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Gebrehiwot NT, Liu Y, Li J, Liu HM. Molecular Alterations in Gastric Intestinal Metaplasia Shed Light on Alteration of Methionine Metabolism: Insight into New Diagnostic and Treatment Approaches. Biomedicines 2025; 13:964. [PMID: 40299656 PMCID: PMC12025106 DOI: 10.3390/biomedicines13040964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/01/2025] Open
Abstract
Gastric intestinal metaplasia (GIM) is a precancerous lesion and the key risk factor in the development of gastric cancer (GC), but early detection and treatment remain challenging. The traditional endoscopic diagnosis of metaplastic lesions is complicated by an increased rate of inappropriateness and false negativity. Although early interventions with H. pylori eradication, as well as endoscopic therapy results, were promising, there is still a significant unmet need to control GIM progression and recurrences. Molecular alterations, such as an increased DNA methylation index, have been identified as a crucial factor in the downregulation of tumor suppressor genes, such as the caudal-type homeobox (CDX2) gene, which regulates epithelial cell proliferation and GIM progression and is associated with treatment failure. CDX2 is downregulated by promoter hypermethylation in the colonic-type epithelium, in which the methylation was correlated with reduced intake of dietary folate sources. Tumor cells alter to dietary methionine sources in the biosynthesis of S-Adenosylmethionine, a universal methyl donor for transmethylation, under the conditions of limited folate and B12 availability. The gut microbiota also exhibited a shift in microbial composition, which could influence the host's dietary methionine metabolism. Meanwhile, activated oncogenic signaling via the PI3K/Akt/mTORC1/c-MYC pathway could promotes rewiring dietary methionine and cellular proliferation. Tumor methionine dependence is a metabolic phenotype that could be helpful in predictive screening of tumorigenesis and as a target for preventive therapy to enhance precision oncology. This review aimed to discuss the molecular alterations in GIM to shed light on the alteration of methionine metabolism, with insight into new diagnostic and treatment approaches and future research directions.
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Affiliation(s)
- Nigatu Tadesse Gebrehiwot
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
| | - Juan Li
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, China;
- Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Ministry of Education, Zhengzhou 450001, China
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Lee CM. A Review on the Antimutagenic and Anticancer Effects of Cysteamine. Adv Pharmacol Pharm Sci 2023; 2023:2419444. [PMID: 37731680 PMCID: PMC10508993 DOI: 10.1155/2023/2419444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 08/03/2023] [Accepted: 08/17/2023] [Indexed: 09/22/2023] Open
Abstract
Cancer is one of the leading causes of death worldwide. First-line treatments usually include surgery, radiotherapy, and/or systemic therapy. These methods can be associated with serious adverse events and can be toxic to healthy cells. Despite the new advances in cancer therapies, there is still a continuous need for safe and effective therapeutic agents. Cysteamine is an aminothiol endogenously synthetized by human cells during the degradation of coenzyme-A. It has been safely used in humans for the treatment of several pathologies including cystinosis and neurodegenerative diseases. Cysteamine has been shown to be a potent antimutagenic, anticarcinogenic, and antimelanoma in various in vitro and in vivo studies, but a review on these aspects of cysteamine's use in medicine is lacking in the current literature. The efficacy of cysteamine has been shown in vitro and in vivo for the treatment of different types of cancer, such as gastrointestinal cancer, pancreatic cancer, sarcomas, hepatocellular carcinoma, and melanoma, leading to the significant reduction of lesions and/or the increase of survival time. Although the mechanisms of action are not fully understood, possible explanations are (i) free radical scavenging, (ii) alteration of the tumor cell proliferation by affecting nucleic acid and protein synthesis or inhibition of DNA synthesis, and (iii) hormone regulation. In conclusion, regarding the high safety profile of cysteamine and the current literature data presented in this article, cysteamine might be considered as an interesting molecule for the prevention and the treatment of cancer. Further clinical studies should be performed to support these data in humans.
