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1
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Kamarehei F, Saidijam M, Taherkhani A. Prognostic biomarkers and molecular pathways mediating Helicobacter pylori–induced gastric cancer: a network-biology approach. Genomics Inform 2023; 21:e8. [PMID: 37037466 PMCID: PMC10085735 DOI: 10.5808/gi.22072] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/02/2023] [Indexed: 04/03/2023] Open
Abstract
Cancer of the stomach is the second most frequent cancer-related death worldwide. The survival rate of patients with gastric cancer (GC) remains fragile. There is a requirement to discover biomarkers for prognosis approaches. Helicobacter pylori in the stomach is closely associated with the progression of GC. We identified the genes associated with poor/favorable prognosis in H. pylori–induced GC. Multivariate statistical analysis was applied on the Gene Expression Omnibus (GEO) dataset GSE54397 to identify differentially expressed miRNAs (DEMs) in gastric tissues with H. pylori–induced cancer compared with the H. pylori–positive with non-cancerous tissue. A protein interaction map (PIM) was built and subjected to DEMs targets. The enriched pathways and biological processes within the PIM were identified based on substantial clusters. Thereafter, the most critical genes in the PIM were illustrated, and their prognostic impact in GC was investigated. Considering p-value less than 0.01 and |Log2 fold change| as >1, five microRNAs demonstrated significant changes among the two groups. Gene functional analysis revealed that the ubiquitination system, neddylation pathway, and ciliary process are primarily involved in H. pylori–induced GC. Survival analysis illustrated that the overexpression of DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, and TXNIP was associated with poor prognosis, while increased MRPS5 expression was related to a favorable prognosis in GC patients. DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, TXNIP, and MRPS5 may be considered prognostic biomarkers for H. pylori–induced GC. However, experimental validation is necessary in the future.
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Affiliation(s)
- Farideh Kamarehei
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838678, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan 6517838678, Iran
| | - Amir Taherkhani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan 6517838678, Iran
- Corresponding author E-mail:
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2
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Hoffmann W. Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor. Int J Mol Sci 2022; 23:ijms23105377. [PMID: 35628183 PMCID: PMC9141172 DOI: 10.3390/ijms23105377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022] Open
Abstract
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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3
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Shi Y, Huang X, Du Z, Tan J. Analysis of single-cell RNA-sequencing data identifies a hypoxic tumor subpopulation associated with poor prognosis in triple-negative breast cancer. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:5793-5812. [PMID: 35603379 DOI: 10.3934/mbe.2022271] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of mammary carcinoma characterized by low expression levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Along with the rapid development of the single-cell RNA-sequencing (scRNA-seq) technology, the heterogeneity within the tumor microenvironment (TME) could be studied at a higher resolution level, facilitating an exploration of the mechanisms leading to poor prognosis during tumor progression. In previous studies, hypoxia was considered as an intrinsic characteristic of TME in solid tumors, which would activate downstream signaling pathways associated with angiogenesis and metastasis. Moreover, hypoxia-related genes (HRGs) based risk score models demonstrated nice performance in predicting the prognosis of TNBC patients. However, it is essential to further investigate the heterogeneity within hypoxic TME, such as intercellular communications. In the present study, utilizing single-sample Gene Set Enrichment Analysis (ssGSEA) and cell-cell communication analysis on the scRNA-seq data retrieved from Gene Expression Omnibus (GEO) database with accession number GSM4476488, we identified four tumor subpopulations with diverse functions, particularly a hypoxia-related one. Furthermore, results of cell-cell communication analysis revealed the dominant role of the hypoxic tumor subpopulation in angiogenesis- and metastasis-related signaling pathways as a signal sender. Consequently, regard the TNBC cohorts acquired from The Cancer Genome Atlas (TCGA) and GEO as train set and test set respectively, we constructed a risk score model with reliable capacity for the prediction of overall survival (OS), where ARTN and L1CAM were identified as risk factors promoting angiogenesis and metastasis of tumors. The expression of ARTN and L1CAM were further analyzed through tumor immune estimation resource (TIMER) platform. In conclusion, these two marker genes of the hypoxic tumor subpopulation played vital roles in tumor development, indicating poor prognosis in TNBC patients.
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Affiliation(s)
- Yi Shi
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Xiaoqian Huang
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Zhaolan Du
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Jianjun Tan
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
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4
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Uehara K, Koyanagi-Aoi M, Koide T, Itoh T, Aoi T. Epithelial-derived factors induce muscularis mucosa of human induced pluripotent stem cell-derived gastric organoids. Stem Cell Reports 2022; 17:820-834. [PMID: 35245440 PMCID: PMC9023774 DOI: 10.1016/j.stemcr.2022.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 12/26/2022] Open
Abstract
Human gastric development has not been well studied. The generation of human pluripotent stem cell-derived gastric organoids (hGOs) comprising gastric marker-expressing epithelium without an apparent smooth muscle (SM) structure has been reported. We modified previously reported protocols to generate hGOs with muscularis mucosa (MM) from hiPSCs. Time course analyses revealed that epithelium development occurred prior to MM formation. Sonic hedgehog (SHH) and TGF-β1 were secreted by the epithelium. HH and TGF-β signal inhibition prevented subepithelial MM formation. A mechanical property of the substrate promoted SM differentiation around hGOs in the presence of TGF-β. TGF-β signaling was shown to influence the HH signaling and mechanical properties. In addition, clinical specimen findings suggested the involvement of TGF-β signaling in MM formation in recovering gastric ulcers. HH and TGF-β signaling from the epithelium to the stroma and the mechanical properties of the subepithelial environment may influence the emergence of MM in human stomach tissue.
We successfully induce hGOs with MM by culturing for 8 weeks The emergence of MM occurs after epithelial maturation HH, TGF-β, and the mechanical environment are suggested to be involved in MM formation
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Affiliation(s)
- Keiichiro Uehara
- Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe 6500017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan; Department of Diagnostic Pathology, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan
| | - Michiyo Koyanagi-Aoi
- Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe 6500017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe 6500017, Japan
| | - Takahiro Koide
- Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe 6500017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan; Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan
| | - Tomoo Itoh
- Department of Diagnostic Pathology, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan
| | - Takashi Aoi
- Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe 6500017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe 6500017, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe 6500017, Japan.
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5
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Flores AR, Castro M, Rêma A, Mesquita JR, Taulescu M, Gärtner F, Seixas F, Amorim I. Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues. Animals (Basel) 2021; 11:2855. [PMID: 34679875 PMCID: PMC8532865 DOI: 10.3390/ani11102855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 12/25/2022] Open
Abstract
TFF1 expression is markedly reduced in human GCs, suggesting that TFF1 is a tumor suppressor for human gastric cancer. The present study evaluated the expression and distribution pattern of TFF1 in paraffin-embedded canine gastric tissue samples, including normal mucosa (n = 3), polyps (n = 8), carcinomas (n = 31) and their adjacent non-neoplastic mucosa (n = 30), neoplastic emboli (n = 14), and metastatic lesions (n = 9), by immunohistochemistry (IHC). All normal gastric tissues expressed TFF1 in the superficial foveolar epithelium and mucopeptic cells of the neck region. Most gastric polyps (GPs) displayed immunoreactivity for TFF1 in >75% of the epithelial component. In GCs, the expression of TFF1 was found reduced in 74.2% of the cases. The level of TFF1 expression had a decreased tendency from normal gastric mucosa to GPs and GCs (p < 0.05). No significant differences in the expression of TFF1 were found in GCs, according to age, sex, histological type based on World Health Organization (WHO) and Lauren classification, tumor location, depth of tumor invasion, presence of neoplastic emboli or metastatic lesions. The median survival time of GC patients with preserved and reduced TFF1 immunoexpression were 30 and 12 days, respectively. Kaplan-Meier analysis revealed no significant survival differences between the two groups (p > 0.05). These findings suggest that TFF1 protein may play a role in canine gastric carcinogenesis, and further studies are necessary to define its usefulness as a prognostic indicator in canine gastric carcinoma.
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Affiliation(s)
- Ana R. Flores
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; (A.R.F.); (M.C.); (A.R.); (F.G.); (I.A.)
- Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal
- Animal and Veterinary Research Center (CECAV), Associate Laboratory AL4AnimalS, University of Trás-os-Montes e Alto Douro (UTAD), 5001-801 Vila Real, Portugal;
| | - Marisa Castro
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; (A.R.F.); (M.C.); (A.R.); (F.G.); (I.A.)
| | - Alexandra Rêma
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; (A.R.F.); (M.C.); (A.R.); (F.G.); (I.A.)
| | - João R. Mesquita
- Epidemiology Research Unit (EPIUnit), Instituto de Saúde Pública da Universidade do Porto (ISPUP), 4050-600 Porto, Portugal;
| | - Marian Taulescu
- Department of Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
- Synevovet Laboratory, 81 Pache Protopopescu, 021408 Bucharest, Romania
| | - Fátima Gärtner
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; (A.R.F.); (M.C.); (A.R.); (F.G.); (I.A.)
- Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
| | - Fernanda Seixas
- Animal and Veterinary Research Center (CECAV), Associate Laboratory AL4AnimalS, University of Trás-os-Montes e Alto Douro (UTAD), 5001-801 Vila Real, Portugal;
| | - Irina Amorim
- Department of Pathology and Molecular Immunology of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; (A.R.F.); (M.C.); (A.R.); (F.G.); (I.A.)
- Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
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6
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Braga Emidio N, Brierley SM, Schroeder CI, Muttenthaler M. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacol Transl Sci 2020; 3:583-597. [PMID: 32832864 DOI: 10.1021/acsptsci.0c00023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Indexed: 12/20/2022]
Abstract
Trefoil factor family peptides (TFF1, TFF2, and TFF3) are key players in protecting, maintaining, and repairing the gastrointestinal tract. Accordingly, they have the therapeutic potential to treat and prevent a variety of gastrointestinal disorders associated with mucosal damage. TFF peptides share a conserved motif, including three disulfide bonds that stabilize a well-defined three-loop-structure reminiscent of a trefoil. Although multiple functions have been described for TFF peptides, their mechanisms at the molecular level remain poorly understood. This review presents the status quo of TFF research relating to gastrointestinal disorders. Putative TFF receptors and protein partners are described and critically evaluated. The therapeutic potential of these peptides in gastrointestinal disorders where altered mucosal biology plays a crucial role in the underlying etiology is discussed. Finally, areas of investigation that require further research are addressed. Thus, this review provides a comprehensive update on TFF literature as well as guidance toward future research to better understand this peptide family and its therapeutic potential for the treatment of gastrointestinal disorders.
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Affiliation(s)
- Nayara Braga Emidio
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medicial Research Insittitue (FHMRI), Flinders University, Bedford Park, South Australia 5042, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia
| | - Christina I Schroeder
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.,National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Markus Muttenthaler
- Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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7
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Matsubara D, Yoshimoto T, Soda M, Amano Y, Kihara A, Funaki T, Ito T, Sakuma Y, Shibano T, Endo S, Hagiwara K, Ishikawa S, Fukayama M, Murakami Y, Mano H, Niki T. Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas. Cancer Sci 2020; 111:2183-2195. [PMID: 32237253 PMCID: PMC7293082 DOI: 10.1111/cas.14403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 03/16/2020] [Accepted: 03/24/2020] [Indexed: 12/25/2022] Open
Abstract
Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor‐1 (TTF‐1)/NK2 homeobox 1 (NKX2‐1)‐positive terminal respiratory unit (TRU) types and rarely in non‐TRU types. To elucidate the molecular characteristics of the major subtypes of non‐TRU‐type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non‐TRU types). A characteristic of non‐TRU‐type cell lines was the strong expression of TFF‐1 (trefoil factor‐1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF‐1 was positive in 31 cases (13%). Expression of TFF‐1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF‐1 correlated with the expression of HNF4‐α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF‐1/NKX2‐1 (P < .0001). These results indicate that TFF‐1 is characteristically expressed in non‐TRU‐type adenocarcinomas with gastrointestinal features. The TFF‐1‐positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF‐1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF‐1 inhibited cell proliferation and soft‐agar colony formation and induced apoptosis in a TFF‐1‐high and KRAS‐mutated lung adenocarcinoma cell line. These results indicate that TFF‐1 is not only a biomarker, but also a potential molecular target for non‐TRU‐type lung adenocarcinomas.
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Affiliation(s)
- Daisuke Matsubara
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan.,Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Taichiro Yoshimoto
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan
| | - Manabu Soda
- Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yusuke Amano
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan
| | - Atsushi Kihara
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan
| | - Toko Funaki
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takeshi Ito
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yuji Sakuma
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan
| | - Tomoki Shibano
- Department of Thoracic Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Shunsuke Endo
- Department of Thoracic Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Koichi Hagiwara
- Department of Respiratory Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Shumpei Ishikawa
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masashi Fukayama
- Human Pathology Department, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Toshiro Niki
- Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan
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8
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Jahan R, Shah A, Kisling SG, Macha MA, Thayer S, Batra SK, Kaur S. Odyssey of trefoil factors in cancer: Diagnostic and therapeutic implications. Biochim Biophys Acta Rev Cancer 2020; 1873:188362. [PMID: 32298747 DOI: 10.1016/j.bbcan.2020.188362] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/01/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023]
Abstract
Trefoil factors 1, 2, and 3 (TFFs) are a family of small secretory molecules involved in the protection and repair of the gastrointestinal tract (GI). TFFs maintain and restore epithelial structural integrity via transducing key signaling pathways for epithelial cell migration, proliferation, and invasion. In recent years, TFFs have emerged as key players in the pathogenesis of multiple diseases, especially cancer. Initially recognized as tumor suppressors, emerging evidence demonstrates their key role in tumor progression and metastasis, extending their actions beyond protection. However, to date, a comprehensive understanding of TFFs' mechanism of action in tumor initiation, progression and metastasis remains obscure. The present review discusses the structural, functional and mechanistic implications of all three TFF family members in tumor progression and metastasis. Also, we have garnered information from studies on their structure and expression status in different organs, along with lessons from their specific knockout in mouse models. In addition, we highlight the emerging potential of using TFFs as a biomarker to stratify tumors for better therapeutic intervention.
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Affiliation(s)
- Rahat Jahan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA
| | - Sophia G Kisling
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA; Department of Otolaryngology-Head & Neck Surgery, University of Nebraska Medical Center, NE, 68198, USA; Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India -191201
| | - Sarah Thayer
- Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, NE, 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE 68198, USA.
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, NE, 68198, USA.
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9
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Heuer J, Heuer F, Stürmer R, Harder S, Schlüter H, Braga Emidio N, Muttenthaler M, Jechorek D, Meyer F, Hoffmann W. The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions. Int J Mol Sci 2020; 21:ijms21072508. [PMID: 32260357 PMCID: PMC7177788 DOI: 10.3390/ijms21072508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/30/2020] [Accepted: 04/02/2020] [Indexed: 12/15/2022] Open
Abstract
TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).
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Affiliation(s)
- Jörn Heuer
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Franziska Heuer
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - René Stürmer
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Sönke Harder
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Hartmut Schlüter
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Nayara Braga Emidio
- Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Markus Muttenthaler
- Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia
- Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Dörthe Jechorek
- Institute of Pathology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Frank Meyer
- Department of Surgery, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
- Correspondence:
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10
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Znalesniak EB, Salm F, Hoffmann W. Molecular Alterations in the Stomach of Tff1-Deficient Mice: Early Steps in Antral Carcinogenesis. Int J Mol Sci 2020; 21:ijms21020644. [PMID: 31963721 PMCID: PMC7014203 DOI: 10.3390/ijms21020644] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/07/2020] [Accepted: 01/14/2020] [Indexed: 02/07/2023] Open
Abstract
TFF1 is a peptide of the gastric mucosa co-secreted with the mucin MUC5AC. It plays a key role in gastric mucosal protection and repair. Tff1-deficient (Tff1KO) mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas. Thus, these mice represent a model for gastric tumorigenesis. Here, we compared the expression of selected genes in Tff1KO mice and the corresponding wild-type animals (RT-PCR analyses). Furthermore, we systematically investigated the different molecular forms of Tff1 and its heterodimer partner gastrokine-2 (Gkn2) in the stomach (Western blot analyses). As a hallmark, a large portion of murine Tff1 occurs in a monomeric form. This is unexpected because of its odd number of seven cysteine residues. Probably the three conserved acid amino acid residues (EEE) flanking the 7th cysteine residue allow monomeric secretion. As a consequence, the free thiol of monomeric Tff1 could have a protective scavenger function, e.g., for reactive oxygen/nitrogen species. Furthermore, a minor subset of Tff1 forms a disulfide-linked heterodimer with IgG Fc binding protein (Fcgbp). Of special note, in Tff1KO animals a homodimeric form of Gkn2 was observed. In addition, Tff1KO animals showed strongly reduced Tff2 transcript and protein levels, which might explain their increased sensitivity to Helicobacter pylori infection.
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11
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Disruption of the Tff1 gene in mice using CRISPR/Cas9 promotes body weight reduction and gastric tumorigenesis. Lab Anim Res 2018; 34:257-263. [PMID: 30671113 PMCID: PMC6333602 DOI: 10.5625/lar.2018.34.4.257] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/07/2018] [Accepted: 12/08/2018] [Indexed: 01/27/2023] Open
Abstract
Trefoil factor 1 (TFF1, also known as pS2) is strongly expressed in the gastrointestinal mucosa and plays a critical role in the differentiation of gastric glands. Since approximately 50% of all human gastric cancers are associated with decreased TFF1 expression, it is considered a tumor suppressor gene. TFF1 deficiency in mice results in histological changes in the antral and pyloric gastric mucosa, with severe hyperplasia and dysplasia of epithelial cells, resulting in the development of antropyloric adenoma. Here, we generated TFF1-knockout (KO) mice, without a neomycin resistant (NeoR) cassette, using the clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRSIPR/Cas9) system. Though our TFF1-KO mice showed phenotypes very similar to the previous embryonic stem (ES)-cell-based KO mice, they differed from the previous reports in that a reduction in body weight was observed in males. These results demonstrate that these newly established TFF1-KO mice are useful tools for investigating genetic and environmental factors influencing gastric cancer, without the effects of artificial gene insertion. Furthermore, these findings suggest a novel hypothesis that TFF1 expression influences gender differences.
