum. The majority of these bacteria are oxidase-positive microaerophiles indicating an electron transport chain with molecular oxygen as terminal electron acceptor. However, numerous members of the epsilon-proteobacteria also grow in the absence of oxygen. The common presence of menaquinone and fumarate reduction activity suggests anaerobic fumarate respiration which was demonstrated for the rumen bacterium Wolinella succinogenes as well as for Sulfurospirillum deleyianum, Campylobacter fetus, Campylobacter rectus and Dehalospirillum multivorans. To date, complete genome sequences of Helicobacter pylori and Campylobacter jejuni are available. These bacteria and W. succinogenes contain the genes frdC, A and B encoding highly similar heterotrimeric enzyme complexes belonging to the family of succinate:quinone oxidoreductases. The crystal structure of the W. succinogenes quinol:fumarate reductase complex (FrdCAB) was solved recently, thus providing a model of succinate:quinone oxidoreductases from epsilon-proteobacteria. Succinate:quinone oxidoreductases are being discussed as possible therapeutic targets in the treatment of several pathogenic epsilon-proteobacteria.
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Affiliation(s)
- C Roy D Lancaster
- Max Planck Institute of Biophysics, Department of Molecular Membrane Biology, Frankfurt am Main, Germany.
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22
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Radisky D, Hagios C, Bissell MJ. Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol 2001; 11:87-95. [PMID: 11322828 DOI: 10.1006/scbi.2000.0360] [Citation(s) in RCA: 120] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Many cancer investigations have focussed on the eradication of the cancer cell itself and in doing so, overlook the inherent complexity and heterogeneity of solid tumors. Here, we argue that, in many cases, it is the altered communication within the tumor, rather than mutations per se, that is the defining characteristic of cancer. As a result, tumorigenesis can be indirectly initiated by environmental or inherited factors that affect the stromal cells. We propose that anticancer research might be more effective if aimed at eradicating the cause of abnormality rather than just treating the end result.
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Affiliation(s)
- D Radisky
- Life Science Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA
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23
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Abstract
Carcinoma of the stomach is one of the most prevalent cancer types in the world today. Two major forms of gastric cancer are distinguished according to their morphological and clinicopathological classifications (well differentiated/intestinal type and poorly differentiated/diffuse type), characteristics that could also be attributed to the altered expression of different types of oncogenes or tumor suppressor genes. Significant differences exist for gastric cancer incidence comparing people of different ethnic origins, implicating various genetic and epigenetic factors for gastric oncogenesis. There are only a limited number of molecular markers available for gastric cancer detection and prognostic evaluation, among which are tyrosine kinases. There is convincing evidence that tyrosine kinases are involved in oncogenesis and disease progression for many human cancers. Amplifications of certain tyrosine kinases (c-met, k-sam and erbB2/neu) have been associated with human gastric cancer progression. Alternatively spliced transcripts and enhanced protein-expression levels for some of these tyrosine kinases are correlated with clinical outcomes for gastric cancer patients. With advent of high throughput techniques, it is now possible to detect nearly all expressed tyrosine kinases in a single screen. This increases the chance to identify additional tyrosine kinases as predictive markers for gastric cancers. In this article, we will first review the literature data concerning certain tyrosine kinases implicated in gastric carcinogenesis and then summarize more recent work which provide comprehensive tyrosine kinase profiles for gastric cancer specimens and cell lines. Two new gastric cancer molecular markers (tie-1 and mkk4) have been identified through the use of these profiles and demonstrated effective as clinical prognostic indicators.
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Affiliation(s)
- W Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China
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