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Affiliation(s)
- Chun-Man Lee
- Frimley Health NHS Foundation Trust, Portsmouth Road, Frimley, Camberley GU16 7UJ, UK
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Li G, Kelly DR, Mroczek-Musulman E, Wang K, Council L, Zhao L. Gastric Antral Mucosal Changes in Children With Intestinal Metaplasia. Pediatr Dev Pathol 2022; 25:511-517. [PMID: 35510382 DOI: 10.1177/10935266221096939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Objectives: The gastric mucosal change accompanying gastric antral intestinal metaplasia (IM) in the pediatric population and its clinical implications remain unclear. Methods: We retrieved all patients younger than 18 years who had upper GI endoscopy with a pathology diagnosis of antral IM between 2009 and 2020. Each biopsy was evaluated for the presence of dysplasia, Helicobacter pylori, gastritis, and other pathologic changes. Results: A total of 134 patients with antral IM were identified; 72 (53.7%) with coexisting pathology including chronic gastritis (n = 22), reactive gastropathy (n = 16), focal mild chronic inflammation (n = 13), gastric eosinophilia (n = 9), chronic active gastritis associated with (n = 2) and without Helicobacter infection (n = 3), and others (n = 7). The remaining 62 (46.3%) showed isolated IM. Gastric IM increased with age, and was often accompanied by other pathologic changes, especially in female children. Twenty-seven patients had follow up biopsies; 11 of the 27 patients (40.7%) showed persistent IM in at least one repeat biopsies. None demonstrated dysplasia. Conclusions: In children, antral IM increases with age and often coexists with other pathologic changes. Gastric IM could persist for at least months to years in a significant subset of patients with chronic gastritis and gastric eosinophilia.
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Affiliation(s)
- Geling Li
- Department of Pathology and Laboratory Medicine, 22078Children's of Alabama, Birmingham, AL, USA.,Department of Pathology, 9968University of Alabama at Birmingham, Birmingham, AL, USA
| | - David R Kelly
- Department of Pathology and Laboratory Medicine, 22078Children's of Alabama, Birmingham, AL, USA.,Department of Pathology, 9968University of Alabama at Birmingham, Birmingham, AL, USA
| | - Elizabeth Mroczek-Musulman
- Department of Pathology and Laboratory Medicine, 22078Children's of Alabama, Birmingham, AL, USA.,Department of Pathology, 9968University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kai Wang
- Department of Pathology, 9968University of Alabama at Birmingham, Birmingham, AL, USA
| | - Leona Council
- Department of Pathology, 9968University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lei Zhao
- Department of Pathology, Harvard Medical School, 1861Brigham and Women's Hospital, Boston, MA, USA
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Li H, Wu Q, Li T, Liu C, Xue L, Ding J, Shi Y, Fan D. The miR-17-92 cluster as a potential biomarker for the early diagnosis of gastric cancer: evidence and literature review. Oncotarget 2018; 8:45060-45071. [PMID: 28178677 PMCID: PMC5542167 DOI: 10.18632/oncotarget.15023] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 01/19/2017] [Indexed: 12/20/2022] Open
Abstract
Purpose Intestinal metaplasia is considered to be a pre-cancerous lesion of gastric cancer. The miR-17-92 cluster was previously reported to have clinical value in the prediction of cancer development. This study aimed to test the diagnostic value of miR-17-92 in gastric cancer and the intestinal metaplasia patients compared with the normal ones. Results The results showed that miR-17-92 members were over-expressed in the serum of both gastric cancer and intestinal metaplasia patients, compared with healthy controls. Serum miR-17-92 members could also distinguish patients with gastric cancer and intestinal metaplasia from healthy controls. Materials and Methods Serum miR-17-92 expression levels were detected using quantitative real-time PCR in 75 patients with gastric cancer, 104 patients with intestinal metaplasia and 38 healthy controls. The Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were then analyzed to test the efficacy of the miR-17-92 members in distinguishing gastric cancer, intestinal metaplasia and healthy controls. Conclusions In conclusion, the miR-17-92 cluster might be useful as a potential serum biomarker for the early detection of gastric cancer.
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Affiliation(s)
- Hong Li
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Qiong Wu
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ting Li
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Changhao Liu
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Lin Xue
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jie Ding
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yongquan Shi
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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Gomez JM, Patrie JT, Bleibel W, Frye JW, Sauer BG, Shami VM, Stelow EB, Moskaluk CA, Wang AY. Gastric intestinal metaplasia is associated with gastric dysplasia but is inversely correlated with esophageal dysplasia. World J Gastrointest Endosc 2017; 9:61-69. [PMID: 28250898 PMCID: PMC5311474 DOI: 10.4253/wjge.v9.i2.61] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/19/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine which clinical factors might be associated with gastric intestinal metaplasia (IM) in a North American population.