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12
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Binding of Helicobacter pylori to Human Gastric Mucins Correlates with Binding of TFF1. Microorganisms 2018; 6:microorganisms6020044. [PMID: 29783620 PMCID: PMC6027488 DOI: 10.3390/microorganisms6020044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/23/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori binds to the gastric mucin, MUC5AC, and to trefoil factor, TFF1, which has been shown to interact with gastric mucin. We examined the interactions of TFF1 and H. pylori with purified gastrointestinal mucins from different animal species and from humans printed on a microarray platform to investigate whether TFF1 may play a role in locating H. pylori in gastric mucus. TFF1 bound almost exclusively to human gastric mucins and did not interact with human colonic mucins. There was a strong correlation between binding of TFF1 and H. pylori to human gastric mucins, and between binding of both TFF1 and H. pylori to gastric mucins with that of Griffonia simplicifolia lectin-II, which is specific for terminal non-reducing α- or β-linked N-acetyl-d-glucosamine. These results suggest that TFF1 may help to locate H. pylori in a discrete layer of gastric mucus and hence restrain their interactions with epithelial cells.
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13
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Koehorst SG, Spapens ME, Van Der Kallen CJ, Van 'T Verlaat JW, Blaauw G, Thijssen JH, Blankenstein MA. Progesterone Receptor Synthesis in Human Meningiomas: Relation to the Estrogen-Induced Proteins pS2 and Cathepsin-D and Influence of Epidermal Growth Factor, Forskolin and Phorbol Ester in vitro. Int J Biol Markers 2018; 13:16-23. [PMID: 9681295 DOI: 10.1177/172460089801300104] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Autonomous expression of progesterone receptors (PR) in human meningiomas is well established. To evaluate whether, similar to progesterone receptors, other estrogen-inducible proteins are also autonomously expressed in meningiomas, concentrations of pS2 and cathepsin-D (Cath-D) were measured in 52 meningiomas. No pS2 protein was detectable in 52/52 tested meningiomas. The Cath-D protein was measurable in all 52 meningiomas, but the mean concentration of Cath-D in meningioma cytosols was 2.4-fold lower than that of a group of 54 breast tumors (p < 0.001). These results indicate that autonomous expression is a PR-related rather than an estrogen receptor-related phenomenon and, consequently, that estradiol is probably not responsible for PR synthesis in human meningiomas. To evaluate the role of other, non-estradiol-dependent signalling pathways in PR synthesis, the effects of EGF, Forskolin and phorbol ester on PR synthesis were tested in vitro. No PR was detectable after the addition of EGF to six different primary cultures. Forskolin and TPA addition caused a morphological change in meningioma cells, but did not induce PR or pS2 synthesis in two different primary meningioma cultures. We conclude that PR synthesis in human meningiomas cannot be triggered by switching on the signalling pathways activated by these growth factors.
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Affiliation(s)
- S G Koehorst
- Department of Endocrinology, University Hospital Utrecht, The Netherlands
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14
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Racca S, Conti G, Pietribiasi F, Stramignoni D, Tampellini M, Valetto MR, Ghezzo F, Di Carlo F. Correlation between pS2 protein positivity, steroid receptor status and other prognostic factors in breast cancer. Int J Biol Markers 2018; 10:87-93. [PMID: 7561244 DOI: 10.1177/172460089501000204] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The cytosolic levels of pS2, an estrogen-regulated protein, were measured in 100 cases of primary breast cancer and related to several conventional histological and biochemical prognostic factors. The data were statistically analyzed on the basis of two different cutoff points for pS2: 4 and 11 ng/mg of cytosolic proteins. pS2 positivity (cutoff 11 ng/mg) was shown to be associated with smaller tumor size (p = 0.05), a higher differentiation grade (p = 0.007) and a smaller number of mitoses (p = 0.004), but not with menopausal status, lymph node involvement, cathepsin D levels, or proliferative activity determined by the monoclonal antibody Ki67. With the cutoff of 4 ng/mg, the statistical significance was confirmed only for the number of mitoses (p = 0.03), which was also the most closely related covariate in multivariate analysis (p = 0.008). As regards steroid receptor status, a significant difference was observed between pS2+ and pS2– cases (Chi-square = 8.9; p - 0.04, cutoff 4 ng/mg). In conclusion, pS2 positivity, being preferentially expressed in hormone-dependent cells and related to other well-known positive markers, may either indicate a good prognosis or predict responsiveness to endocrine treatment.
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Affiliation(s)
- S Racca
- Dipartimento di Scienze Cliniche e Biologiche, Facoltà di Medicina, Orbassano, Torino, Italy
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15
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Suárez C, Vizoso F, Rodríguez JC, García I, Raigoso P, Allende MT, García-Muñíz JL, García-Morán M. Prognostic Significance of Cytosolic pS2 Protein Content in Gastric Cancer. Int J Biol Markers 2018; 16:37-44. [PMID: 11288953 DOI: 10.1177/172460080101600105] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
pS2, a 60-amino-acid chain peptide which is the most widespread estrogen-induced RNA messenger in MCF-7 breast cancer cells, is normally detected in the epithelium of gastric mucosa. The aims of this work were to evaluate the cytosolic pS2 content and its clinical significance in gastric carcinomas. Cytosolic pS2 levels were examined by immunoradiometric methods in 108 patients with primary gastric adenocarcinomas. The mean follow-up period was 23.3 months. The cytosolic pS2 levels of the tumors ranged widely, i.e., from 0.1 to 3217 ng/mg protein. There were no significant differences in pS2 content between tumors (mean ± standard error: 137.2±31.4 ng/mg protein) and paired adjacent mucosa samples (n=84; mean ± standard error: 249.6±32.6 ng/mg protein), nor were there any significant differences in tumoral pS2 levels with respect to clinicopathologic parameters such as patient age and sex or tumor location, stage, histologic type or grade. However, the results indicated that high intratumoral pS2 levels were significantly and independently associated with an unfavorable outcome in the overall group of patients (p=0.0266) and in patients with resectable gastric cancer (p=0.003). In conclusion, pS2 may represent a useful biological marker in gastric cancer.
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Affiliation(s)
- C Suárez
- Department of General Surgery, Hospital de Jove, Gijón, Spain
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16
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Vizoso FJ, Fagilde MC, Corte MD, Corte MG, Gava R, Bongera M, Allende MT, García-Muñiz JL. Cytosolic Levels of An Estrogen-Induced Breast Cancer-Associated Peptide (TFF1/pS2) in Colorectal Cancer: Clinical Significance and Relationship with Steroid Receptors. Int J Biol Markers 2018; 18:301-10. [PMID: 14756547 DOI: 10.1177/172460080301800409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA in MCF-7 breast cancer cells and is also expressed by colorectal carcinomas. The objective of this work was to evaluate the cytosolic TFF1 content in colorectal carcinomas, its possible relationship with estrogen and progesterone receptors as well as with clinicopathological tumor parameters, and its potential prognostic significance. Methods Cytosolic TFF1 levels were examined by immunoradiometric assay in 178 patients with resectable colorectal cancer. The mean follow-up period was 32 months. Results There was a wide variability of cytosolic TFF1 levels in tumor-surrounding mucosa samples (0.09-42.5 ng/mg protein) as well as in tumors (0.01-270 ng/mg protein). Comparison of paired mucosa and carcinoma samples showed significantly higher TFF1 levels in tumors (mean: 17.1 ng/mg protein) than in mucosa samples (10 ng/mg protein) (p=0.027). TFF1 levels were significantly higher in mucosa samples surrounding distal colon and rectal tumors (p=0.0001) and in tumor samples obtained from older patients (p=0.007). However, there were no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, tumor location, stage, histological grade, ploidy, S-phase, or tumor estrogen and progesterone receptors. In addition, there was no significant relationship between tumor TFF1 levels and disease outcome. Conclusions TFF1 may play an as yet undetermined role in the tumorigenesis of colorectal carcinomas. However, cytosolic levels of TFF1 do not seem to have any prognostic significance in colorectal carcinomas.
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Affiliation(s)
- F J Vizoso
- Servicio de Cirugía General, Hospital de Jove, , Asturias, Gijón, Spain.
