ArticleCancer research2013
Loss of TGF-β adaptor β2SP activates notch signaling and SOX9 expression in esophageal adenocarcinoma.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 70 citations in OpenAlex.
- Trial
- Targeting APE1-Redox Function Reverses SOX9-mediated Chemoresistance in Esophageal Adenocarcinoma.Gastroenterology · 2026Article
- Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies.Oncology reviews · 2026Review
- YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis.Cancer heterogeneity and plasticity · 2026Article
- Cirrhosis Promotes Cardiac Fibrosis Development by Inhibiting Notch1 in Cardiac Fibroblasts.JACC. Basic to translational science · 2025Article
- SOX9 is regulated by AURKA in response to Helicobacter pylori infection via EIF4E-mediated cap-dependent translation.Cancer letters · 2024Article
- SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division.Gastroenterology · 2023Article
- BMP-4 and BMP-7 Inhibit EMT in a Model of Anterior Subcapsular Cataract in Part by Regulating the Notch Signaling Pathway.Investigative ophthalmology & visual science · 2023Article
- Signaling pathways and therapeutic interventions in gastric cancer.Signal transduction and targeted therapy · 2022Review
- Notch-Sox9 Axis Mediates Hepatocyte Dedifferentiation inInternational journal of molecular sciences · 2022Article
- Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targetingGut · 2022Article
- Expression and Potential Prognostic Value of SOX9, MCL-1 and SPOCK1 in Gastric Adenocarcinoma.Pathology oncology research : POR · 2022Article
- β2SP/TET2 complex regulates gene 5hmC modification after cerebral ischemia.Journal of cellular and molecular medicine · 2021Article
- EditingInternational journal of molecular sciences · 2021Review
- TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.Gastroenterology · 2021Review
- Drug resistance and Cancer stem cells.Cell communication and signaling : CCS · 2021Review
- PIK3R1, SPNB2, and CRYAB as Potential Biomarkers for Patients with Diabetes and Developing Acute Myocardial Infarction.International journal of endocrinology · 2021Article
- Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma.Molecular oncology · 2020Article
- SOX9: The master regulator of cell fate in breast cancer.Biochemical pharmacology · 2020Review
- From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma.Biochimica et biophysica acta. Reviews on cancer · 2019Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. Loss of TGF-β signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear. Here we report that loss of TGF-β adapter β2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells. Expression of the stem cell marker SOX9 was markedly higher in esophageal adenocarcinoma tumor tissues than normal tissues, and its higher nuclear staining in tumors correlated with poorer survival and lymph node invasion in esophageal adenocarcinoma patients. Downregulation of β2SP by lentivirus short hairpin RNA increased SOX9 transcription and expression, enhancing nuclear localization for both active Notch1 (intracellular Notch1, ICN1) and SOX9. In contrast, reintroduction into esophageal adenocarcinoma cells of β2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity. Tumor sphere formation and invasive capacity in vitro and tumor growth in vivo were increased in β2SP-silenced esophageal adenocarcinoma cells. Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of β2SP. Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of β2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-β targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin. Taken together, our findings suggest that loss of β2SP switches TGF-β signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9.
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Registered trials
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