{"gene":"PRSS3","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2010,"finding":"PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway in pancreatic cancer cells, promoting proliferation, invasion, and metastasis.","method":"PRSS3 overexpression/silencing in cancer cell lines, VEGF ELISA, ERK inhibitor treatment, in vivo metastasis models","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement by gain/loss-of-function with defined molecular readouts, single lab","pmids":["20947888"],"is_preprint":false},{"year":2012,"finding":"PRSS3/mesotrypsin promotes prostate cancer invasion through its proteolytic activity; a catalytically inactive mesotrypsin mutant cannot drive the invasive phenotype, and recombinant active mesotrypsin is sufficient to promote invasion.","method":"Recombinant mesotrypsin treatment, catalytically inactive mutant comparison, Matrigel transwell invasion assay, 3D cell culture, mesotrypsin-specific inhibitor, orthotopic mouse model with bioluminescent imaging","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity requirement demonstrated by mutant rescue and specific inhibitor, multiple orthogonal assays","pmids":["23258495"],"is_preprint":false},{"year":2016,"finding":"TFPI-2 (a Kunitz-type serine proteinase inhibitor) is a direct substrate of PRSS3; active PRSS3 cleaves TFPI-2 in a cell-free system and removes it from the extracellular matrix of tumor endothelial cells, thereby promoting their migration.","method":"Cell-free proteolytic assay (western blot), siRNA silencing of PRSS3 in tumor-derived endothelial cells, wound healing migration assay","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — direct substrate cleavage demonstrated in vitro with functional consequence shown by siRNA","pmids":["27161730"],"is_preprint":false},{"year":2019,"finding":"circ-ADAM9 acts as a ceRNA that sponges miR-217, thereby relieving miR-217-mediated suppression of PRSS3, which in turn activates the ERK/VEGF signalling pathway to promote pancreatic cancer progression.","method":"miR-217 and circ-ADAM9 overexpression/silencing in cell lines and xenograft models, luciferase reporter assays (implied by ceRNA analysis), in vivo tumor growth assays","journal":"Artificial cells, nanomedicine, and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2–3 — ceRNA mechanism with functional readouts, single lab, confirms upstream regulation of PRSS3-ERK/VEGF axis","pmids":["31810373"],"is_preprint":false},{"year":2022,"finding":"PRSS3 variant 3 (brain trypsinogen isoform) physically interacts with Enterovirus A71 nonstructural 3A protein in human neuroblastoma cells, and PRSS3 facilitates EV-A71 replication.","method":"Pull-down assay with LC-MS/MS identification, siRNA-mediated PRSS3 knockdown and overexpression in SH-SY5Y cells, viral replication assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by pull-down/MS and functional role by KD/OE, single lab","pmids":["35896602"],"is_preprint":false},{"year":2022,"finding":"Individual PRSS3 splice variants (V1–V4) have distinct and opposing functions in hepatocellular carcinoma: PRSS3-V2 is oncogenic while PRSS3-V1, -V3, and -V4 are tumor-suppressive; their expression is controlled by site-specific CpG methylation at the PRSS3 promoter.","method":"CRISPR/Cas9 deletion of PRSS3 followed by re-expression of individual isoform constructs, gain/loss-of-function cell models, qPCR, methylation analysis of public datasets","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — isoform-specific function established with CRISPR and isoform re-expression, single lab","pmids":["35480112"],"is_preprint":false},{"year":2023,"finding":"Shear stress triggers PRSS3 to cleave the N-terminal inhibitory domain of PAR2 within 2 hours; activated PAR2 then signals via Gαi to the Src-ERK/p38/JNK-FRA1/cJUN axis, upregulating EMT markers and further PRSS3 expression, promoting metastasis of circulating lung cancer