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17
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Wang W, Li Z, Wang J, Du M, Li B, Zhang L, Li Q, Xu J, Wang L, Li F, Zhang D, Xu H, Yang L, Gong W, Qiang F, Zhang Z, Xu Z. A functional polymorphism in TFF1 promoter is associated with the risk and prognosis of gastric cancer. Int J Cancer 2017; 142:1805-1816. [PMID: 29210057 DOI: 10.1002/ijc.31197] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 11/05/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022]
Abstract
Trefoil Factor 1 (TFF1, also named pS2), which serves as the gastrointestinal mucosal protector, is known as gastric-specific tumor suppressor gene. However, the genetic variants of TFF1 are still not well studied. In our study, we aim to explore the effects of tagging single nucleotide polymorphisms (tagSNPs) of TFF1 on risk and prognosis of gastric cancer. Seven tagSNPs of TFF1 gene were first analyzed in the discovery set, which was consisted of 753 cases and 950 cancer-free controls. Then, the validation set (940 cases and 1,042 controls) was used for further evaluation. Moreover, we also tested the relation between these tagSNPs and prognosis of gastric cancer (GC). A series of experiments were performed to investigate the underlying mechanisms. We found that rs3761376 AA in the promoter region of TFF1, could reduce the expression of TFF1 by affecting the binding affinity of estrogen receptor 1 (ESR1, ERα), and thereby increased the risk of GC (1.29, 1.08-1.53). Moreover, the rs3761376 AA genotype was also found associated with worse prognosis among patients receiving 5-FU based chemotherapy after surgery (1.71, 1.18-2.48). Further functional assays demonstrated that TFF1 could increase the chemosensitivity of 5-FU by modulating NF-κB targeted genes. These results identified the effect of rs3761376 on TFF1 expression, which accounted for the correlation with susceptibility and prognosis of GC; and this genetic variant may be a potential biomarker to predict the risk and survival of GC.
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Affiliation(s)
- Weizhi Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zheng Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiwei Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of General Surgery, Xuzhou Central Hospital, Xuzhou, China
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Bowen Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lei Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianghao Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Linjun Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fengyuan Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Diancai Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Yang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of General Surgery, Yixing Tumor Hospital, Yixing, China
| | - Fulin Qiang
- Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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18
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Kim O, Yoon JH, Choi WS, Ashktorab H, Smoot DT, Nam SW, Lee JY, Park WS. Heterodimeric interaction between GKN2 and TFF1 entails synergistic antiproliferative and pro-apoptotic effects on gastric cancer cells. Gastric Cancer 2017; 20:772-783. [PMID: 28150071 PMCID: PMC5718056 DOI: 10.1007/s10120-017-0692-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 01/14/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND GKN2 and TFF1 form a heterodimer that is only generated in the mucus-secreting cells of the normal stomach. The formation of this heterodimer is frequently disrupted in gastric cancer. However, the precise roles of GKN2 alone and in the heterodimer with TFF1 as well as the contributions of GKN2 and the heterodimer to gastric carcinogenesis are poorly understood. METHODS Cell viability, proliferation, and apoptosis were analyzed in AGS, MKN1, MKN28, and MKN45 gastric cancer cells transfected with GKN2 and/or TFF1 using MTT, BrdU incorporation, and apoptosis assays, respectively. In addition, cell viability was examined in HFE-145 non-neoplastic gastric epithelial cells after GKN2 and/or TFF1 silencing. Furthermore, the cell cycle and the expression of cell cycle and apoptosis related proteins were assessed. The interaction between GKN2 and TFF1 was confirmed by co-immunoprecipitation. Immunohistochemistry was employed to explore TFF1 expression in 169 gastric cancer tissues. RESULTS Co-transfection with GKN2 and TFF1 significantly inhibited cell viability and proliferation by inducing G1/S cell cycle arrest and suppressing positive cell cycle regulators. Simultaneous knockdown of GKN2 and TFF1 in HFE-145 cells resulted in markedly increased cell viability. Moreover, the interaction of GKN2 and TFF1 promoted cell death by enhancing caspase-3/7 activity and upregulating pro-apoptotic proteins. At the mRNA level, GKN2 and TFF1 were found to be positively correlated in non-tumor and tumor samples. Immunohistochemistry revealed loss of TFF1 expression in 128 (75.73%) of 169 gastric cancers. There was a borderline-significant association between GKN2 and TFF1 protein expression in gastric cancers (P = 0.0598). CONCLUSION Collectively, our data demonstrated that the interaction between GKN2 and TFF1 can have synergistic antiproliferative and pro-apoptotic effects on gastric cancer.
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Affiliation(s)
- Olga Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea
| | - Won Suk Choi
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC, 20060, USA
| | - Duane T Smoot
- Department of Medicine, Howard University, Washington, DC, 20060, USA
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea
| | - Jung Young Lee
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, Korea.
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19
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Gastric toxicity involving alterations of gastritis-related protein expression in mice following long-term exposure to nano TiO 2. Food Res Int 2017; 95:38-45. [DOI: 10.1016/j.foodres.2017.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Abstract
Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.
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Affiliation(s)
- Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Kristen A Engevik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Marshall H Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
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21
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Khaidakov M, Lai KK, Roudachevski D, Sargsyan J, Goyne HE, Pai RK, Lamps LW, Hagedorn CH. Gastric Proteins MUC5AC and TFF1 as Potential Diagnostic Markers of Colonic Sessile Serrated Adenomas/Polyps. Am J Clin Pathol 2016; 146:530-537. [PMID: 28430953 PMCID: PMC5377921 DOI: 10.1093/ajcp/aqw142] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES A subset of colon cancers originates from sessile serrated adenomas/polyps (SSA/Ps). Our goal was to identify markers for SSA/Ps that could aid in distinguishing them from hyperplastic polyps (HPs). METHODS We performed immunostaining for gastric proteins MUC5AC and TFF1 in formalin-fixed, paraffin-embedded (FFPE) samples of HPs (n = 47), SSA/Ps (n = 37), and normal colon (n = 30). RESULTS Control mucosa expressed only trace amounts of MUC5AC and TFF1. HPs exhibited an 11.3- and 11.4-fold increase in MUC5AC and TFF1 expression confined to the upper segments of the crypts near the luminal surface of the polyps. SSA/Ps displayed on average 1.6-fold (MUC5AC, P < .008) and 1.4-fold (TFF1, P < .03) higher signal intensity for these markers than HPs, with a dramatic coexpression of MUC5AC and TFF1 typically occupying the entire length of the crypt. Immunoperoxidase results were similar to immunofluorescence staining for both MUC5AC and TFF1. CONCLUSIONS Our results suggest that the analysis of expression of MUC5AC and TFF1 may be useful for differentiating SSA/Ps from HPs. We also suggest the possibility that crypt morphology may be at least partly due to overproduction of highly viscous gastric mucins and that these proteins may play a role in the serrated pathway to colon carcinogenesis.
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Affiliation(s)
- Magomed Khaidakov
- From the Department of Medicine
- Central Arkansas Veterans Healthcare System, Little Rock
| | - Keith K. Lai
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | | | | | - Hannah E. Goyne
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Rish K. Pai
- Department of Pathology, Mayo Clinic, Scottsdale, AZ
| | - Laura W. Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Curt H. Hagedorn
- From the Department of Medicine
- Central Arkansas Veterans Healthcare System, Little Rock
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22
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Song X, Xin N, Wang W, Zhao C. Wnt/β-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis. Oncotarget 2016; 6:35579-88. [PMID: 26417932 PMCID: PMC4742126 DOI: 10.18632/oncotarget.5758] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022] Open
Abstract
A section of gastric cancers presents nuclear β-catenin accumulation correlated with H. pylori infection. H. pylori stimulate Wnt/β-catenin pathway by activating oncogenic c-Met and epidermal growth factor receptor (EGFR), or by inhibiting tumor suppressor Runx3 and Trefoil factor 1 (TFF1). H. pylori also trigger Wnt/β-catenin pathway by recruiting macrophages. Moreover, Wnt/β-catenin pathway is found involved in H. pylori-induced gastric cancer stem cell generation. Recently, by using gastroids, researchers have further revealed that H. pylori induce gastric epithelial cell proliferation through β-catenin. These findings indicate that Wnt/β-catenin is an oncogenic pathway activated by H. pylori. Therefore, this pathway is a potential therapy target for H. pylori-related gastric cancer.
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Affiliation(s)
- Xiaowen Song
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Na Xin
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Wei Wang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Chenghai Zhao
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
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23
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Wang Z, Butler LM, Wu AH, Koh WP, Jin A, Wang R, Yuan JM. Reproductive factors, hormone use and gastric cancer risk: The Singapore Chinese Health Study. Int J Cancer 2016; 138:2837-45. [PMID: 26829904 DOI: 10.1002/ijc.30024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 12/22/2015] [Accepted: 01/19/2016] [Indexed: 12/16/2022]
Abstract
Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone-related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT) and oral contraceptive (OC) use was collected through in-person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus <45 years: HR = 0.50, 95% CI: 0.25-0.99), type of menopause (other versus natural: HR = 0.48, 95% CI: 0.27-0.87) and greater years of menstrual cycling (fourth versus first quartile: HR = 0.67, 95% CI: 0.46-0.96) were associated with a decreased risk of gastric cancer. Ever use of OCs and HRT was also associated with reduced risk of gastric cancer; the multivariable-adjusted HRs (95% CIs) were 0.40 (0.17-0.90) for use of HRT >3 years and 0.67 (0.47-0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer.
