ArticleGastroenterology2019
Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer.
Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- VSIG10L is a major determinant of esophageal homeostasis and inherited predisposition to Barrett's esophagus.Nature communications · 2026Article
- AI-driven pathology in esophageal cancer: from early screening to precision prognostics.Frontiers in oncology · 2026Review
- JNK inhibitor SP600125 alleviates TGF-β2-induced epithelial-mesenchymal transition in RPE cellInternational journal of ophthalmology · 2026Article
- Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge.Functional & integrative genomics · 2025Review
- Aging-associated mechanisms and metabolic vulnerabilities in esophageal carcinoma: an integrative review.Frontiers in cell and developmental biology · 2025Review
- Metabolic reprogramming and immunological changes in the microenvironment of esophageal cancer: future directions and prospects.Frontiers in immunology · 2025Review
- 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
- Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Review
- The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers.Biomolecules · 2023Review
- Cancer Risk in Barrett's Esophagus: A Clinical Review.International journal of molecular sciences · 2023Review
- HNF4A Defines Molecular Subtypes and Vulnerability to Transforming Growth Factor β-Pathway Targeted Therapies in Cancers of the Distal Esophagus.Gastroenterology · 2022Article
- The Ephrin B2 Receptor Tyrosine Kinase Is a Regulator of Proto-oncogene MYC and Molecular Programs Central to Barrett's Neoplasia.Gastroenterology · 2022Article
- Article
- Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications.Frontiers in immunology · 2022Review
- Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment.Frontiers in oncology · 2022Review
- TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.Gastroenterology · 2021Review
- Characterization of TGFβ-associated molecular features and drug responses in gastrointestinal adenocarcinoma.BMC gastroenterology · 2021Article
- ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling.Journal of experimental & clinical cancer research : CR · 2021Article
- YAP-TEAD up-regulates IRS2 expression to induce and deteriorate oesophageal cancer.Journal of cellular and molecular medicine · 2021Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsEsophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression.
methodsWe collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice.
resultsComparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells.
conclusionsIn a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of 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.