cells.","method":"Microfluidic circulatory system generating arteriosus shear stress, transcriptome profiling, PAR2 cleavage assay, Gαi signaling pathway analysis, in vivo metastasis assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 — direct cleavage of PAR2 by PRSS3 demonstrated with temporal resolution, downstream pathway mapped by multiple methods","pmids":["37395651"],"is_preprint":false},{"year":2023,"finding":"UHRF1/DNMT1 complex mediates intragenic CpG island methylation at the PRSS3 locus by interfering with binding of MZF1 transcription factor, leading to isoform-specific silencing (particularly PRSS3-V3) and divergent oncogenic vs. tumor-suppressive outputs in lung cancer.","method":"Site-specific methylation analysis (BALF and tumor tissues), ChIP/MZF1 binding assays, UHRF1/DNMT1 complex characterization, 5-aza-2'-deoxycytidine and diallyl trisulfide treatment, isoform-specific qPCR","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic writer complex (UHRF1/DNMT1) and reader (MZF1) identified with functional isoform consequences, single lab","pmids":["37250150"],"is_preprint":false},{"year":2024,"finding":"Mesotrypsin (PRSS3) processes pro-filaggrin in keratinocytes and, when expressed in HaCaT cells, causes a flattened phenotype, reduced proliferation, altered F-actin assembly, enhanced E-cadherin adhesion, and facilitated tight junction formation without overtly affecting epidermal differentiation.","method":"Venus-mesotrypsin fusion expression in HaCaT keratinocytes, immunofluorescence for F-actin, E-cadherin and tight junction markers, proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — defined cellular phenotypes with specific molecular readouts from gain-of-function, single lab","pmids":["38811772"],"is_preprint":false},{"year":2025,"finding":"PRSS3-V1 (splice isoform 1) interacts with protease-activated receptor 2 (PAR2) and enhances ERK1/2 phosphorylation in breast cancer cells; PRSS3 silencing induces ferroptosis via downregulation of SLC7A11 and GPX4, accumulation of labile iron, ROS, lipid peroxidation, and NLRP3 inflammasome activation, which can be rescued by PAR2 agonist or TfR1 inhibitor ferrostatin II.","method":"Gain/loss-of-function cell models, co-immunoprecipitation (PRSS3-V1 and PAR2), ERK1/2 phosphorylation western blot, ferroptosis markers (MDA, LDH, ROS), mitochondrial membrane potential assay, NLRP3 inflammasome activation, in vivo xenograft","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing PRSS3-V1/PAR2/ERK axis and ferroptosis mechanism, single lab","pmids":["41046946"],"is_preprint":false},{"year":2017,"finding":"PRSS3 overexpression in hepatocellular carcinoma cells suppresses proliferation by arresting the cell cycle at G1/S phase, accompanied by downregulation of CCND1/CDK4 and CCNE1/CDK2 complexes, and inhibits migration/invasion via downregulation of MMP2 and reduced MEK1/2 and ERK1/2 phosphorylation; these effects are reversed by PRSS3 knockdown.","method":"PRSS3 overexpression and siRNA knockdown in HCC cell lines, cell cycle analysis, western blot for cyclins/CDKs/MMP2/pMEK/pERK, proliferation and invasion assays","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with defined molecular pathway readouts, single lab","pmids":["28844099"],"is_preprint":false},{"year":2010,"finding":"The PRSS3 T167A variant shows normal secretion and trypsin activity in functional assays, indicating this amino acid position is not critical for mesotrypsin catalytic function.","method":"Transient transfection of HEK 293T cells, secretion assay, enzymatic activity assay","journal":"Pancreatology","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assay with specific variant, single lab","pmids":["20484962"],"is_preprint":false}],"current_model":"PRSS3/mesotrypsin is a serine protease with isoform-specific functions: its proteolytic activity drives cancer invasion and metastasis primarily by cleaving and activating protease-activated receptors (PAR1, PAR2) to engage ERK/VEGF signaling, by directly degrading extracellular inhibitors such as TFPI-2, and by interacting with PAR2 to inhibit ferroptosis via SLC7A11/GPX4 downregulation; its expression is controlled by isoform-specific intragenic CpG methylation regulated by the UHRF1/DNMT1–MZF1 axis, with distinct splice variants (V1–V4) exerting opposing oncogenic or tumor-suppressive functions depending on cellular context."