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Affiliation(s)
- Zhensheng Wang
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Lesley M Butler
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of South California, Los Angeles, CA
| | - Woon-Puay Koh
- Office of Clinical Sciences, Duke-NUS Medical School, Singapore, Singapore.,Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Aizhen Jin
- National Registry of Diseases Office, Health Promotion Board, Singapore, Singapore
| | - Renwei Wang
- Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
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Choudhary A, Smitha C, Suresh D. Trefoils: An unexplored natural protective shield of oral cavity. J Oral Biol Craniofac Res 2015; 5:226-31. [PMID: 26587385 PMCID: PMC4623889 DOI: 10.1016/j.jobcr.2015.06.009] [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: 04/05/2015] [Accepted: 06/24/2015] [Indexed: 01/27/2023] Open
Abstract
The new mammalian growth factor peptide family consists of three peptides, TFF1, TFF2, and TFF3, which are secreted mainly from mucous epithelia with mucus gel. The predominant secretion of trefoil factor (TFF) occurs from gastric mucosal lining, small and large intestine, oral mucosal cells, and salivary glands. Research regarding trefoil factors is an immerging aspect in the dental field. The mucosal healing and restitution function describes about its novel role in case of chronic inflammatory conditions, but its expression from different tissue at different pathological condition shows its importance in immune response. At present, TFF expression has been detected from the severe periodontal diseased tissue samples. Future research from mild to moderate chronic periodontal diseased condition should be carried out to assess the protective response of TFF in gingival tissues. In future, assessment of TFF levels and its expression in oral mucosal tissues and oral secretions, such as saliva and gingival crevicular fluid, will provide a negative biomarker for chronic periodontal diseases and a novel therapeutic agent in oral mucosal healing.
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Affiliation(s)
- Akanksha Choudhary
- PG Student, Department of Periodontology and Oral Implantology, MMCDSR, Mullana, Ambala, India
| | - C.N. Smitha
- Professor, Department of Periodontology and Oral Implantology, MMCDSR, Mullana, Ambala, India
| | - D.K. Suresh
- Professor and Head, Department of Periodontology and Oral Implantology, MMCDSR, Mullana, Ambala, India
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25
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Li Y, Arao Y, Hall JM, Burkett S, Liu L, Gerrish K, Cavailles V, Korach KS. Research Resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol 2015; 28:2072-81. [PMID: 25321415 DOI: 10.1210/me.2014-1229] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Human ovarian cancer BG-1 cells are a valuable in vitro model that has enabled several laboratories to study the estrogenic responses of ovarian cancers. We recently discovered that there are two different BG-1 cell lines being used for experiments, denoted here as BG-1 FR and BG-1 NIEHS, which exhibit striking morphological differences. The objective of this study was to methodically analyze these two BG-1 variants and compare their characteristics. Short tandem repeat analysis revealed that the DNA profile of BG-1 FR cells was unique, yet the Short tandem repeat pattern of BG-1 NIEHS was identical with that of MCF-7 cells. From a cytogenetic analysis, it became apparent that the BG-1 FR line had the same profile as previously reported, whereas the BG-1 NIEHS and MCF-7 cells share a similar genetic display. A significant number of unique chromosomal translocations were observed between the BG-1 NIEHS and MCF-7 cells, suggesting that acquired genotypic differences resulted in the formation of two lines from a common origin. Although all cell types demonstrated a similar estrogen responsiveness in reporter gene assays, a microarray analysis revealed distinct estrogen-responsive gene expression patterns with surprisingly moderate to low overlap. We conclude that BG-1 FR is the original ovarian cancer cell line, whereas the BG-1 NIEHS is a variant from the MCF-7 cells. These findings provide much needed clarification of the identities and characteristics of key cell line models that are widely used to study estrogen action in female reproductive cancers.
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Affiliation(s)
- Yin Li
- Laboratory of Reproductive and Developmental Toxicology (Y.L., Y.A., K.S.K.) and Molecular Genomics Core Facility (L.L., K.G.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; College of Pharmacy and Health Sciences (J.M.H.), Campbell University, Buies Creek, North Carolina 27506; Center for Cancer Research (S.B.), National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702; and Institut de Recherche en Cancérologie de Montpellier (V.C.), Institut de Recherche en Cancerologie de Montpellier and INSERM Unité 896, Universite Montpellier1, F-34298 Montpellier, France
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26
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Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W. Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut 2015; 64:1028-39. [PMID: 25107557 PMCID: PMC4320984 DOI: 10.1136/gutjnl-2014-307191] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 07/16/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVE In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis. DESIGN Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway. RESULTS Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis. CONCLUSIONS Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.
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Affiliation(s)
- Mohammed Soutto
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - DunFa Peng
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Ahmed Katsha
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Zheng Chen
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Maria Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Pelayo Correa
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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May FEB, Westley BR. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer. Endocr Relat Cancer 2015; 22:465-79. [PMID: 25900183 PMCID: PMC4455223 DOI: 10.1530/erc-15-0129] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2015] [Indexed: 12/13/2022]
Abstract
The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis.
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Affiliation(s)
- Felicity E B May
- Department of Pathology Faculty of Medical Sciences, Northern Institute for Cancer Research and Newcastle University Institute for Ageing, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
| | - Bruce R Westley
- Department of Pathology Faculty of Medical Sciences, Northern Institute for Cancer Research and Newcastle University Institute for Ageing, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
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Aamann L, Vestergaard EM, Grønbæk H. Trefoil factors in inflammatory bowel disease. World J Gastroenterol 2014; 20:3223-3230. [PMID: 24696606 PMCID: PMC3964394 DOI: 10.3748/wjg.v20.i12.3223] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/24/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.
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Wu JF, Zhang J, Xue G, Zhang HQ. Expression and localization of trefoil factor family genes in rat submandibular glands. Biotech Histochem 2014; 89:424-32. [PMID: 24588600 DOI: 10.3109/10520295.2014.885565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The trefoil factor (TFF) family, which comprises TFF1, TFF2 and TFF3, plays an essential role in epithelial regeneration within the gastrointestinal tract. All three TFFs are present in human saliva; TFF3 is the predominant trefoil peptide. Little is known about the expression and tissue distribution of TFFs in rats, which are commonly used as a model system for human studies. We investigated the localization of the TFF genes that encode secretory peptides in rat submandibular glands (SMG). All three TFFs were expressed in rat SMG, although their location varied. Substantial amounts of TFF1 were detected only in the cytoplasm of epithelial cells in the SMG granular convoluted tubules (GCT), while TFF2 and TFF3 were widely distributed in the cytoplasm of epithelial cells of intercalated ducts (ID), striated ducts (SD) and interlobular ducts (ILD). The three TFFs also were detected especially in the lumens of the SD and ILD. Semi-quantitative RT-PCR and in situ hybridization experiments confirmed TFF1, TFF2 and TFF3 mRNA expressions in the SMG. Greater expression of TFF peptides and mRNA was observed in male rats than in females. The broad expression of TFFs in rat SMG cells and lumens suggests that TFFs function in this organ by their secretion into the duct lumens. We also found differences in TFF expression profiles between rat and human SMG; therefore, caution should be exercised when using rats as a model for human TFF studies.
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Affiliation(s)
- J F Wu
- Department of Histology and Embryology, Hebei North University , Zhangjiakou
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30
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Liu J, Wang X, Yang X, Liu Y, Shi Y, Ren J, Guleng B. miRNA423-5p regulates cell proliferation and invasion by targeting trefoil factor 1 in gastric cancer cells. Cancer Lett 2014; 347:98-104. [PMID: 24486742 DOI: 10.1016/j.canlet.2014.01.024] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 01/16/2014] [Accepted: 01/24/2014] [Indexed: 12/23/2022]
Abstract
TFF1 is a small, secreted protein in the TFF family that has a pivotal role as a motogenic factor in epithelial restitution and cell motility, and as a tumor suppressor gene in the stomach. In this study, we identified TFF1 as a novel target gene of miRNA-423-5p. miRNA-423-5p negatively regulated the expression of TFF1 by binding to its 3'UTR and participated in proliferation/invasion-related processes via a TFF1-dependent manner in gastric cancer cells. Our findings suggested that miR-423-5p may be a novel target for the future development of specific therapeutic interventions for gastric cancer.
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Affiliation(s)
- Jingjing Liu
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, Fujian Province, PR China
| | - Xu Wang
- Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen 361005, Fujian Province, PR China
| | - Xiaoning Yang
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, Fujian Province, PR China
| | - Yunpeng Liu
- Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen 361005, Fujian Province, PR China
| | - Ying Shi
- Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen 361005, Fujian Province, PR China
| | - Jianlin Ren
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, Fujian Province, PR China; Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen 361005, Fujian Province, PR China.
| | - Bayasi Guleng
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, Fujian Province, PR China; Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen 361005, Fujian Province, PR China.
