ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2024
Stabilization of TGF-β Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-β Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- TGF‑β1 in cancer: From tumour suppressor to promoter, molecular mechanisms, and precision therapeutic strategies (Review).International journal of oncology · 2026Review
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review).International journal of molecular medicine · 2026Review
- CRISPR Screening in Hepatocellular Carcinoma: From Tumor Progression to Immune Evasion and Therapeutic Resistance.International journal of molecular sciences · 2026Review
- Comprehensive analysis of disulfidptosis-related genes identifies clinically actionable prognostic biomarkers in cholangiocarcinoma.Discover oncology · 2026Article
- Integrative bioinformatics and machine learning approaches identify novel diagnostic signatures for oxaliplatin-resistant colorectal cancer.International journal of colorectal disease · 2026Article
- Systems pharmacology approaches decipher the anti-cancer efficacy of ethnopharmacological agents in hepatocellular carcinoma.Scientific reports · 2025Article
- Targeting hepatocytic TβRI ameliorates liver metastatic outcomes by revitalizing stem-like CD8Nature communications · 2025Article
- IL27RA promotes the proliferation and metastasis of hepatocellular carcinoma cells by regulating TGFβR1.Scientific reports · 2025Article
- Diverse Biological Processes Contribute to Transforming Growth Factor β-Mediated Cancer Drug Resistance.Cells · 2025Review
- Reproducible autosomal gene expression changes with loss of typical X and Y complement across tumor types.bioRxiv : the preprint server for biology · 2025Article
- Cancer pain: molecular mechanisms and management.Molecular biomedicine · 2025Review
- Advances in pharmacological research on myocardial remodeling agents: A decade in review.Medicine · 2025Review
- PLOD1 promotes the malignancy of hepatocellular carcinoma by facilitating the NF-κB/IL-6/STAT3-dependent TCA cycle.JHEP reports : innovation in hepatology · 2025Article
- Article
- Stabilization of TGF-β Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-β Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Identification of E3 ubiquitin ligase-associated prognostic genes and construction of a prediction model for uterine cervical cancer based on bioinformatics analysis.Discover oncology · 2024Article
Corrections and comments
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Authors and funding
24 authors.
Funding
Abstract
Dysregulation of the transforming growth factor-β (TGF-β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-β receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-β-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-β signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.
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