Impaired transforming growth factor beta signalling in Barrett's carcinogenesis due to frequent SMAD4 inactivation.

Abstract:

BACKGROUND AND AIMS:Transforming growth factor beta (TGF-beta) is frequently involved in gastrointestinal carcinogenesis although its contribution to oesophageal adenocarcinoma (AC) and its precursor Barrett's oesophageal epithelium (BE) metaplasia are unclear. METHODS:Expression of TGF-beta signalling components was assessed by reverse transcription-polymerase chain reaction (PCR), western blot, and immunohistochemistry in oesophageal endoscopic biopsies and cell lines. Genomic alterations in SMAD4 were characterised by fluorescence in situ hybridisation, methylation specific PCR, and sequencing. Functional integrity of TGF-beta signalling was assessed by characterisation of p21 and proliferation status. Smad4 negative BIC-1 cells were transiently transfected with smad4 and TGF-beta responsiveness evaluated. RESULTS:smad4 mRNA expression was progressively reduced in the metaplasia-dysplasia-adenocarcinoma sequence (p<0.01). A quarter of AC samples displayed an abnormal Smad4 protein isoform, with no corresponding changes in gene sequence or organisation. Methylation of smad4 has not been described previously but we found promoter methylation in 70% of primary AC samples. In 6/8 oesophageal cell lines, chromosomal rearrangements affected the smad4 locus. Lack of smad4 expression in BIC-1 cells occurred secondary to loss of one copy and extensive deletion of the second allele's promoter region. TGF-beta dependent induction of p21 and downregulation of minichromosome maintenance protein 2 was lost in >80% of BE and AC. TGF-beta failed to inhibit proliferation in 5/8 oesophageal cell lines. In BIC-1, the antiproliferative response was restored following transient transfection of smad4 cDNA. CONCLUSIONS:In BE carcinogenesis, downregulation of Smad4 occurs due to several different mechanisms, including methylation, deletion, and protein modification. Frequent alterations in TGF-beta signalling lead to a functionally significant impairment of TGF-beta mediated growth suppression.

journal_name

Gut

journal_title

Gut

authors

Onwuegbusi BA,Aitchison A,Chin SF,Kranjac T,Mills I,Huang Y,Lao-Sirieix P,Caldas C,Fitzgerald RC

doi

10.1136/gut.2005.076430

keywords:

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

764-74

issue

6

eissn

0017-5749

issn

1468-3288

pii

gut.2005.076430

journal_volume

55

pub_type

杂志文章

相关文献

GUT文献大全
  • Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus.

    abstract:BACKGROUND:Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from decreased mast cell acti...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.2007.120238

    authors: The FO,Bennink RJ,Ankum WM,Buist MR,Busch OR,Gouma DJ,van der Heide S,van den Wijngaard RM,de Jonge WJ,Boeckxstaens GE

    更新日期:2008-01-01 00:00:00

  • Open access gastroscopy: second survey of current practice in the United Kingdom.

    abstract::In June 1990 a survey of members of the endoscopy section of the British Society of Gastroenterology showed that 47% of respondents were offering some form of open access gastroscopy (OAG). Only 10% offered true (non-censored) OAG. The survey was repeated in June 1994. The overall provision of OAG had risen to 74%, mo...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.40.2.192

    authors: Silcock JG,Bramble MG

    更新日期:1997-02-01 00:00:00

  • The effect of heritability and host genetics on the gut microbiota and metabolic syndrome.

    abstract:OBJECTIVE:Metabolic syndrome (MetS) arises from complex interactions between host genetic and environmental factors. Although it is now widely accepted that the gut microbiota plays a crucial role in host metabolism, current knowledge on the effect of host genetics on specific gut microbes related to MetS status remain...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gutjnl-2015-311326

    authors: Lim MY,You HJ,Yoon HS,Kwon B,Lee JY,Lee S,Song YM,Lee K,Sung J,Ko G

    更新日期:2017-06-01 00:00:00

  • Novel human and mouse genes encoding an acid phosphatase family member and its downregulation in W/W(V) mouse jejunum.

    abstract:BACKGROUND AND AIMS:Interstitial cells of Cajal (ICC) are pacemakers and mediators of motor neurotransmission in gastrointestinal smooth muscles. ICC require cellular signalling via Kit, a receptor tyrosine kinase, for development and maintenance of phenotype. Much of the evidence demonstrating the functions of ICC com...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.50.6.790

    authors: Takayama I,Daigo Y,Ward SM,Sanders KM,Walker RL,Horowitz B,Yamanaka T,Fujino MA

    更新日期:2002-06-01 00:00:00

  • Dietary nucleotides and gut mucosal defence.