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31
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Markićević M, Džodić R, Buta M, Kanjer K, Mandušić V, Nešković-Konstantinović Z, Nikolić-Vukosavljević D. Trefoil factor 1 in early breast carcinoma: a potential indicator of clinical outcome during the first 3 years of follow-up. Int J Med Sci 2014; 11:663-73. [PMID: 24843314 PMCID: PMC4025164 DOI: 10.7150/ijms.8194] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 03/15/2014] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND A role of an estrogen-regulated, autocrine motogenic factor was assumed to be a major biological role of trefoil factor 1 (TFF1) in breast cancer. TFF1 is regarded as a predictive factor for positive response to endocrine therapy in breast cancer patients. The aim of our study was to examine TFF1 level distribution in breast carcinomas in order to distinguish estrogen-independent from estrogen-dependent TFF1 expression and to evaluate clinical usefulness of TFF1 status in early breast cancer during the first 3 years of follow-up. METHODS The study included 226 patients with primary operable invasive early breast carcinomas for whom an equal, a 3-year follow-up was conducted. TFF1 levels as well as estrogen receptor (ER) and progesterone receptor (PR) levels were measured in cytosolic extracts of tumor samples by immunoradiometric assay or by use of classical biochemical method, respectively. Non-parametric statistical tests were applied for data analyses. RESULTS Statistical analysis revealed that TFF1 levels were significantly higher in premenopausal patients (p=0.02), or in tumors with: lower histological grade (p<0.001), positive ER or PR status (p<0.001, in both cases). On the basis of TFF1 level distribution between ER-negative and ER-positive postmenopausal patients with tumors of different histological grade, 14 ng/mg was set as the cut-off value to distinguish estrogen-independent from estrogen-dependent TFF1 expression in breast cancer. Depending on menopausal and PR status, positive TFF1 status identified patients at opposite risk for relapse among ER-positive patients with grade II tumors. Among ER- and PR-positive premenopausal patients with grade II tumors, TFF1 status alone identified patients at opposite risk for relapse. CONCLUSIONS Determination of TFF1 status might identify patients at different risk for relapse and help in making decision on administering adjuvant therapy for early breast cancer patients during the first 3 years of follow-up.
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Affiliation(s)
- Milan Markićević
- 1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Radan Džodić
- 2. Surgical Oncology Clinic, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; ; 3. University of Belgrade School of Medicine, Dr Subotića 8, 11000 Belgrade, Serbia
| | - Marko Buta
- 2. Surgical Oncology Clinic, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Ksenija Kanjer
- 1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Vesna Mandušić
- 4. Vinča Institute of Nuclear Science, Mike Petrovića Alasa 12-14, 11000 Belgrade, Serbia
| | - Zora Nešković-Konstantinović
- 5. Clinic of Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
| | - Dragica Nikolić-Vukosavljević
- 1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
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Feng G, Zhang Y, Yuan H, Bai R, Zheng J, Zhang J, Song M. DNA methylation of trefoil factor 1 (TFF1) is associated with the tumorigenesis of gastric carcinoma. Mol Med Rep 2013; 9:109-17. [PMID: 24190027 DOI: 10.3892/mmr.2013.1772] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 09/05/2013] [Indexed: 01/28/2023] Open
Abstract
Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease‑resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas (GCs), the tumorigenic pathways that are affected have yet to be determined. The aim of the current study was to identify the mechanism(s) by which the TFF1 gene is regulated in gastric carcinogenesis. In this study, TFF1 was shown to be silenced or downregulated in gastric tumor tissue compared with matched non‑cancerous tissue. In addition, human gastric cells weakly expressed TFF1. The hypermethylation status in the promoter CpG islands appeared to be correlated with TFF1 expression levels in gastric cell lines or specimen tissue. Further molecular analysis indicated that the CpG islands play a role in the promoter activity of the TFF1 gene. The expression of TFF1 and DNA methylation of its promoter affected cell proliferation and apoptosis. The expression of TFF1 in gastric cell lines was restored with a demethylating agent, 5‑azacytidine. Low expression of TFF1 in gastric cell lines and cancer tissue is associated with TP 53. In conclusion, the current study demonstrates that DNA methylation is a key mechanism of silencing TFF1 expression in human gastric cells and TFF1 gene hypermethylation of the CpG islands is a potential biomarker for GC.
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Affiliation(s)
- Guoxun Feng
- Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China
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Žurek J, Fedora M. Trefoil factor 1 as a marker of mucosal damage of the gastrointestinal tract in children with sepsis. Biomarkers 2013; 18:338-42. [PMID: 23627615 DOI: 10.3109/1354750x.2013.783116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Intestinal ischemia and reperfusion is a common pathway for many diseases in children. The objective of our study was an analysis of Trefoil factor 1 levels dynamics in patients with SIRS or septic condition during a 5-day period. Analysis of TFF1 levels dynamics revealed that TFF1 levels kept steady state during the 5-day period. TFF1 levels were similar in patients with SIRS, sepsis and severe sepsis. Significantly higher levels of TFF1 were in patients with septic shock and MODS.
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Affiliation(s)
- Jiří Žurek
- Department of Anesthesia and Intensive Care, University Children's Hospital, Brno, 62500, Czech Republic.
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Tanaka T, Nakamura J, Kitajima Y, Kai K, Miyake S, Hiraki M, Ide T, Koga Y, Noshiro H. Loss of trefoil factor 1 is regulated by DNA methylation and is an independent predictive factor for poor survival in advanced gastric cancer. Int J Oncol 2013; 42:894-902. [PMID: 23291975 DOI: 10.3892/ijo.2013.1759] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 11/30/2012] [Indexed: 02/05/2023] Open
Abstract
Trefoil factor 1 (TFF1) is considered to be a tumor suppressor gene in gastric cancer. However, the role of TFF1 expression and its regulation in gastric cancer patients remain unclear. The aims of this study were to clarify the clinical significance of TFF1 and to determine its regulatory mechanisms. We assessed the immunohistochemical expression of TFF1 in 182 gastric cancer patients and examined whether or not TFF1 is associated with the clinicopathological factors and patient survival. In vitro study using TFF1 knockdown gastric cancer cells evaluated the role of TFF1 in cancer invasion. Bisulfite sequencing was performed to assess DNA methylation of TFF1 in cells and resected tissues. Patients with low expression of TFF1 showed a significantly deeper invasion of the tumor than those with high expression (p=0.037). Low expression of TFF1 was also associated with a poor survival (p=0.029) in 108 patients who were treated by surgery alone. Both TFF1 expression and lymph node metastasis are independent predictive factors for disease-specific survival in a multivariate analysis. In an in vitro study, invasive power of the cells was significantly increased in the TFF1‑deficient cells compared with the control cells. Bisulfate sequencing showed that TFF1 expression is strongly dependent on DNA methylation in both gastric cancer cells and tissues. Interestingly, methylation status of two specific CpG sites, which are located close to a TATA box and hypoxia response element (HRE), determined the TFF1 expression in the resected tissues. TFF1 expression is silenced by DNA methylation and is associated with tumor invasion and a poor survival in gastric cancer patients. The expression and̸or methylation status of TFF1 may, therefore, serve as a useful biomarker for predicting survival in patients with advanced gastric cancer.
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Affiliation(s)
- Tomokazu Tanaka
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC. Mouse models of gastric cancer. Cancers (Basel) 2013; 5:92-130. [PMID: 24216700 PMCID: PMC3730302 DOI: 10.3390/cancers5010092] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/08/2013] [Accepted: 01/15/2013] [Indexed: 12/12/2022] Open
Abstract
Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field.
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Affiliation(s)
- Yoku Hayakawa
- Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
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MAO WEI, CHEN JIE, PENG TIELI, YIN XIAOFEI, CHEN LIANZHOU, CHEN MINHU. Role of trefoil factor 1 in gastric cancer and relationship between trefoil factor 1 and gastrokine 1. Oncol Rep 2012; 28:1257-62. [DOI: 10.3892/or.2012.1939] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 06/18/2012] [Indexed: 11/05/2022] Open
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Moghanibashi M, Mohamadynejad P, Rasekhi M, Ghaderi A, Mohammadianpanah M. Polymorphism of estrogen response element in TFF1 gene promoter is associated with an increased susceptibility to gastric cancer. Gene 2012; 492:100-3. [DOI: 10.1016/j.gene.2011.10.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 10/25/2011] [Accepted: 10/27/2011] [Indexed: 12/12/2022]
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Kawai T, Takagi Y, Fukuzawa M, Yamagishi T, Goto S. The role of trefoil factor family in apparently healthy subjects administrated gastroprotective agents for the primary prevention of gastrointestinal injuries from low-dose acetylsalicylic acid: a preliminary study. J Clin Biochem Nutr 2011; 49:136-40. [PMID: 21980231 PMCID: PMC3171679 DOI: 10.3164/jcbn.11-10] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 02/09/2011] [Indexed: 12/21/2022] Open
Abstract
It is well-known that acetylsalicylic acid induces gastrointestinal complication. Recently, trefoil factor family has been reported as a mucosal protective factor. We focused on trefoil factor family as one of defensive system for gastrointestinal injuries. The aim of this trial was to evaluate trefoil factor family levels in the serum of healthy subjects with low-dose acetylsalicylic acid. Low-dose acetylsalicylic acid with placebo or proton pump inhibitor or rebamipide were administered in 30 healthy subjects. Transnasal endoscopy was performed at 0, 24 h, 3 and 7 day. Changing of trefoil factor family (1,2,3) and numbers of gastric injuries were evaluated. The numbers of gastric injuries were significantly increased in the placebo group at 3 and 7 days. Injuries in the proton pump inhibitor group were not induced, in the rebamipide group were slightly induced. Trefoil factor family level in the placebo group were decreased in 3 and 7 days compared with prior to starting the trial. Trefoil factor family may have an important association with acetylsalicylic acid-induced gastrointestinal damage. Proton pump inhibitor and rebamipide prevented low-dose acetylsalicylic acid-induced gastrointestinal complications compared with the placebo group.