METHODS Pathology and endoscopy databases at an academic medical center were reviewed to identify patients with and without gastric IM on biopsies for a retrospective cohort study. Patient demographics, insurance status, and other clinical factors were reviewed.
RESULTS Four hundred and sixty-eight patients with gastric IM (mean age: 61.0 years ± 14.4 years, 55.5% female) and 171 without gastric IM (mean age: 48.8 years ± 20.8 years, 55.0% female) were compared. The endoscopic appearance of atrophic gastritis correlated with finding gastric IM on histopathology (OR = 2.05, P = 0.051). Gastric IM was associated with histologic findings of chronic gastritis (OR = 2.56, P < 0.001), gastric ulcer (OR = 6.97, P = 0.015), gastric dysplasia (OR = 6.11, P = 0.038), and gastric cancer (OR = 6.53, P = 0.027). Histologic findings of Barrett’s esophagus (OR = 0.28, P = 0.003) and esophageal dysplasia (OR = 0.11, P = 0.014) were inversely associated with gastric IM. Tobacco use (OR = 1.73, P = 0.005) was associated with gastric IM.
CONCLUSION Patients who smoke or have the endoscopic finding of atrophic gastritis are more likely to have gastric IM and should have screening gastric biopsies during esophagogastroduodenoscopy (EGD). Patients with gastric IM are at increased risk for having gastric dysplasia and cancer, and surveillance EGD with gastric biopsies in these patients might be reasonable.
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Sakamoto H, Asahara T, Chonan O, Yuki N, Mutoh H, Hayashi S, Yamamoto H, Sugano K. Comparative analysis of gastrointestinal microbiota between normal and caudal-related homeobox 2 (cdx2) transgenic mice. Intest Res 2015; 13:39-49. [PMID: 25691842 PMCID: PMC4316220 DOI: 10.5217/ir.2015.13.1.39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 10/29/2014] [Accepted: 11/05/2014] [Indexed: 12/27/2022] Open
Abstract
Background/Aims Caudal-related homeobox 2 (Cdx2) is expressed in the human intestinal metaplastic mucosa and induces intestinal metaplastic mucosa in the Cdx2 transgenic mouse stomach. Atrophic gastritis and intestinal metaplasia commonly lead to gastric achlorhydria, which predisposes the stomach to bacterial overgrowth. In the present study, we determined the differences in gut microbiota between normal and Cdx2 transgenic mice, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Methods Twelve normal (control) and 12 Cdx2 transgenic mice were sacrificed, and the gastric, jejunal, ileac, cecal and colonic mucosa, and feces were collected. To quantitate bacterial microbiota, we used real-time qRTPCR with 16S rRNA gene-targeted, species-specific primers. Results The total numbers of bacteria in the gastric, jejunal, ileac, cecal, and colonic mucosa of the Cdx2 transgenic mice were significantly higher than those of the normal mice. The Bacteroides fragilis group and also Prevotella were not detected in the stomach of the normal mice, although they were detected in the Cdx2 transgenic mice. Moreover, the Clostridium coccoides group, Clostridium leptum subgroup, Bacteroides fragilis group, and Prevotella were not detected in the jejunum or ileum of the normal mice, although they were detected in the Cdx2 transgenic mice. The fecal microbiota of the normal mice was similar to that of the Cdx2 transgenic mice. Conclusions Our results showed the differences in composition of gut microbiota between normal and Cdx2 transgenic mice, which may be caused by the development of gastric achlorhydria and intestinal metaplasia in Cdx2 transgenic mice.
