ArticleOncogene2020
NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Strawberry Notch 1 Acts as a Transcriptional Regulator Driving Oncogenic Programs in Liver Carcinogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Preclinical mouse models for studying cholangiocarcinoma.Liver research (Beijing, China) · 2026Review
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Identification and characterization of mitochondrial autophagy-related genes in osteosarcoma and predicting clinical prognosis.Scientific reports · 2025Article
- Comparative Analysis of Transcription Factors TWIST2, GATA3, and HES5 in Glioblastoma Multiforme : Evaluating Biomarker Potential and Therapeutic Targets Using in Silico Methods.Journal of Korean Neurosurgical Society · 2025Article
- Notch signaling in cancers: mechanism and potential therapy.Frontiers in cell and developmental biology · 2025Review
- Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.Life science alliance · 2024Article
- A Notch signaling pathway-related gene signature: Characterizing the immune microenvironment and predicting prognosis in hepatocellular carcinoma.Journal of translational internal medicine · 2024Article
- AIBP promotes cell proliferation and migration through the ERK1/2-MAPK signaling pathway in hepatocellular carcinoma.Translational cancer research · 2024Article
- Article
- The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer.ACS pharmacology & translational science · 2023Review
- Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway.Experimental & molecular medicine · 2023Article
- Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo.Biomedicines · 2023Article
- Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma.International journal of molecular sciences · 2023Review
- Article
- Identification of Potential RBPJ-Specific Inhibitors for Blocking Notch Signaling in Breast Cancer Using a Drug Repurposing Strategy.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Notch signaling pathway: architecture, disease, and therapeutics.Signal transduction and targeted therapy · 2022Review
- Transcriptome Analysis in Vulvar Squamous Cell Cancer.Cancers · 2021Article
- Supervised learning based on tumor imaging and biopsy transcriptomics predicts response of hepatocellular carcinoma to transarterial chemoembolization.Cell reports. Medicine · 2021Article
- HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes.Cell death discovery · 2021Article
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NOTCH receptor signaling plays a pivotal role in liver homeostasis and hepatocarcinogenesis. However, the role of NOTCH pathway mutations and the NOTCH target gene HES5 in liver tumorigenesis are poorly understood. Here we performed whole-exome sequencing of 54 human HCC specimens and compared the prevalence of NOTCH pathway component mutations with the TCGA-LIHC cohort (N = 364). In addition, we functionally characterized the NOTCH target HES5 and the patient-derived HES5-R31G mutation in vitro and in an orthotopic mouse model applying different oncogenic backgrounds, to dissect the role of HES5 in different tumor subgroups in vivo. We identified nonsynonymous mutations in 14 immediate NOTCH pathway genes affecting 24.1% and 16.8% of HCC patients in the two independent cohorts, respectively. Among these, the HES5-R31G mutation was predicted in silico to have high biological relevance. Functional analyses in cell culture showed that HES5 reduced cell migration and clonogenicity. Further analyses revealed that the patient-derived HES5-R31G mutant protein was non-functional due to loss of DNA binding and greatly reduced nuclear localization. Furthermore, HES5 exhibited a negative feedback loop by directly inhibiting the NOTCH target HES1 and downregulated the pro-proliferative MYC targets ODC1 and LDHA. Interestingly, HES5 inhibited MYC-dependent hepatocarcinogenesis, whereas it promoted AKT-dependent liver tumor formation and stem cell features in a murine model. Thus, NOTCH pathway component mutations are commonly observed in HCC. Furthermore, the NOTCH target gene HES5 has both pro- and anti-tumorigenic functions in liver cancer proposing a driver gene dependency and it promotes tumorigenesis with its interaction partner AKT.
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