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Affiliation(s)
- Takashi Kawai
- Endoscopy Center, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
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Soutto M, Belkhiri A, Piazuelo MB, Schneider BG, Peng D, Jiang A, Washington MK, Kokoye Y, Crowe SE, Zaika A, Correa P, Peek RM, El-Rifai W. Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans. J Clin Invest 2011; 121:1753-67. [PMID: 21490402 PMCID: PMC3083788 DOI: 10.1172/jci43922] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2010] [Accepted: 01/26/2011] [Indexed: 12/21/2022] Open
Abstract
Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.
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Affiliation(s)
- Mohammed Soutto
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Abbes Belkhiri
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Barbara G. Schneider
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - DunFa Peng
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Aixiang Jiang
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Kay Washington
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yasin Kokoye
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sheila E. Crowe
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alexander Zaika
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Pelayo Correa
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M. Peek
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wael El-Rifai
- Department of Surgery,
Division of Gastroenterology,
Department of Biostatistics,
Department of Pathology, and
Division of Animal Care, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Deficiency in trefoil factor 1 (TFF1) increases tumorigenicity of human breast cancer cells and mammary tumor development in TFF1-knockout mice. Oncogene 2011; 30:3261-73. [PMID: 21358676 PMCID: PMC3141110 DOI: 10.1038/onc.2011.41] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Although trefoil factor 1 (TFF1; previously named pS2) is abnormally expressed in about 50% of human breast tumors, its physiopathological role in this disease has been poorly studied. Moreover, controversial data have been reported. TFF1 function in the mammary gland therefore needs to be clarified. In this study, using retroviral vectors, we performed TFF1 gain- or loss-of-function experiments in four human mammary epithelial cell lines: normal immortalized TFF1-negative MCF10A, malignant TFF1-negative MDA-MB-231 and malignant TFF1-positive MCF7 and ZR75.1. The expression of TFF1 stimulated the migration and invasion in the four cell lines. Forced TFF1 expression in MCF10A, MDA-MB-231 and MCF7 cells did not modify anchorage-dependent or -independent cell proliferation. By contrast, TFF1 knockdown in MCF7 enhanced soft-agar colony formation. This increased oncogenic potential of MCF7 cells in the absence of TFF1 was confirmed in vivo in nude mice. Moreover, chemically induced tumorigenesis in TFF1-deficient (TFF1-KO) mice led to higher tumor incidence in the mammary gland and larger tumor size compared with wild-type mice. Similarly, tumor development was increased in the TFF1-KO ovary and lung. Collectively, our results clearly show that TFF1 does not exhibit oncogenic properties, but rather reduces tumor development. This beneficial function of TFF1 is in agreement with many clinical studies reporting a better outcome for patients with TFF1-positive breast primary tumors.
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Ota H, Harada O, Uehara T, Hayama M, Ishii K. Aberrant expression of TFF1, TFF2, and PDX1 and their diagnostic value in lobular endocervical glandular hyperplasia. Am J Clin Pathol 2011; 135:253-61. [PMID: 21228366 DOI: 10.1309/ajcpqmao3pw4ogof] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Lobular endocervical glandular hyperplasia (LEGH) is a distinct benign glandular lesion expressing gastric gland mucous cell-type mucin (N-acetylglucosaminα1 → 4galactose → R [GlcNAcα1 → 4Gal → R]). To investigate histogenesis and diagnostic markers of LEGH, we examined the immunohistochemical expression profile of gastric surface mucous cell (MUC5AC and TFF1), gastric gland mucous cell (MUC6, TFF2, and GlcNAcα1 → 4Gal → R), gastric pyloric epithelial cell (PDX1), and endocervical cell (keratan sulfate) markers in normal endocervix samples and benign glandular lesions (nabothian cysts, tunnel clusters, and LEGHs). MUC5AC and MUC6 were expressed in normal endocervical mucosa and benign glandular lesions. TFF1, TFF2, GlcNAcα1 → 4Gal → R, and PDX1 were expressed only in LEGH. Keratan sulfate was expressed in normal endocervical mucosa and benign glandular lesions. In LEGH, gastric surface mucous cell and gastric gland mucous cell differentiation were demonstrated, and transdifferentiation from endocervical mucosa into gastric pyloric mucosa was suggested. In addition to GlcNAcα1 → 4Gal → R, TFF1, TFF2, and PDX1 are additional useful markers for LEGH.
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Affiliation(s)
- Hiroyoshi Ota
- Department of Biomedical Sciences, School of Health Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Oi Harada
- Division of Surgical Pathology, Nippon Medical School Hospital, Tokyo, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Masayoshi Hayama
- Department of Biomedical Sciences, School of Health Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Keiko Ishii
- Department of Pathology, Okaya Municipal Hospital, Okaya, Japan
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Jung KH, Kim PJ, Kim JK, Noh JH, Bae HJ, Eun JW, Xie HJ, Shan JM, Ping WY, Park WS, Lee JY, Nam SW. Decreased expression of TFF2 and gastric carcinogenesis. Mol Cell Toxicol 2010; 6:261-269. [DOI: 10.1007/s13273-010-0036-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Sun Y, Wu W, Wang L, Liang G, Zhang Y, Lv S, Wang Z, Wang S, Peng X. Overexpression of hTFF2 in the pET system and its in vitro pharmacological characterization. Biomed Pharmacother 2009; 64:343-7. [PMID: 20074900 DOI: 10.1016/j.biopha.2009.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 12/01/2009] [Indexed: 12/12/2022] Open
Abstract
The trefoil factor family 2 (TFF2), a member of the trefoil factor family, plays a critical role in the defense and repair of gastrointestinal mucosa. However, its widespread application is hampered by difficulties in large-scale production of the recombinant protein suitable for clinical use. The aim of the present study was to produce hTFF2 by Escherichia coli expression system and explore its in vitro pharmacological characterization. hTFF2 gene encoding mature peptide was obtained by RT-PCR, and then inserted into the expression vector pET32a to construct the recombinant pET32a-hTFF2. After confirmation by gene sequencing, pET32a-hTFF2 was transformed into E. coli Origami B(DE3), and TrxA-hTFF2 fusion protein was expressed by conventional IPTG induction in a shake flask and analyzed with SDS-PAGE and Western-blot. Subsequently, TrxA-hTFF2 was isolated by Ni-NTA affinity chromatography, and ultrafiltration. Finally, we tested the effect of hTFF2 on cell migration in an in vitro restitution model and cell proliferation by MTT assay. The data revealed that the recombinant vector pET32a-hTFF2 was constructed successfully. TrxA-hTFF2 fusion protein was expressed to 246.5mg/L and its purity was above 95% after purification. SDS-PAGE and Western blot analyses showed that the fusion protein presented as a single band with a molecular weight of 32kDa. In vitro model of wounding demonstrated that hTFF2 enhanced migration activity by three folds. MTT assay exhibited a statistically significant dose-dependent growth-enhanced effect. Collectively, the results suggest that the recombinant hTFF2 was expressed in E. coli with high production, purity and biological activity.
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Affiliation(s)
- Yong Sun
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, The Third Military Medical University, Gaotanyan Street, Chongqing 400038, PR China
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44
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Sun Y, Wu W, Zhang Y, Lv S, Wang L, Wang S, Peng X. Stability analysis of recombinant human TFF2 and its therapeutic effect on burn-induced gastric injury in mice. Burns 2009; 35:869-74. [PMID: 19487079 DOI: 10.1016/j.burns.2008.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Accepted: 12/03/2008] [Indexed: 11/26/2022]
Abstract
The trefoil factor family 2 (TFF2), a member of the trefoil factor family, plays a critical role in maintaining homeostasis throughout the gastrointestinal tract. In the present study, we expressed recombinant human TFF2 by Escherichia coli expression system with the purity above 95%. In an in vitro simulated gastrointestinal environment, rhTFF2 was shown to exhibit resistance to proteases, heat, acid and alkali. In addition, in mouse burn-induced gastric injury models, rhTFF2 was demonstrated to accelerate the healing of gastric mucosal lesions. This study provides a new way to treat burn-induced gastric injury.
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Affiliation(s)
- Yong Sun
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, The Third Military Medical University, Chongqing 40038, PR China.