    abstract::The informational aspects of nucleic acid synthesis have attracted much more attention than the quantitative significance of DNA, rRNA, tRNA, and nucleotide synthesis. Animal and human studies suggest that in energetic terms, 5-10% of the energy used in synthesising tissue protein is expended in manufacturing an appro...

    journal_title:Gut

    pub_type: 杂志文章,评审

    doi:10.1136/gut.35.1_suppl.s46

    authors: Grimble GK

    更新日期:1994-01-01 00:00:00

  • Echo enhanced ultrasound: a new valid initial imaging approach for severe acute pancreatitis.

    abstract:AIM:This prospective study aimed to compare the accuracy of echo enhanced ultrasound with spiral computed tomography (CT) in assessing acute pancreatitis and to explore the correlation between ultrasound findings and clinical outcome. METHODS:Thirty one patients (24 men and 7 women, median age 39 years, range 19-67 ye...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.2005.070276

    authors: Rickes S,Uhle C,Kahl S,Kolfenbach S,Monkemuller K,Effenberger O,Malfertheiner P

    更新日期:2006-01-01 00:00:00

  • Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

    abstract:OBJECTIVES:Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN:Retrospective multinational study including SCN diagnosed between 1990 and 2014. ...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gutjnl-2015-309638

    authors: Jais B,Rebours V,Malleo G,Salvia R,Fontana M,Maggino L,Bassi C,Manfredi R,Moran R,Lennon AM,Zaheer A,Wolfgang C,Hruban R,Marchegiani G,Fernández Del Castillo C,Brugge W,Ha Y,Kim MH,Oh D,Hirai I,Kimura W,Jang JY

    更新日期:2016-02-01 00:00:00

  • The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma.

    abstract:BACKGROUND:Melanoma inhibitory activity 2 (MIA2) is a novel gene of the MIA gene family. The selective expression of MIA2 in hepatocytes is controlled by hepatocyte nuclear factor (HNF) 1 binding sites in the MIA2 promotor. In contrast, in most hepatocellular carcinomas (HCC) MIA2 expression is down-regulated or lost. ...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.2007.129544

    authors: Hellerbrand C,Amann T,Schlegel J,Wild P,Bataille F,Spruss T,Hartmann A,Bosserhoff AK

    更新日期:2008-02-01 00:00:00

  • An investigation into the reversibility of the morphological and cytokinetic changes seen in the small intestine of riboflavin deficient rats.

    abstract:BACKGROUND:Impaired iron handling in riboflavin deficiency is thought to be partially a result of significant morphological and cytokinetic changes within the small intestine. AIMS:The aim of the study was to find out if the responses of the rat small intestine to riboflavin deficiency induced at weaning could be reve...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.39.2.220

    authors: Williams EA,Rumsey RD,Powers HJ

    更新日期:1996-08-01 00:00:00

  • Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised, double blind, crossover, placebo controlled study.

    abstract:BACKGROUND:High dose growth hormone, glutamine, and a high carbohydrate diet may improve intestinal function in short bowel patients. AIMS:To investigate if growth hormone with glutamine and no change in diet improved intestinal function. PATIENTS AND METHODS:Eight short bowel patients were randomised in a double bli...

    journal_title:Gut

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1136/gut.47.2.199

    authors: Szkudlarek J,Jeppesen PB,Mortensen PB

    更新日期:2000-08-01 00:00:00

  • Diagnostic utility of reflux disease symptoms.

    abstract::Symptom assessment, by structured interview or questionnaire, is central to the diagnosis of gastro-oesophageal reflux disease (GORD). However, empiric support for the diagnostic utility of reflux symptom measures is lacking. Reliable reflux symptom questionnaires have been developed with content validity. These quest...

    journal_title:Gut

    pub_type: 杂志文章,评审

    doi:10.1136/gut.2003.034280

    authors: Shaw M

    更新日期:2004-05-01 00:00:00

  • Comparison of the Rome IV criteria with the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care.

    abstract:OBJECTIVES:Despite being proposed 4 years ago, there has been no independent validation study of the Rome IV criteria for IBS. We assessed their performance for the diagnosis of IBS in secondary care and compared them with the previous iteration, the Rome III criteria. DESIGN:We collected complete symptom data from co...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gutjnl-2020-322519

    authors: Black CJ,Craig O,Gracie DJ,Ford AC

    更新日期:2020-09-24 00:00:00

  • Factors influencing postoperative recurrence of Crohn's disease in childhood.

    abstract::We have reviewed the outcome of all patients undergoing their first intestinal resection for Crohn's disease at this hospital between 1970 and 1987. Recurrence rates, defined by recurrent intestinal symptoms and radiological confirmation of mucosal disease, were calculated using survival analysis. Age, sex, anatomical...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.32.5.491

    authors: Griffiths AM,Wesson DE,Shandling B,Corey M,Sherman PM

    更新日期:1991-05-01 00:00:00

  • Normal deglutitive responses of the human lower oesophageal sphincter.

