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Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.
Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM
(2015) Cancer 121: 4348-58
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Chemokine CXCL5, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, I-kappa B Kinase, In Vitro Techniques, Inflammation, Interleukin-1beta, Mice, Mice, Knockout, Peptides, Phosphorylation, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-4, Stomach, Stomach Neoplasms, Transcription Factor RelA, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added September 28, 2015
BACKGROUND - Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.
METHODS - For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.
RESULTS - The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.
CONCLUSIONS - These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.
© 2015 American Cancer Society.
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3 Members
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24 MeSH Terms
Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis.
Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, Peek RM, El-Rifai W
(2015) Oncotarget 6: 17911-22
MeSH Terms: Active Transport, Cell Nucleus, Adenocarcinoma, Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Down-Regulation, Gastric Mucosa, Gene Expression Regulation, Neoplastic, HEK293 Cells, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Mice, Knockout, Peptides, RNA, Messenger, Signal Transduction, Stomach Neoplasms, Transfection, Trefoil Factor-1, Tumor Suppressor Proteins, beta Catenin
Show Abstract · Added September 28, 2015
Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.
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3 Members
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23 MeSH Terms
Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis.
Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W
(2015) Gut 64: 1028-39
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Growth Inhibitors, Immunohistochemistry, Mice, Mice, Knockout, Peptides, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, Stomach Neoplasms, Transcriptional Activation, Trefoil Factor-1, beta Catenin
Show Abstract · Added February 19, 2015
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.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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2 Members
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17 MeSH Terms
TFF1 activates p53 through down-regulation of miR-504 in gastric cancer.
Soutto M, Chen Z, Saleh MA, Katsha A, Zhu S, Zaika A, Belkhiri A, El-Rifai W
(2014) Oncotarget 5: 5663-73
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Down-Regulation, Female, Humans, Mice, Mice, Nude, MicroRNAs, Stomach Neoplasms, Trefoil Factor-1, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays
Show Abstract · Added July 21, 2014
The expression of TFF1 is frequently down-regulated in human gastric cancer whereas its knockout leads to the development of gastric adenomas and carcinomas in mouse models. The molecular mechanisms underlying the TFF1 tumor suppressor functions remain unclear. In this study, we demonstrate, using colony formation assay and Annexin V staining, that reconstitution of TFF1 expression in gastric cancer cell models suppresses cell growth and promotes cell death. Furthermore, using a tumor xenograft mouse model of gastric cancer, we demonstrated that reconstitution of TFF1 suppresses tumor growth in vivo. The results from PG13-luciferase reporter assay and Western blot analysis indicated that TFF1 promotes the expression and transcription activity of p53 protein. Further analysis using cycloheximide-based protein assay and quantitative real-time PCR data suggested that TFF1 does not interfere with p53 mRNA levels or protein stability. Alternatively, we found that the reconstitution of TFF1 down-regulates miR-504, a negative regulator of p53. Western blot analysis data demonstrated that miR-504 abrogates TFF1-induced p53 protein expression and activity. In conclusion, the in vitro and in vivo data demonstrate, for the first time, a novel mechanism by which the tumor suppressor functions of TFF1 involve activation of p53 through down-regulation of miR-504.
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3 Members
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16 MeSH Terms
Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy.
Limaye SA, Haddad RI, Cilli F, Sonis ST, Colevas AD, Brennan MT, Hu KS, Murphy BA
(2013) Cancer 119: 4268-76
MeSH Terms: Administration, Topical, Adolescent, Adult, Aged, Antineoplastic Agents, Female, Head and Neck Neoplasms, Humans, Induction Chemotherapy, Lactococcus lactis, Male, Middle Aged, Mouth Mucosa, Mouthwashes, Stomatitis, Trefoil Factor-1, Tumor Suppressor Proteins, Young Adult
Show Abstract · Added March 7, 2014
BACKGROUND - Oral mucositis (OM) is a significant toxicity of induction chemotherapy for locally advanced head and neck cancer (LAHNC). The safety and tolerability of AG013, an oral rinse containing recombinant Lactococcus lactis secreting mucosal protectant human trefoil factor 1 (hTFF1), was evaluated in a phase 1b study in LAHNC subjects who received induction with cisplatin, 5-fluorouracil, with or without docetaxel. Preliminary efficacy data were also obtained.