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The Trefoil Peptide Family: Small But Versatile — From Anti-Apoptosis to Neoplasia in the Digestive Tract. POLISH JOURNAL OF SURGERY 2009. [DOI: 10.2478/v10035-009-0079-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Hernández C, Santamatilde E, McCreath KJ, Cervera AM, Díez I, Ortiz-Masiá D, Martínez N, Calatayud S, Esplugues JV, Barrachina MD. Induction of trefoil factor (TFF)1, TFF2 and TFF3 by hypoxia is mediated by hypoxia inducible factor-1: implications for gastric mucosal healing. Br J Pharmacol 2008; 156:262-72. [PMID: 19076725 DOI: 10.1111/j.1476-5381.2008.00044.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Mucosal microcirculation is compromised during gastric damage induced by non-steroidal anti-inflammatory drugs, such as aspirin. Consequently, oxygen supply to epithelial cells is decreased. The trefoil factor (TFF) peptides are involved in mechanisms of defence and repair in the gastrointestinal tract but their regulation at sites of gastric injury is unknown. EXPERIMENTAL APPROACH Hypoxia and expression of TFF genes and peptides were measured in the damaged stomach of aspirin-treated rats. In a human gastric cell line (AGS cells), the effects of hypoxia and of hypoxia inducible factor (HIF)-1 (through transient transfection of HIF-1alpha siRNA or over-expression of HIF-1alpha) on TFF gene expression were evaluated. KEY RESULTS Hypoxyprobe immunostaining, up-regulation of TFF2 (1.9-fold) and TFF3 (1.8-fold) and a non-significant increase of TFF1 (1.5-fold) mRNA were observed in the damaged stomach of aspirin-treated rats, compared with control animals. Hypoxia (3% O(2), 16 h) induced mRNA for TFF1 (5.8-fold), TTF2 (9.1-fold) and TFF3 (9.3-fold) in AGS cells, an effect mediated by HIF-1, as transient transfection of HIF-1alpha siRNA reduced the effects of hypoxia. Over-expression of HIF-1alpha by transfection in non-hypoxic epithelial cells produced a similar pattern of TFF induction to that observed with hypoxia and transactivated a TFF1 reporter construct. CONCLUSIONS AND IMPLICATIONS Hypoxia inducible factor-1 mediated the induction of TFF gene expression by hypoxia in gastric epithelial cells. Low oxygen levels and up-regulation of TFF gene expression in the damaged stomach of aspirin-treated rats suggest that hypoxia induced expression of TFF genes at sites of gastric injury.
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Affiliation(s)
- C Hernández
- Departamento de Farmacología and CIBEREHD, Valencia, Spain
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Karam SM, Tomasetto C, Rio M. Amplification and invasiveness of epithelial progenitors during gastric carcinogenesis in trefoil factor 1 knockout mice. Cell Prolif 2008; 41:923-935. [PMID: 19040570 PMCID: PMC6496233 DOI: 10.1111/j.1365-2184.2008.00562.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2007] [Accepted: 03/12/2008] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE It is not known whether or not epithelial progenitors of the pyloric antrum are involved in gastric carcinogenesis. Normally, these progenitors give rise to two main cell lineages: pit and gland mucous cells. This study was designed to examine the changes that occur in pyloric antral mucous cell lineages and their progenitors during development of gastric adenoma and carcinoma in trefoil factor 1 (TFF1) knockout mice. MATERIALS AND METHODS Pyloric antral mucosal tissues of TFF1 knockout mice at ages from 3 days to 17 months were processed for histochemical analysis using Ulex europaeus and Grifforia simplifolica lectins as markers for pit and gland mucous cells, respectively. The dividing epithelial progenitors were identified by using immunohistochemical and electron microscopy techniques. RESULTS TFF1 loss was associated with amplification of both mucus-secreting pit and gland cells. Both lectins examined bound not only to mature mucous cells, but also to most of epithelial progenitors which gradually amplified with age and frequently were seen in mitosis. Analysis of 12- to 17-month-old TFF1-deficient stomachs revealed occasional groups of poorly differentiated mucosal cells with features similar to those of epithelial progenitors (or stem cells), in the basal portion of the antral mucosa. These cells eventually invaded the muscularis mucosa while maintaining some capacity to differentiate. CONCLUSION This study shows that the progenitors of pit and gland mucous cells contribute to gastric carcinogenesis in the pyloric antrum of TFF1 knockout mice, strongly supporting the concept of stem cell origin of cancer.
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Affiliation(s)
- S. M. Karam
- Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, and
| | - C. Tomasetto
- Institute of Genetics and Molecular and Cellular Biology, Department of Cancer Biology, University of Louis Pasteur, Illkirch cedex, France
| | - M.‐C. Rio
- Institute of Genetics and Molecular and Cellular Biology, Department of Cancer Biology, University of Louis Pasteur, Illkirch cedex, France
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High-throughput cell-based screening reveals a role for ZNF131 as a repressor of ERalpha signaling. BMC Genomics 2008; 9:476. [PMID: 18847501 PMCID: PMC2577665 DOI: 10.1186/1471-2164-9-476] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 10/11/2008] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Estrogen receptor alpha (ERalpha) is a transcription factor whose activity is affected by multiple regulatory cofactors. In an effort to identify the human genes involved in the regulation of ERalpha, we constructed a high-throughput, cell-based, functional screening platform by linking a response element (ERE) with a reporter gene. This allowed the cellular activity of ERalpha, in cells cotransfected with the candidate gene, to be quantified in the presence or absence of its cognate ligand E2. RESULTS From a library of 570 human cDNA clones, we identified zinc finger protein 131 (ZNF131) as a repressor of ERalpha mediated transactivation. ZNF131 is a typical member of the BTB/POZ family of transcription factors, and shows both ubiquitous expression and a high degree of sequence conservation. The luciferase reporter gene assay revealed that ZNF131 inhibits ligand-dependent transactivation by ERalpha in a dose-dependent manner. Electrophoretic mobility shift assay clearly demonstrated that the interaction between ZNF131 and ERalpha interrupts or prevents ERalpha binding to the estrogen response element (ERE). In addition, ZNF131 was able to suppress the expression of pS2, an ERalpha target gene. CONCLUSION We suggest that the functional screening platform we constructed can be applied for high-throughput genomic screening candidate ERalpha-related genes. This in turn may provide new insights into the underlying molecular mechanisms of ERalpha regulation in mammalian cells.
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Vestergaard EM, Nexo E, Wendt A, Guthmann F. Trefoil factors in human milk. Early Hum Dev 2008; 84:631-5. [PMID: 18502057 DOI: 10.1016/j.earlhumdev.2008.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2008] [Revised: 04/07/2008] [Accepted: 04/08/2008] [Indexed: 01/29/2023]
Abstract
We measured concentrations of the gastrointestinal protective peptides Trefoil factors in human milk. By the use of in-house ELISA we detected high amounts of TFF3, less TFF1 and virtually no TFF2 in human breast milk obtained from 46 mothers with infants born extremely preterm (24-27 wk gestation), preterm (28-37 wk gestation), and full term (38-42 wk gestation). Samples were collected during the first, second, third to fourth weeks and more than 4 wks postpartum. Median (range) TFF1 [TFF3] concentrations in human milk were 320 (30-34000) [1500 (150-27,000)] pmol/L in wk 1, 120 (30-720) [310 (50-7100)] pmol/L in wk 2, 70 (20-670) [120 (20-650)] pmol/L in wks 3 to 4, and 60 (30-2500) [80 (20-540)] pmol/L in >4 wks after delivery. The lowest concentrations of TFF1 and TFF3 were found later than 2 wks after birth. In conclusion, TFF was present in term and preterm human milk with rapidly declining concentrations during the first weeks post partum. The clinical significance of TFF present in human milk remains to be explored, both regarding development of the fetal gut and protection against necrotizing enterocolitis.
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Affiliation(s)
- Else Marie Vestergaard
- Department of Clinical Biochemistry, Aarhus University Hospital Skejby, Aarhus, Denmark.
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50
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Travaglini L, Vian L, Billi M, Grignani F, Nervi C. Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status. Int J Biochem Cell Biol 2008; 41:225-34. [PMID: 18789398 DOI: 10.1016/j.biocel.2008.08.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Revised: 08/09/2008] [Accepted: 08/11/2008] [Indexed: 01/10/2023]
Abstract
Estrogen receptors (ERs) are a recognized prognostic factor and therapeutic target in breast cancer. The loss of ER expression relates to poor prognosis, poor clinical outcome and impairs the use of anti-estrogenic treatment. Histone deacetylase inhibitors are candidate drugs for cancer therapy. Among them, valproic acid (VPA) is a long used and safe anti-epileptic drug. We studied the biological consequences of the chromatin remodeling action of VPA in a normal human mammary epithelial cell line and in ERalpha-positive and ERalpha-negative breast cancer cell lines. In these cells and regardless of their ER status, VPA-induced cell differentiation, as shown by increased milk lipids production, decreased expression of the CD44 antigen and growth arrest in the G(0)-G(1) phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21(WAF1/CIP1) gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G(2). ERalpha expression decreased in ERalpha-positive, increased in ERalpha-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERalpha target. VPA decreased the expression of the invasiveness marker pS2 in ERalpha-positive breast cancer cells, but did not cause its re-expression in ERalpha-negative cells. Overall, these data suggest that in both ERalpha-positive and -negative malignant mammary epithelial cells VPA reprograms the cells to a more differentiated and "physiologic" phenotype that may improve the sensitivity to endocrine therapy and/or chemotherapy in breast cancer patients.
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Affiliation(s)
- Lorena Travaglini
- Department of Histology & Medical Embryology, University of Rome La Sapienza, Italy
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