    abstract::The responses to deglutition of the lower oesophageal high pressure zone were studied in 13 healthy subjects. The recording assembly included three perfused pressure recording catheters, whose recording orifices were at the same axial level, and a more distally situated pH electrode. Relaxation and contraction progres...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.13.5.352

    authors: Kaye MD,Showalter JP

    更新日期:1972-05-01 00:00:00

  • Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis.

    abstract::A patient presented with pruritus and recent elevation of aminotransferases. The case fulfilled most of the criteria for the diagnosis of autoimmune hepatitis and achieved clinical and complete biochemical response to steroid therapy. However, the liver biopsy specimen revealed an unusual histological pattern consisti...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.41.2.269

    authors: Te HS,Koukoulis G,Ganger DR

    更新日期:1997-08-01 00:00:00

  • Refractory pouchitis: does it reflect underlying Crohn's disease?

    abstract::Typical 'pouchitis' is a well recognised complication of ileal pouches in ulcerative colitis. Infrequently, a refractory pouchitis (RP) presents with certain clinical, endoscopic, and pathological features resembling Crohn's disease and is often ascribed to misdiagnosis of the initial colitis. To test that hypothesis ...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.34.11.1539

    authors: Subramani K,Harpaz N,Bilotta J,Bodian C,Rubin PH,Janowitz HD,Gelernt IM,Sachar DB

    更新日期:1993-11-01 00:00:00

  • Anticipation in familial pancreatic cancer.

    abstract:BACKGROUND:Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. PATIENTS AND METHODS:A total of 1223 individuals at risk from 106 families (264 affected individuals) w...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.2005.065045

    authors: McFaul CD,Greenhalf W,Earl J,Howes N,Neoptolemos JP,Kress R,Sina-Frey M,Rieder H,Hahn S,Bartsch DK,European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC).,German National Case Collection for Familial

    更新日期:2006-02-01 00:00:00

  • Mast cells are an important cellular source of tumour necrosis factor alpha in human intestinal tissue.

    abstract:BACKGROUND:Several inflammatory disorders of the intestine are characterised by enhanced expression of tumour necrosis factor alpha (TNF-alpha). Monocytes and macrophages have been suggested as a major cellular source of TNF-alpha in human gut, whereas mast cells, although known to be capable of producing TNF-alpha, ha...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.44.5.643

    authors: Bischoff SC,Lorentz A,Schwengberg S,Weier G,Raab R,Manns MP

    更新日期:1999-05-01 00:00:00

  • Hepatitis C virus: epidemiology and genotypes in the north east of England.

    abstract::The epidemiology of hepatitis C virus (HCV) infection was studied in an English teaching hospital over an 18 month period. A total of 104 HCV antibody positive patients were referred for further investigation. They were divided into those diagnosed through screening (blood donors and intravenous drug abusers) and thos...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.38.2.269

    authors: Watson JP,Brind AM,Chapman CE,Bates CL,Gould FK,Johnson SJ,Burt AD,Ferguson J,Simmonds P,Bassendine MF

    更新日期:1996-02-01 00:00:00

  • Zollinger-Ellison syndrome type 1: clinical and pathological correlations in a case.

    abstract::Some patients with the Zollinger-Ellison syndrome appear to have hypergastrinaemia and hyperplasia of the antral G cells but no tumour. This subgroup has been classified as Zollinger-Ellison syndrome type 1. We have treated such a patient by vagotomy and antrectomy, the fasting plasma gastrin and acid secretion subseq...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.14.1.25

    authors: Cowley DJ,Dymock IW,Boyes BE,Wilson RY,Stagg BH,Lewin MR,Polak JM,Pearse AG

    更新日期:1973-01-01 00:00:00

  • 13C labelled cholesteryl octanoate breath test for assessing pancreatic exocrine insufficiency.

    abstract:BACKGROUND:A non-invasive test for assessment of fat digestion has been developed based on the intraluminal hydrolysis of cholesteryl-[1-13C]octanoate by pancreatic esterase. AIMS:To determine the diagnostic performance of this breath test in the assessment of exocrine pancreatic function. METHODS:The test was perfor...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.42.1.81

    authors: Ventrucci M,Cipolla A,Ubalducci GM,Roda A,Roda E

    更新日期:1998-01-01 00:00:00

  • Endothelin and vascular function in liver disease.

    abstract::The endothelins are a group of three related peptides with two receptor subtypes, ET(A) and ET(B). Following the discovery of endothelin 1 as a potent vasoconstrictor, there has been intense interest in the role of endothelin on vascular function in liver disease. Speculation on the role of endothelin in the pathogene...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.2003.024703

    authors: Moore K

    更新日期:2004-02-01 00:00:00

  • RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours.