METHODS - A total of 25 of 52 LAHNC subjects who were followed during induction cycle 1 developed ulcerative oral mucositis (UOM; World Health Organization grade > 2) and were randomized to AG013:placebo (5:2 ratio) for cycle 2. Dosing schedules of 1, 3, or 6 times daily were evaluated (2 × 10(11) , 6 × 10(11) , and 1.2 × 10(12) colony forming units per day, respectively). OM was evaluated daily from cycle 2, day 1 through 14, using World Health Organization criteria. Pharmacokinetic assessment was also conducted.
RESULTS - AG013 bacteria were not detected in blood. Oral live AG013 bacterial and hTFF1 levels in saliva and oral mucosa were equivalent among treatment groups. The most frequently occurring adverse events were nausea, oral pain, fatigue, diarrhea, and mucosal inflammation. Only 12% (3 of 25 adverse events), mainly nausea, were attributed to the investigational medicinal product: AG013 or placebo. Efficacy analysis showed a 35% reduction in percentage of days with UOM in AG013-subjects versus placebo. All placebo subjects experienced ≥ 2 days of UOM, whereas 29% of AG013 subjects had UOM for 0 or 1 day. AG013 use resulted in fewer unscheduled office and emergency room visits. No differences were noted in mouth and throat soreness, opioid use, or gastrostomy tube placement.
CONCLUSIONS - AG013 was safe and well tolerated. Preliminary efficacy data support further study.
© 2013 American Cancer Society.
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1 Members
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18 MeSH Terms
Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia.
Katsha A, Soutto M, Sehdev V, Peng D, Washington MK, Piazuelo MB, Tantawy MN, Manning HC, Lu P, Shyr Y, Ecsedy J, Belkhiri A, El-Rifai W
(2013) Gastroenterology 145: 1312-22.e1-8
MeSH Terms: Adenocarcinoma, Animals, Aurora Kinase A, Azepines, Carcinogenesis, Cell Line, Tumor, Disease Models, Animal, Female, Gastric Mucosa, Heterografts, Humans, In Vitro Techniques, Inflammation, Mice, Knockout, Mice, Nude, NF-kappa B, Peptides, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, Stomach Neoplasms, Trefoil Factor-1, Up-Regulation
Show Abstract · Added September 3, 2013
BACKGROUND & AIMS - Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis.
METHODS - We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1(-/-) mice, growth of tumor xenografts, and human tissues.
RESULTS - We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1(-/-) mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1(-/-) mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue.
CONCLUSIONS - In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer.
Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
1 Communities
6 Members
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23 MeSH Terms
Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans.
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
(2011) J Clin Invest 121: 1753-67
MeSH Terms: Animals, Disease Progression, Gastric Mucosa, Gene Expression Profiling, Humans, I-kappa B Proteins, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-KappaB Inhibitor alpha, NF-kappa B, Oligonucleotide Array Sequence Analysis, Peptides, Phosphorylation, Stomach Neoplasms, Trefoil Factor-1, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins
Show Abstract · Added July 26, 2012
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.
1 Communities
6 Members
0 Resources
19 MeSH Terms
Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal adenocarcinomas.
McChesney PA, Aiyar SE, Lee OJ, Zaika A, Moskaluk C, Li R, El-Rifai W
(2006) Cancer Res 66: 1346-53
MeSH Terms: Adenocarcinoma, Binding Sites, Cell Line, Tumor, DNA, Neoplasm, Esophageal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Nuclear Proteins, RNA, Messenger, Stomach Neoplasms, Transcription Factor AP-1, Transcription Factors, Trefoil Factor-1, Tumor Suppressor Proteins
Show Abstract · Added March 5, 2014
Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs. Immunohistochemical analysis of UGC tissue arrays that contained 70 tumor samples showed moderate-strong staining for COBRA1 in 60 (84%) tumors. Interestingly, the tumor samples showed absent-weak staining for TFF1 in 45 (65%) of the tumors. Simultaneous loss of TFF1 expression and overexpression of COBRA1 was observed in 42 of 70 (60%) tumors. Using small interfering RNA technology with gastric cancer cells, we have shown that COBRA1 inhibition leads to increased TFF1 promoter activity and gene expression. Promoter analysis of TFF1 indicated that regulation of TFF1 by COBRA1 is estrogen independent in contrast to breast cancer. Moreover, COBRA1 regulation of TFF1 in gastric cancer cells was independent of NELF-E. Using several truncated mutants and site mutants of the TFF1 promoter, we have shown that COBRA1 can negatively regulate the activator protein-1 (AP-1) complex at the TFF1 promoter and thus down-regulate TFF1 expression in gastric cancer cell lines. Electrophoretic mobility shift assay showed that COBRA1 attenuates AP-1 binding to DNA. Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia.
