ArticleBritish journal of cancer2013
Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells.
Article in British journal of cancer, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 1 of them a synthesis that pooled it.
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Who cites it
111 citing papers in PubMed, 1 synthesis or guideline pooled it, 232 citations in OpenAlex.
- Melatonin in cancer treatment.The Cochrane database of systematic reviews · 2025Pooled it
- Melatonin supplementation for quality of life in older patients with advanced cancer: a randomized controlled trial.BMC geriatrics · 2025Trial
- SPP1 integrates trophoblast-endothelial crosstalk via the αVβ3-PI3K/Akt-MMP-9 axis to govern vascular remodeling in preeclampsia.Molecular biology reports · 2026Article
- Hepatocellular Carcinoma Around the Clock.Current oncology (Toronto, Ont.) · 2026Review
- Therapeutic efficacy of canagliflozin against hepatocarcinogenesis induced by CDD/DEN/TAA in a rat model: regulation of AMPK/HIF-1α/YAP-1/TAZ signaling pathways.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Mechanisms of drug resistance in hepatocellular carcinoma.Biological procedures online · 2025Review
- Tumor vascular endothelial cells promote immune escape by upregulating PD-L1 expression via crosstalk between NF-κB and STAT3 signaling pathways in nasopharyngeal carcinoma.Cell death & disease · 2025Article
- Monocyte/macrophage-derived IL-15 activates STAT5 to trigger the EFNA1/NCOA2-positive feedback loop, facilitating retinal angiogenesis in high-glucose environments.Molecular vision · 2025Article
- Autophagy modulation attenuates sorafenib resistance in HCC induced in rats.Cell death & disease · 2024Article
- Aclarubicin: contemporary insights into its mechanism of action, toxicity, pharmacokinetics, and clinical standing.Cancer chemotherapy and pharmacology · 2024Review
- Inhibition of STAT3-NF-κB pathway facilitates SSPH I-induced ferroptosis in HepG2 cells.Medical oncology (Northwood, London, England) · 2024Article
- Aerobic glycolysis of vascular endothelial cells: a novel perspective in cancer therapy.Molecular biology reports · 2024Review
- Protective Effects of Melatonin against Carcinogen-Induced Oxidative Damage in the Thyroid.Cancers · 2024Review
- Linking fatty liver diseases to hepatocellular carcinoma by hepatic stellate cells.Journal of the National Cancer Center · 2024Review
- Unveiling the Protective Role of Melatonin in Osteosarcoma: Current Knowledge and Limitations.Biomolecules · 2024Review
- Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine-deficient kinase 1.Molecular carcinogenesis · 2024Article
- Dysregulation of lysine acetylation in the pathogenesis of digestive tract cancers and its clinical applications.Frontiers in cell and developmental biology · 2024Review
- Nature's Elixir for Cancer Treatment: Targeting Tumor-induced Neovascularization.Current medicinal chemistry · 2024Review
- Role of Angiogenesis and Its Biomarkers in Development of Targeted Tumor Therapies.Stem cells international · 2024Review
- Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
51 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 1 country.
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Abstract
backgroundHepatocellular carcinoma (HCC) growth relies on angiogenesis via vascular endothelial growth factor (VEGF) release. Hypoxia within tumour environment leads to intracellular stabilisation of hypoxia inducible factor 1 alpha (Hif1α) and signal transducer and activator of transcription (STAT3). Melatonin induces apoptosis in HCC, and shows anti-angiogenic features in several tumours. In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate the anti-angiogenic effects of melatonin.
methodsHepG2 cells were treated with melatonin under normoxic or CoCl2-induced hypoxia. Gene expression was analysed by RT-qPCR and western blot. Melatonin-induced anti-angiogenic activity was confirmed by in vivo human umbilical vein endothelial cells (HUVECs) tube formation assay. Secreted VEGF was measured by ELISA. Immunofluorescence was performed to analyse Hif1α cellular localisation. Physical interaction between Hif1α and its co-activators was analysed by immunoprecipitation and chromatin immunoprecipitation (ChIP).
resultsMelatonin at a pharmacological concentration (1 mM) decreases cellular and secreted VEGF levels, and prevents HUVECs tube formation under hypoxia, associated with a reduction in Hif1α protein expression, nuclear localisation, and transcriptional activity. While hypoxia increases phospho-STAT3, Hif1α, and CBP/p300 recruitment as a transcriptional complex within the VEGF promoter, melatonin 1 mM decreases their physical interaction. Melatonin and the selective STAT3 inhibitor Stattic show a synergic effect on Hif1α, STAT3, and VEGF expression.
conclusionMelatonin exerts an anti-angiogenic activity in HepG2 cells by interfering with the transcriptional activation of VEGF, via Hif1α and STAT3. Our results provide evidence to consider this indole as a powerful anti-angiogenic agent for HCC treatment.
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