ArticleThe Journal of biological chemistry2017
Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 62 citations in OpenAlex.
- Prognostic Significance of NOTCH1-ICD Expression in Renal Cell Carcinoma.Journal of kidney cancer and VHL · 2026Article
- Notch2 Inhibition and Kidney Cyst Growth in Autosomal Dominant Polycystic Kidney Disease.Journal of the American Society of Nephrology : JASN · 2025Article
- Tumor dormancy and relapse: understanding the molecular mechanisms of cancer recurrence.Military Medical Research · 2025Review
- Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies.Biomolecules · 2024Review
- Notch activation defines immune-suppressive subsets of ccRCCs with unfavorable benefits from immunotherapy over VEGFR/mTOR inhibitors.iScience · 2024Article
- Article
- Kidney Injury: Focus on Molecular Signaling Pathways.Current medicinal chemistry · 2024Review
- Regulation of Notch1 Signalling by Long Non-Coding RNAs in Cancers and Other Health Disorders.International journal of molecular sciences · 2023Review
- Metastatic clear-cell renal cell carcinoma: a frequent NOTCH1 mutation predictive of response to anti-NOTCH1 CB-103 treatment.Experimental hematology & oncology · 2023Article
- MiR-146b-5p/SEMA3G regulates epithelial-mesenchymal transition in clear cell renal cell carcinoma.Cell division · 2023Article
- Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment.Molecular cancer · 2023Review
- Overexpression of notch signaling in renin cells leads to a polycystic kidney phenotype.Clinical science (London, England : 1979) · 2023Article
- Article
- Review
- A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors.International journal of molecular sciences · 2022Review
- Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2022Review
- Review
- Notch signaling pathway: architecture, disease, and therapeutics.Signal transduction and targeted therapy · 2022Review
- Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease.International journal of molecular sciences · 2022Article
- Single-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma.Nature communications · 2022Article
Corrections and comments
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Authors and funding
28 authors at 4 institutions in 1 country.
Funding
Abstract
Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.
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Registered trials
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.