0 Communities
2 Members
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14 MeSH Terms
Expression of tight-junction protein claudin-7 is an early event in gastric tumorigenesis.
Johnson AH, Frierson HF, Zaika A, Powell SM, Roche J, Crowe S, Moskaluk CA, El-Rifai W
(2005) Am J Pathol 167: 577-84
MeSH Terms: Adenocarcinoma, Aged, Aged, 80 and over, Animals, Claudins, DNA-Binding Proteins, Early Growth Response Protein 1, Estrogens, Female, Gastric Mucosa, Gene Expression Profiling, Growth Inhibitors, Humans, Immediate-Early Proteins, Male, Membrane Proteins, Metaplasia, Mice, Mice, Knockout, Middle Aged, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, Receptors, Cell Surface, Stomach Neoplasms, Tight Junctions, Transcription Factors, Trefoil Factor-1, Tumor Suppressor Proteins
Show Abstract · Added March 5, 2014
Trefoil factor-1 (Tff1) expression is remarkably down-regulated in nearly all human gastric cancers. Therefore, we used the Tff1 knockout mouse model to detect molecular changes in preneoplastic gastric dysplasia. Oligonucleotide microarray gene expression analysis of gastric dysplasia of Tff1-/- mice was compared to that of normal gastric mucosa of wild-type mice. The genes most overexpressed in Tff1-/- mice included claudin-7 (CLDN7), early growth response-1 (EGR1), and epithelial membrane protein-1 (EMP1). Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that Cldn7 was overexpressed in all 10 Tff1-/- gastric dysplasia samples. Comparison with our serial analysis of gene expression database of human gastric cancer revealed similar deregulation in human gastric cancers. Quantitative real-time reverse transcriptase-polymerase chain reaction of human gastric adenocarcinoma samples indicated that, of these three genes, CLDN7 was the most frequently up-regulated gene. Using immunohistochemistry, both mouse and human gastric glands overexpressed Cldn7 in dysplastic but not surrounding normal glands. Cldn7 expression was observed in 30% of metaplasia, 80% of dysplasia, and 70% of gastric adenocarcinomas. Interestingly, 82% of human intestinal-type gastric adenocarcinomas expressed Cldn7 whereas diffuse-type gastric adenocarcinomas did not (P < 0.001). These results suggest that Cldn7 expression is an early event in gastric tumorigenesis that is maintained throughout tumor progression.
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2 Members
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28 MeSH Terms
Decreased abundance of trefoil factor 1 transcript in the majority of gastric carcinomas.
Beckler AD, Roche JK, Harper JC, Petroni G, Frierson HF, Moskaluk CA, El-Rifai W, Powell SM
(2003) Cancer 98: 2184-91
MeSH Terms: Adenocarcinoma, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Peptides, Proteins, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms, Transcription, Genetic, Trefoil Factor-1, Tumor Suppressor Proteins
Show Abstract · Added March 5, 2014
BACKGROUND - Gastric carcinoma is one of the leading causes of cancer-related death worldwide, but the mechanisms underlying its development and progression still remain largely uncharacterized. As loss of trefoil factor 1 (TFF1) expression leads to neoplastic growth in the antropyloric mucosa of mice, the authors sought to comprehensively study the human TFF1 gene in primary gastric carcinomas.
METHODS - The authors studied the human TFF1 gene in primary gastric carcinomas and normal gastric mucosa at the DNA, RNA, and protein levels through DNA sequencing, quantitative real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry.
RESULTS - Strikingly, TFF1 mRNA expression was significantly decreased in all 37 gastric carcinomas studied compared with normal gastric mucosa. Furthermore, six tumor/normal pairs with available histologic samples demonstrated a marked decrease in protein expression in tumor samples. Screening of the entire TFF1 coding region in a panel of 42 human gastric tumors did not reveal any somatic mutations, although a few rare germline sequence variants were identified.
CONCLUSIONS - These findings demonstrated a significant decrease in the TFF1 transcript in the majority of human gastric carcinomas along with a corresponding reduction in protein expression, both of which occurred in the absence of gene mutation. Dysregulation of TFF1 expression at the transcript level was a critical event in the development of most gastric carcinomas.
Copyright 2003 American Cancer Society.
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11 MeSH Terms