ArticlePloS one2013
Autocrine extra-pancreatic trypsin 3 secretion promotes cell proliferation and survival in esophageal adenocarcinoma.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- Engineering selective amyloid precursor protein inhibitors by machine learning and deep mutational scanning.Protein science : a publication of the Protein Society · 2026Article
- CpG Methylation-Driven Pleiotropic Spliced Isoforms of PRSS3 Facilitate Gastric Intratumor Heterogeneity and Metastasis.Cancer science · 2026Article
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
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- 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
- UHRF1/DNMT1-MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions ofActa pharmaceutica Sinica. B · 2023Article
- Barrett's Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models.International journal of molecular sciences · 2022Article
- Serine Protease 3 Promotes Progression of Diffuse Large B-Cell Lymphoma and Serves as a Novel Prognostic Predictor.Disease markers · 2022Article
- CpG Site-Specific Methylation-Modulated Divergent Expression ofFrontiers in oncology · 2022Article
- Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis.Journal of pancreatic cancer · 2020Review
- Identification of microRNAs as novel biomarkers for esophageal squamous cell carcinoma: a study based on The Cancer Genome Atlas (TCGA) and bioinformatics.Chinese medical journal · 2019Article
- Epigenetic silencing of PRSS3 provides growth and metastasis advantage for human hepatocellular carcinoma.Journal of molecular medicine (Berlin, Germany) · 2017Article
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- Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.The Biochemical journal · 2016Article
- Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates.The Journal of biological chemistry · 2015Article
- Protease-activated receptor 2 agonist increases cell proliferation and invasion of human pancreatic cancer cells.Experimental and therapeutic medicine · 2015Article
- Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Trypsin or Tumor associated trypsin (TAT) activation of Protease-activated receptor 2 (PAR-2) promotes tumor cell proliferation in gastrointestinal cancers. The role of the trypsin/PAR-2 network in esophageal adenocarcinoma (EA) development has not yet been investigated. The aim of this study is to investigate the role of trypsin/PAR-2 activation in EA tumorogenesis and therapy. We found that esophageal adenocarcinoma cells (EACs) and Barrett's Metaplasia (BART) expressed high levels of type 3 extra-pancreatic trypsinogen (PRSS3), a novel type of TAT. Activity of secreted trypsin was detected in cultured media from EA OE19 and OE33 cultures but not from BART culture. Surface PAR-2 expression in BART and EACs was confirmed by both flow cytometry and immunofluorescence. Trypsin induced cell proliferation (~ 2 fold; P<0.01) in all tested cell lines at a concentration of 10 nM. Inhibition of PAR-2 activity in EACs via the PAR-2 antagonist ENMD (500 µM), anti-PAR2 antibody SAM-11 (2 µg/ml), or siRNA PAR-2 knockdown, reduced cell proliferation and increased apoptosis by up to 4 fold (P<0.01). Trypsin stimulation led to phosphorylation of ERK1/2, suggesting involvement of MAPK pathway in PAR-2 signal transduction. Inhibition of PAR-2 activation or siRNA PAR-2 knockdown in EACs prior to treatment with 5 FU reduced cell viability of EACs by an additional 30% (P<0.01) compared to chemotherapy alone. Our data suggest that extra-pancreatic trypsinogen 3 is produced by EACs and activates PAR-2 in an autocrine manner. PAR-2 activation increases cancer cell proliferation, and promotes cancer cell survival. Targeting the trypsin activated PAR-2 pathway in conjunction with current chemotherapeutic agents may be a viable therapeutic strategy in EA.
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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.