ArticleThe Journal of clinical investigation2009
Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.
Article in The Journal of clinical investigation, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 148 papers.
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Who cites it
148 citing papers in PubMed, 217 citations in OpenAlex.
- SMAD4 Expression and Its Association With Treatment Resistance and Clinical Outcomes in Oral Squamous Cell Carcinoma Treated With Preoperative Chemoradiotherapy.Cancer reports (Hoboken, N.J.) · 2026Article
- Multifactorial effects of LGALS1 blockade sensitize tumors to immune checkpoint inhibitor.Experimental hematology & oncology · 2026Article
- TGFβ limits proximal CD8+ TCR signaling via PTPN22 following strong and moderate agonism.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Advancing oral squamous cell carcinoma research: the evolving role of patient-derived cell lines, xenografts, and organoid models.3 Biotech · 2025Review
- Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response.Nature reviews. Cancer · 2025Review
- Article
- Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.Life science alliance · 2024Article
- Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma.The Journal of pathology · 2024Article
- Dysregulation of exosomal miRNAs and their related genes in head and neck cancer patients.Future oncology (London, England) · 2024Article
- Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model, cellular platform, and clinical human data.Animal models and experimental medicine · 2023Review
- CircLDLRAD3 inhibits Oral squamous cell carcinoma progression by regulating miR-558/Smad4/TGF-β.Journal of cellular and molecular medicine · 2023Article
- TGF-β signaling in health and disease.Cell · 2023Review
- Methylation status, mRNA and protein expression of the SMAD4 gene in patients with non-melanocytic skin cancers.Molecular biology reports · 2023Article
- The PCOS-NAFLD Multidisease Phenotype Occurred in Medaka Fish Four Generations after the Removal of Bisphenol A Exposure.Environmental science & technology · 2023Article
- 5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling.Cell reports · 2023Article
- Preclinical models in head and neck squamous cell carcinoma.British journal of cancer · 2023Review
- Endotype Characterization Reveals Mechanistic Differences Across Brain Regions in Sporadic Alzheimer's Disease.Journal of Alzheimer's disease reports · 2023Article
- The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma.Frontiers in medicine · 2023Article
- Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- HPV-mediated regulation of SMAD4 modulates the DNA damage response in head and neck cancer.Journal of experimental & clinical cancer research : CR · 2022Article
88 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-beta1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.
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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.