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Affiliation(s)
- Hirotsugu Sakamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Takashi Asahara
- Yakult Honsha Co., Ltd., Yakult Central Institute, Kunitachi, Japan
| | - Osamu Chonan
- Yakult Honsha Co., Ltd., Yakult Central Institute, Kunitachi, Japan
| | - Norikatsu Yuki
- Yakult Honsha Co., Ltd., Yakult Central Institute, Kunitachi, Japan
| | - Hiroyuki Mutoh
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Shunji Hayashi
- Department of Microbiology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hironori Yamamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Kentaro Sugano
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
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Gomez JM, Wang AY. Gastric intestinal metaplasia and early gastric cancer in the west: a changing paradigm. Gastroenterol Hepatol (N Y) 2014; 10:369-378. [PMID: 25013389 PMCID: PMC4080873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Gastric cancer remains the fifth leading cancer diagnosis worldwide, and it is the third leading cause of cancer-related mortality. The incidence of gastric cancer within the United States, however, has remained substantially lower than elsewhere, which has led to a lack of screening and surveillance in clinical practice. Patients with known premalignant lesions, such as gastric intestinal metaplasia, which can increase the risk of gastric cancer by as much as 6-fold, might benefit from surveillance guidelines to detect gastric cancer at an earlier, potentially curative stage. Chro-moendoscopy with optical magnification, narrow-band imaging, and other image-enhanced endoscopic techniques are commercially available to assist in the diagnosis of premalignant gastric lesions and early gastric cancer. Furthermore, endoscopic mucosal resection and endoscopic submucosal dissection have become more widely available and offer potentially curative endoscopic resection for dysplastic lesions of the stomach and early gastric cancers, which is an alternative to traditional surgical resection.
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Affiliation(s)
- Justin M Gomez
- Dr Gomez is a clinical instructor in the Department of Medicine and Dr Wang is an associate professor of medicine in the Division of Gastroenterology and Hepatology at the University of Virginia in Charlottesville, Virginia
| | - Andrew Y Wang
- Dr Gomez is a clinical instructor in the Department of Medicine and Dr Wang is an associate professor of medicine in the Division of Gastroenterology and Hepatology at the University of Virginia in Charlottesville, Virginia
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Rossi AFT, Duarte MC, Poltronieri AB, Valsechi MC, Jorge YC, de-Santi Neto D, Rahal P, Oliani SM, Silva AE. Deregulation of annexin-A1 and galectin-1 expression in precancerous gastric lesions: intestinal metaplasia and gastric ulcer. Mediators Inflamm 2014; 2014:478138. [PMID: 24719523 PMCID: PMC3955591 DOI: 10.1155/2014/478138] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 01/15/2014] [Accepted: 01/15/2014] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Annexin-A1 (ANXA1/AnxA1) and galectin-1 (LGALS1/Gal-1) are mediators that play an important role in the inflammatory response and are also associated with carcinogenesis. We investigated mRNA and protein expression in precancerous gastric lesions that participate in the progression cascade to gastric cancer, such as intestinal metaplasia (IM) and gastric ulcer (GU). METHODS Quantitative real-time PCR (qPCR) and immunohistochemical techniques were used to analyze the relative quantification levels (RQ) of ANXA1 and LGALS1 mRNA and protein expression, respectively. RESULTS Increased relative expression levels of ANXA1 were found in 100% of cases, both in IM (mean RQ = 6.22 ± 0.06) and in GU (mean RQ = 6.69 ± 0.10). However, the LGALS1 presented basal expression in both groups (IM: mean RQ = 0.35 ± 0.07; GU: mean RQ = 0.69 ± 0.09). Immunohistochemistry revealed significant positive staining for both the AnxA1 and Gal-1 proteins in the epithelial nucleus and cytoplasm as well as in the stroma of the IM and GU groups (P < 0.05) but absence or low immunorectivity in normal mucosa. CONCLUSION Our results bring an important contribution by evidencing that both the AnxA1 and Gal-1 anti-inflammatory proteins are deregulated in precancerous gastric lesions, suggesting their involvement in the early stages of gastric carcinogenesis, possibly due to an inflammatory process in the gastric mucosa.
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Affiliation(s)
- Ana Flávia Teixeira Rossi
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Márcia Cristina Duarte
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Ayla Blanco Poltronieri
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Marina Curado Valsechi
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Yvana Cristina Jorge
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Dalísio de-Santi Neto
- Legal Medicine Department and Pathology Service, Hospital de Base, Avenida Brigadeiro Faria Lima 5544, 15090-000 São José do Rio Preto, SP, Brazil
| | - Paula Rahal
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Sonia Maria Oliani
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
| | - Ana Elizabete Silva
- Department of Biology, São Paulo State University (UNESP), Câmpus São José do Rio Preto, Rua Cristóvão Colombo 2265, 15054-000 São José do Rio Preto, SP, Brazil
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