ArticleMolecular cancer2016
Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells - evidence for a role in hepatocellular carcinoma growth in vivo.
Article in Molecular cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 37 citations in OpenAlex.
- Blood and lymphatic vascular remodeling in intervertebral disc degeneration.Frontiers in immunology · 2026Review
- The Function and Clinical Significance of TRPV2 in Human Colon Cancer.Annals of surgical oncology · 2025Article
- The Role of PAR2 in MASLD Progression and HCC Development.International journal of molecular sciences · 2025Review
- Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke.Translational stroke research · 2025Review
- Bioinformatics and experimental insights into F2RL1 as a key biomarker in cervical cancer diagnosis and prognosis.Scientific reports · 2025Article
- Myeloid cell differentiation-related gene signature for predicting clinical outcome, immune microenvironment, and treatment response in lung adenocarcinoma.Scientific reports · 2024Article
- Xa inhibitor edoxaban ameliorates hepatic ischemia-reperfusion injury via PAR-2-ERK 1/2 pathway.PloS one · 2024Article
- Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
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- Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies.Cancer biology & medicine · 2023Review
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- The tumor microenvironment of hepatocellular carcinoma and its targeting strategy by CAR-T cell immunotherapy.Frontiers in endocrinology · 2022Review
- Electrospun tube reduces adhesion in rabbit Achilles tendon 12 weeks post-surgery without PAR-2 overexpression.Scientific reports · 2021Article
- Article
- The Small GTPase RAC1B: A Potent Negative Regulator of-and Useful Tool to Study-TGFβ Signaling.Cancers · 2020Review
- Proteinase‑activated receptor 2 deficiency is a protective factor against cardiomyocyte apoptosis during myocardial ischemia/reperfusion injury.Molecular medicine reports · 2019Article
- PRSS1 mutation: a possible pathomechanism of pancreatic carcinogenesis and pancreatic cancer.Molecular medicine (Cambridge, Mass.) · 2019Article
- Proteinase-activated receptor-2 enhances Bcl2-like protein-12 expression in lung cancer cells to suppress p53 expression.Archives of medical science : AMS · 2019Article
- An imbalance between stellate cells and γδT cells contributes to hepatocellular carcinoma aggressiveness and recurrence.Hepatology international · 2019Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPrevious studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model.
methodsPAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca(2+)]i measurements, respectively. The impact of LX-2-expressed PAR2 on tumour growth in vivo was monitored using HCC xenotransplantation experiments in SCID mice, in which HCC-like tumours were induced by coinjection of LX-2 cells and Hep3B cells. To characterise the effects of PAR2 activation in LX-2 cells, various signalling pathways were analysed by immunoblotting and proteome profiler arrays.
resultsFollowing verification of functional PAR2 expression in LX-2 cells, in vivo studies showed that these cells promoted tumour growth and angiogenesis of HCC xenografts in mice. These effects were significantly reduced when F2RL1 (encoding PAR2) was downregulated by RNA interference (RNAi). In vitro studies confirmed these results demonstrating RNAi mediated inhibition of PAR2 attenuated Smad2/3 activation in response to TGF-β1 stimulation in LX-2 cells and blocked the pro-mitotic effect of LX-2 derived conditioned medium on Hep3B cells. Furthermore, PAR2 stimulation with trypsin or a PAR2-selective activating peptide (PAR2-AP) led to activation of different intracellular signalling pathways, an increased secretion of pro-angiogenic and pro-mitotic factors and proteinases, and an enhanced migration rate across a collagen-coated membrane barrier. Silencing F2RL1 by RNAi or pharmacological inhibition of Src, hepatocyte growth factor receptor (Met), platelet-derived growth factor receptor (PDGFR), p42/p44 mitogen activated protein kinase (MAPK) or matrix-metalloproteinases (MMPs) blocked PAR2-AP-induced migration.
conclusionPAR2 in HSCs plays a crucial role in promoting HCC growth presumably by mediating migration and secretion of pro-angiogenic and pro-mitotic factors. Therefore, PAR2 in stromal HSCs may have relevance as a therapeutic target of HCC.
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