ArticleCellular and molecular gastroenterology and hepatology2021
Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus.
Article in Cellular and molecular gastroenterology and hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Phylogenetic analysis of paired breast carcinomas identifies genetic events associated with clonal recurrence and invasive progression.The Journal of pathology · 2026Article
- MiRNA expression analysis from circulating exosomes in Barrett's esophagus patients with visceral obesity.Scientific reports · 2025Article
- The Interplay Between Esophageal Adenocarcinoma and Its Tumor Microenvironment: Toward Innovative Therapies.Cells · 2025Review
- Aging-associated mechanisms and metabolic vulnerabilities in esophageal carcinoma: an integrative review.Frontiers in cell and developmental biology · 2025Review
- Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.Life science alliance · 2024Article
- 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
- Modelling esophageal adenocarcinoma and Barrett's esophagus with patient-derived organoids.Frontiers in molecular biosciences · 2024Review
- SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications.Diagnostics (Basel, Switzerland) · 2023Review
- CNETML: maximum likelihood inference of phylogeny from copy number profiles of multiple samples.Genome biology · 2023Article
- Article
- Smad4 and p53 synergize in suppressing autochthonous intestinal cancer.Cancer medicine · 2022Article
- Drivers of Esophageal Adenocarcinoma and Opportunities for Cancer Interception.Cellular and molecular gastroenterology and hepatology · 2021Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsEsophageal adenocarcinoma (EAC) develops from its precursor Barrett's esophagus through intermediate stages of low- and high-grade dysplasia. However, knowledge of genetic drivers and molecular mechanisms implicated in disease progression is limited. Herein, we investigated the effect of Mothers against decapentaplegic homolog 4 (SMAD4) loss on transforming growth factor β (TGF-β) signaling functionality and in vivo tumorigenicity in high-grade dysplastic Barrett's cells.
methodsAn in vivo xenograft model was used to test tumorigenicity of SMAD4 knockdown or knockout in CP-B high-grade dysplastic Barrett's cells. RT
resultsWe found that SMAD4 knockout significantly alters the TGF-β pathway target gene expression profile. SMAD4 knockout positively regulates potential oncogenes such as CRYAB, ACTA2, and CDC6, whereas the CDKN2A/B tumor-suppressor locus was regulated negatively. We verified that SMAD4 in combination with CDC6-CDKN2A/B or CRYAB genetic alterations in patient tumors have significant predictive value for poor prognosis. Importantly, we investigated the effect of SMAD4 inactivation in Barrett's tumorigenesis. We found that genetic knockdown or knockout of SMAD4 was sufficient to promote tumorigenesis in dysplastic Barrett's esophagus cells in vivo. Progression to invasive EAC was accompanied by distinctive and consistent copy number alterations in SMAD4 knockdown or knockout xenografts.
conclusionsAltogether, up-regulation of oncogenes, down-regulation of tumor-suppressor genes, and chromosomal instability within the tumors after SMAD4 loss implicates SMAD4 as a protector of genome integrity in EAC development and progression. Foremost, SMAD4 loss promotes tumorigenesis from dysplastic Barrett's toward EAC.
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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.