    abstract:OBJECTIVE:We aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). DESIGN:Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational s...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gutjnl-2018-317632

    authors: Longerich T,Endris V,Neumann O,Rempel E,Kirchner M,Abadi Z,Uhrig S,Kriegsmann M,Weiss KH,Breuhahn K,Mehrabi A,Weber TF,Wilkens L,Straub BK,Rosenwald A,Schulze F,Brors B,Froehling S,Pellegrino R,Budczies J,Schirmac

    更新日期:2019-07-01 00:00:00

  • A ne method for studying gut transit times using radioopaque markers.

    abstract::A simple technique for measuring gastrointestinal transit times using radioopaque pellets of barium-impregnated polythene has been developed and validated. A normal range has been established by studying 25 normal subjects; all passed the first marker within three days and most passed 80% of the markers within five da...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.10.10.842

    authors: Hinton JM,Lennard-Jones JE,Young AC

    更新日期:1969-10-01 00:00:00

  • Gastric epithelial cell turnover, mucus production, and healing of gastric ulcers with carbenoxolone.

    abstract::Nineteen healthy subjects were studied and 17 patients with gastric ulcer before and after ulcer healing with carbenoxolone. Gastric deoxytibonucleic acid (DNA) loss was measured as an index of epithelial cell turnover, and N-acetylneuraminic acid (NANA) content of gastric juice as an index of mucus secretion. In norm...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.18.10.817

    authors: Domschke W,Domschke S,Hagel J,Demling L,Croft DN

    更新日期:1977-10-01 00:00:00

  • Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation.

    abstract:BACKGROUND:The role of intestinal transporter regulation in optimising nutrient absorption has been studied extensively in rodent and cell line models but not in human subjects. AIMS:The aim of the present study was to investigate the response in vivo of zinc transporters in the human enterocyte to dietary zinc supple...

    journal_title:Gut

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1136/gut.2004.041962

    authors: Cragg RA,Phillips SR,Piper JM,Varma JS,Campbell FC,Mathers JC,Ford D

    更新日期:2005-04-01 00:00:00

  • Proliferation cell nuclear antigen (clone 19A2) correlates with 5-bromo-2-deoxyuridine labelling in human colonic epithelium.

    abstract::Measurements of cell proliferation can be used as biomarkers of preneoplastic change. In this study, two immunocytochemical methods that measure different components of the cell cycle were compared to assess cell proliferation on biopsy samples from human colonic mucosa. These methods are based on a monoclonal antibod...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.34.11.1587

    authors: Weisgerber UM,Boeing H,Nemitz R,Raedsch R,Waldherr R

    更新日期:1993-11-01 00:00:00

  • Pancreatic surgery, not pancreatitis, is the primary cause of diabetes after acute fulminant pancreatitis.

    abstract::Acute fulminant pancreatitis is associated with significant morbidity and mortality. To examine the outcome of conservative and surgical treatment of this disorder, 36 patients who survived an initial episode were restudied after a mean of six years. Fifty three per cent had developed diabetes mellitus, half of whom r...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.33.6.843

    authors: Eriksson J,Doepel M,Widén E,Halme L,Ekstrand A,Groop L,Höckerstedt K

    更新日期:1992-06-01 00:00:00

  • Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence.

    abstract:OBJECTIVE:In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9-/- mice are more susceptible to the enteric mouse pathogen C...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gutjnl-2017-314195

    authors: Lamas B,Michel ML,Waldschmitt N,Pham HP,Zacharioudaki V,Dupraz L,Delacre M,Natividad JM,Costa GD,Planchais J,Sovran B,Bridonneau C,Six A,Langella P,Richard ML,Chamaillard M,Sokol H

    更新日期:2018-10-01 00:00:00

  • Mucosal sulfhydryl compounds evaluation by in vivo electron spin resonance spectroscopy in mice with experimental colitis.

    abstract:BACKGROUND:Sulfhydryl (SH) compounds are essential in maintaining mucosal integrity in the gastrointestinal tract. A decrease in colonic mucosal SH compounds affects the redox status of the mucosa, resulting in vulnerability to further attacks. Therefore, there is a strong need for in vivo evaluation of SH compounds in...

    journal_title:Gut

    pub_type: 杂志文章

    doi:10.1136/gut.52.9.1291

    authors: Togashi H,Oikawa K,Adachi T,Sugahara K,Ito J,Takeda T,Watanabe H,Saito K,Saito T,Fukui T,Takeda H,Ohya H,Kawata S

    更新日期:2003-09-01 00:00:00