ArticleCancer research2016
Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors.
Article in Cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
36 citing papers in PubMed, 53 citations in OpenAlex.
- Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications.Molecular cancer · 2025Review
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma.Cell communication and signaling : CCS · 2024Article
- Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2023Article
- Article
- The Clinical Application of Immunohistochemical Expression of Notch4 Protein in Patients with Colon Adenocarcinoma.International journal of molecular sciences · 2023Article
- Review
- Article
- The bioengineered HALOA complex induces anoikis in chronic myeloid leukemia cells by targeting the BCR-ABL/Notch/Ikaros/Redox/Inflammation axis.Journal of medicine and life · 2022Article
- Article
- Identification of Pathologic Grading-Related Genes Associated with Kidney Renal Clear Cell Carcinoma.Journal of immunology research · 2022Article
- Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Pseudogene ACTBP2 increases blood-brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in AβCell death discovery · 2021Article
- Article
- Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives.Cancer management and research · 2021Review
- MAPK and Notch-Mediated Effects of Meso-Xanthin F199 Compounds on Proliferative Activity and Apoptosis of Human Melanocytes in Three-Dimensional Culture.BioMed research international · 2021Article
- Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy.Frontiers in oncology · 2021Review
- A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer.Cancers · 2020Article
- Precision medicine for human cancers with Notch signaling dysregulation (Review).International journal of molecular medicine · 2020Review
- New Insights Into the Role of Phenotypic Plasticity and EMT in Driving Cancer Progression.Frontiers in molecular biosciences · 2020Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial-mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting. Cancer Res; 76(7); 1690-7. ©2016 AACR.
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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.