ArticleOncogene2021
NOTCH3, a crucial target of miR-491-5p/miR-875-5p, promotes gastric carcinogenesis by upregulating PHLDB2 expression and activating Akt pathway.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 34 citations in OpenAlex.
- Cell differentiation-related signaling pathways: biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- THBS2 as a Key Regulator in Gastrointestinal Tumors: from Molecular Mechanisms to Clinical Applications.Current oncology reports · 2026Review
- The dual role of the Notch signaling pathway in digestive system cancers.European journal of medical research · 2026Review
- Liquid‑liquid phase separation of PHLDB2 promotes oral squamous cell carcinoma metastasis through regulating epithelial mesenchymal transition and PIK3CA expression.Molecular medicine reports · 2026Article
- Shared molecular features and candidate pathways underlying gastric cancer-depression comorbidity: a systems biology analysis.Frontiers in bioinformatics · 2026Article
- An emerging targeted strategy for gastric cancer: the multi-pathway regulatory potential of Chinese medicine monomers.Frontiers in oncology · 2026Review
- Absolute quantification of microRNA miR-875-5p in temporal artery biopsies and its biomarker potential for giant cell arteritis.Frontiers in immunology · 2026Article
- Integration of Whole-Genome Sequencing Analysis with Unique Patient-Derived Models Reveals Clinically Relevant Drug Targets in TFCP2 Fusion-Defined Rhabdomyosarcoma.Molecular cancer therapeutics · 2025Article
- Phase Separation of PHLDB2 Drives EMT and Tumor Progression in Triple-Negative Breast Cancer.Cancer medicine · 2025Review
- GWAS study of myelosuppression among NSCLC patients receiving platinum-based combination chemotherapy.Acta biochimica et biophysica Sinica · 2025Article
- Targeting miR-103a-3p/IGFBP5 axis: a potential therapeutic strategy for gastric cancer progression.Discover oncology · 2025Article
- MiR-491-5p Targets B4GalT5 to Alleviate Airway Inflammation and Remodeling in Asthma by Regulating Pulmonary Oxidative Stress.Journal of inflammation research · 2025Article
- NOTCH3 promotes malignant progression of bladder cancer by directly regulating SPP1 and activating PI3K/AKT pathway.Cell death & disease · 2024Article
- Depletion of PHLDB2 Suppresses Epithelial-Mesenchymal Transition and Enhances Anti-Tumor Immunity in Head and Neck Squamous Cell Carcinoma.Biomolecules · 2024Article
- Unraveling the regulatory cell death pathways in gastric cancer: a multi-omics study.Frontiers in pharmacology · 2024Article
- MicroRNA-875-5p inhibits the growth and metastasis of cervical cancer cells by promoting autophagy and apoptosis and inhibiting the epithelial-mesenchymal transition.Frontiers in oncology · 2024Article
- THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway.American journal of cancer research · 2024Article
- Glycerophosphoinositol modulates FGA and NOTCH3 in exercise-induced muscle adaptation and colon cancer progression.Frontiers in pharmacology · 2024Article
- Exploiting branched-chain amino acid metabolism and NOTCH3 expression to predict and target colorectal cancer progression.Frontiers in immunology · 2024Article
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant Notch activation has been implicated in multiple malignancies and the identification of NOTCH receptors and related pathways is critical for targeted therapy. In this study, we aim to delineate the most prominent dysregulated NOTCH receptor and comprehensively reveal its deregulation in gastric cancer (GC). In the four Notch members, NOTCH3 was found uniformly upregulated and associated with poor clinical outcomes in multiple GC datasets. siRNA-mediated NOTCH3 knockdown demonstrated antitumor effects by suppressing cell proliferation, inhibiting monolayer formation, and impairing cell invasion abilities. Its depletion also induced early and late apoptosis. NOTCH3 was confirmed to be a direct target of two tumor suppressor microRNAs (miRNAs), namely miR-491-5p and miR-875-5p. The activation of NOTCH3 is partly due to the silence of these two miRNAs. Through RNA-seq profiling and functional validation, PHLDB2 was identified as a potent functional downstream modulator for NOTCH3 in gastric carcinogenesis. PHLDB2 expression demonstrated a positive correlation with NOTCH3, but was negatively correlated with miR-491-5p. Akt-mTOR was revealed as the downstream signaling of PHLDB2. The NOTCH3-PHLDB2-Akt co-activation was found in 33.7% GC patients and the activation of this axis predicted poor clinical outcome. GC cells treated with siNOTCH3, siPHLDB2, miR-491-5p, miR-875-5p, were more sensitive to Cisplatin and 5-FU. Taken together, the NOTCH3-PHLDB2-Akt cascade plays oncogenic role in gastric carcinogenesis and serves as a therapeutic target. Our study provided insights into Notch-mediated underlying molecular mechanisms and implied translational potential.
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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.