ArticleSignal transduction and targeted therapy2025
Aberrant Notch-signaling promotes tumor angiogenesis in esophageal squamous-cell carcinoma.
Article in Signal transduction and targeted therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Deubiquitinases as Regulators and Therapeutic Targets in Vascular Diseases.International journal of molecular sciences · 2026Review
- Solanum nigrum-Derived Carbon Dots Alleviate Tumor Hypoxia to Potentiate Photodynamic Therapy in Esophageal Squamous Cell Carcinoma.Advanced healthcare materials · 2026Article
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- A multi-level charged micelle-based microneedle transdermal system for immunosuppressive tumor microenvironment regulation and synergistic therapy.Materials today. Bio · 2026Article
- USP5 in cancer: a therapeutic window into metabolism and drug resistance.Journal of translational medicine · 2026Review
- CKS1B is a tumor-intrinsic factor driving CD8Science advances · 2026Article
- Esophageal cancer: from pathogenesis to precision therapies.Signal transduction and targeted therapy · 2026Review
- USP5 regulates purine metabolism and represents a therapeutic target in esophageal cancer.Cell death & disease · 2026Article
- A microfluidic model of human dental pulp angiogenesis for preclinical drug and biomaterial testing.Materials today. Bio · 2026Article
- RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy.Nature communications · 2026Article
- Article
- The dual role of the Notch signaling pathway in digestive system cancers.European journal of medical research · 2026Review
- Notch signaling in the tumor microenvironment: recent advances and targeted therapeutics.Molecular cancer · 2026Review
- Stemness signature RBBP7 reprograms the immune microenvironment to inform a prognostic model in esophageal carcinoma.Frontiers in immunology · 2026Article
- Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies.Oncology reviews · 2026Review
- Overcoming chemoresistance in esophageal cancer with synergistic strategies.Frontiers in immunology · 2026Review
- STAT3 signaling in cancer: mechanisms and targeting therapeutic.Frontiers in immunology · 2026Review
- Immunosuppressive tumor microenvironment and immunotherapy resistance of esophageal carcinoma.Frontiers in immunology · 2026Review
- BACH1-mediated transcriptional repression of pro-angiogenic factors drives angiogenic impairment in hypertension.Frontiers in cardiovascular medicine · 2026Article
- Emerging roles of Notch signaling in the tumor microenvironment of digestive system cancers.Frontiers in molecular biosciences · 2026Review
Corrections and comments
- Erratum issued
Authors and funding
12 authors.
Funding
Abstract
Esophageal squamous-cell carcinoma (ESCC) is one of the most common gastrointestinal cancers in China, characterized by high malignancy and poor prognosis. Nowadays, the therapeutic options for this cancer are very limited. Notch-signaling is often overactivated in ESCC, but its role remains to be fully elucidated. Here, we demonstrate that aberrant Notch-signaling plays an important role in tumor angiogenesis. In clinical ESCC samples, Notch-signaling activation scores were significantly correlated with tumor microvascular density, advanced TNM stages, and short patient survival time. Silencing Notch-signaling substantially suppressed the ability of ESCC cells to promote angiogenesis in vitro and in vivo. By integrating analysis of CUT&Tag and RNA sequencing data, we identified ubiquitin-specific protease 5 (USP5) as a Notch-signaling downstream effector that is transcriptionally upregulated by the NOTCH1 intracellular domain (NICD1)-RBPJ complex and mediates tumor angiogenesis. USP5 stabilized STAT3 via its deubiquitination function, thereby enhancing the production of pro-angiogenic factors by cancer cells, including VEGF, ANGPT2, and CXCL1. We showed that chemotherapy combined with the USP5 inhibitor can additionally repress tumor growth and angiogenesis in mice. These findings explain why ESCC cells have much fewer NOTCH1 mutations than normal and precancerous epithelium, reveal a novel mechanism for Notch-signaling to drive tumor angiogenesis via the NOTCH1-USP5-STAT3 axis, and open a potential new avenue for anti-tumor angiogenesis therapy.
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