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that PRSS3 promotes pancreatic cancer through a defined signaling axis answered how a secreted trypsin isoform could drive metastasis: PRSS3 upregulates VEGF via PAR1-mediated ERK activation.","evidence":"PRSS3 overexpression/silencing in pancreatic cancer cells with VEGF ELISA, ERK inhibitor treatment, and in vivo metastasis models","pmids":["20947888"],"confidence":"Medium","gaps":["Whether PRSS3 directly cleaves PAR1 or acts indirectly was not resolved","Contribution of individual PRSS3 splice variants was not examined","In vivo specificity of the PAR1-ERK-VEGF axis was not validated with receptor-null models"]},{"year":2012,"claim":"Demonstrating that catalytic activity is required for PRSS3-driven invasion resolved whether the protease acts enzymatically or as a scaffold: a catalytically dead mutant failed to promote invasion, and a mesotrypsin-specific inhibitor blocked it.","evidence":"Catalytically inactive mutant, recombinant active mesotrypsin, mesotrypsin-specific inhibitor, Matrigel invasion and 3D culture in prostate cancer cells, orthotopic mouse model","pmids":["23258495"],"confidence":"High","gaps":["The direct proteolytic substrate mediating invasion was not identified","Whether the same catalytic requirement applies in other cancer types was untested"]},{"year":2016,"claim":"Identification of TFPI-2 as a direct substrate revealed how PRSS3 remodels the tumor microenvironment: cleavage of this extracellular matrix-associated inhibitor liberates endothelial cell migration.","evidence":"Cell-free proteolytic cleavage assay plus PRSS3 siRNA in tumor-derived endothelial cells with wound healing migration readout","pmids":["27161730"],"confidence":"Medium","gaps":["Cleavage site on TFPI-2 was not mapped","In vivo relevance of TFPI-2 degradation to angiogenesis was not tested","Other extracellular substrates were not surveyed"]},{"year":2017,"claim":"Paradoxically, PRSS3 overexpression in hepatocellular carcinoma suppressed proliferation and invasion via G1/S arrest and MEK/ERK inhibition, raising the question of context-dependent or isoform-dependent function.","evidence":"PRSS3 overexpression and siRNA knockdown in HCC cell lines with cell cycle, cyclin/CDK, MMP2, and pERK western blot readouts","pmids":["28844099"],"confidence":"Medium","gaps":["Which PRSS3 isoform(s) mediated tumor suppression was not delineated","How PRSS3 both activates and suppresses ERK in different contexts was unexplained"]},{"year":2022,"claim":"Resolution of the oncogene-versus-tumor-suppressor paradox came from dissecting individual splice variants: PRSS3-V2 is oncogenic while V1/V3/V4 are tumor-suppressive, with expression governed by site-specific CpG methylation at the PRSS3 promoter.","evidence":"CRISPR/Cas9 deletion of PRSS3 followed by individual isoform re-expression in HCC cells, methylation analysis","pmids":["35480112"],"confidence":"Medium","gaps":["Structural basis for opposing isoform functions was not determined","Whether isoform-specific methylation patterns hold across cancer types was untested"]},{"year":2023,"claim":"The epigenetic machinery controlling isoform-specific expression was mapped: UHRF1/DNMT1-mediated intragenic CpG methylation blocks MZF1 binding, selectively silencing tumor-suppressive PRSS3-V3 in lung cancer.","evidence":"Site-specific methylation in BALF and tumor tissues, ChIP for MZF1 binding, UHRF1/DNMT1 complex characterization, demethylating agent