ArticleJournal of experimental & clinical cancer research : CR2020
Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/β-catenin positive feedback loop.
Article in Journal of experimental & clinical cancer research : CR, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 29 citations in OpenAlex.
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- Catecholamines Activate a Tumour Progression Program in Differentiated Tumour Hepatocytes.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Neuroimmune Mechanisms in Traumatic Brain Injury and Cancer: Parallel Courses or Existence in Different Orbits.Biomedicines · 2026Review
- Article
- Neural regulation of tumor progression: implications for hepatocellular carcinoma.Frontiers in immunology · 2026Review
- Inhibition of Adrenergic Agonist-Induced Metastatic Potential in Cancer Cells by an Ethanolic Extract ofJournal of pharmacopuncture · 2025Article
- A novel Notch and WNT signaling mechanism contribute to paediatric DCM: a pathway to new therapeutics.bioRxiv : the preprint server for biology · 2025Article
- The Characterization of the Neuroimmune Response in Primary Pterygia.International journal of molecular sciences · 2025Article
- Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.Journal of translational medicine · 2025Review
- Chronic stress: a fourth etiology in tumorigenesis?Molecular cancer · 2025Review
- Central and peripheral neural circuits regulating glucose homeostasis.npj biomedical innovations · 2025Review
- Wnt Signaling in Hepatocellular Carcinoma: Biological Mechanisms and Therapeutic Opportunities.Cells · 2024Review
- Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk.MedComm · 2024Review
- Role of the lncRNA/Wnt signaling pathway in digestive system cancer: a literature review.European journal of medical research · 2024Review
- Stress-induced epinephrine promotes hepatocellular carcinoma progression via the USP10-PLAGL2 signaling loop.Experimental & molecular medicine · 2024Article
- Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Harnessing adrenergic blockade in stress-promoted TNBCFrontiers in pharmacology · 2024Article
- Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity.Annals of medicine · 2023Review
- Norepinephrine inhibits CD8British journal of cancer · 2023Article
- Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1.Open medicine (Warsaw, Poland) · 2023Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundSustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.
methodsHCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.
resultsCM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.
conclusionsWe identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.
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