ArticleGut2006
Impaired transforming growth factor beta signalling in Barrett's carcinogenesis due to frequent SMAD4 inactivation.
Article in Gut, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.
- Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus.Human molecular genetics · 2016Pooled it
- Targeting SMAD3 Improves Response to Oxaliplatin in Esophageal Adenocarcinoma Models by Impeding DNA Repair.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers.Biomolecules · 2023Review
- SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications.Diagnostics (Basel, Switzerland) · 2023Review
- SMAD4 contributes to chondrocyte and osteocyte development.Journal of cellular and molecular medicine · 2022Review
- TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.Gastroenterology · 2021Review
- Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay.Journal, genetic engineering & biotechnology · 2021Article
- RNA-Binding Proteins CLK1 and POP7 as Biomarkers for Diagnosis and Prognosis of Esophageal Squamous Cell Carcinoma.Frontiers in cell and developmental biology · 2021Article
- Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations.Clinical and translational gastroenterology · 2020Article
- From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma.Biochimica et biophysica acta. Reviews on cancer · 2019Review
- Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer.Gastroenterology · 2019Article
- Low Expression of Transforming Growth Factor β in the Epithelium of Barrett's Esophagus.Gastroenterology research · 2018Article
- Runx2-I is an Early Regulator of Epithelial-Mesenchymal Cell Transition in the Chick Embryo.Developmental dynamics : an official publication of the American Association of Anatomists · 2018Article
- Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers.Journal of Cancer · 2018Review
- Esophageal Cancer: Genomic and Molecular Characterization, Stem Cell Compartment and Clonal Evolution.Medicines (Basel, Switzerland) · 2017Review
- The tumor microenvironment in esophageal cancer.Oncogene · 2016Review
- Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma.Oncotarget · 2015Article
- Global changes in gene expression of Barrett's esophagus compared to normal squamous esophagus and gastric cardia tissues.PloS one · 2014Article
- Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction.Cancer biology & therapy · 2013Review
- Loss of TGF-β adaptor β2SP activates notch signaling and SOX9 expression in esophageal adenocarcinoma.Cancer research · 2013Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimsTransforming 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.
methodsExpression 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.
resultssmad4 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.
conclusionsIn 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.