treatment with isoform-specific qPCR","pmids":["37250150"],"confidence":"Medium","gaps":["Whether other transcription factors co-regulate isoform expression was not explored","In vivo rescue of V3 expression by demethylation and its effect on tumor growth was not shown"]},{"year":2023,"claim":"Direct cleavage of PAR2 by PRSS3 was demonstrated with temporal resolution, connecting mechanical shear stress to a PRSS3→PAR2→Gαi→Src-ERK/p38/JNK→EMT positive feedback loop in circulating tumor cells.","evidence":"Microfluidic shear stress system, PAR2 N-terminal cleavage assay, transcriptomics, Gαi pathway dissection, in vivo metastasis assays in lung cancer","pmids":["37395651"],"confidence":"High","gaps":["The precise PAR2 cleavage site for PRSS3 versus other trypsin-like proteases was not compared","Whether PAR1 and PAR2 are cleaved with different kinetics or specificity by PRSS3 was not addressed"]},{"year":2024,"claim":"A non-cancer physiological role emerged: mesotrypsin processes pro-filaggrin in keratinocytes, remodeling the actin cytoskeleton, enhancing E-cadherin adhesion, and promoting tight junction formation.","evidence":"Venus-mesotrypsin fusion expression in HaCaT keratinocytes, immunofluorescence for junctional markers, proliferation assays","pmids":["38811772"],"confidence":"Medium","gaps":["Whether filaggrin processing is the primary substrate event or a bystander cleavage is unclear","Relevance to in vivo epidermal barrier function was not tested","Catalytic requirement was not confirmed with an inactive mutant in this system"]},{"year":2025,"claim":"The PRSS3-V1/PAR2 interaction was shown to suppress ferroptosis by maintaining SLC7A11 and GPX4 levels, linking protease-activated receptor signaling to redox homeostasis and iron metabolism in breast cancer.","evidence":"Co-immunoprecipitation of PRSS3-V1 and PAR2, ferroptosis markers (MDA, ROS, lipid peroxidation, labile iron), rescue by PAR2 agonist and ferrostatin, NLRP3 inflammasome activation, in vivo xenograft","pmids":["41046946"],"confidence":"Medium","gaps":["Whether PRSS3-V1 cleaves PAR2 or signals through a non-catalytic interaction was not resolved","The mechanism linking PAR2/ERK to SLC7A11/GPX4 transcription or stability was not dissected","Whether other PRSS3 isoforms similarly regulate ferroptosis was not tested"]},{"year":null,"claim":"Key unresolved questions include the full substrate repertoire of mesotrypsin, the structural basis for opposing isoform functions, and whether PRSS3's physiological role in epithelial barrier maintenance connects to its tumor biology.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unbiased substrate profiling (e.g., TAILS, N-terminomics) has been performed","Structural models for individual PRSS3 splice variants are lacking","Genetic models (PRSS3-knockout mice) with phenotypic characterization have not been reported in this timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,5,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]}],"complexes":[],"partners":["F2R","F2RL1","TFPI2","MZF1","SLC7A11","GPX4"],"other_free_text":[]},"mechanistic_narrative":"PRSS3 (mesotrypsin) is a serine protease that drives tumor cell invasion, metastasis, and survival primarily through proteolytic activation of protease-activated receptors and degradation of extracellular inhibitors. Its catalytic activity is required for invasion: active PRSS3 cleaves PAR1 and PAR2, engaging ERK/VEGF signaling to promote proliferation and metastasis, and directly degrades the Kunitz-type inhibitor TFPI-2 to facilitate endothelial cell migration [PMID:20947888, PMID:23258495, PMID:27161730, PMID:37395651]. PRSS3-V1 interaction with PAR2 suppresses ferroptosis through maintenance of SLC7A11/GPX4, while the opposing isoform PRSS3-V2 is oncogenic and PRSS3-V1/-V3/-V4 are tumor-suppressive in hepatocellular carcinoma, with isoform-specific expression governed by intragenic CpG methylation controlled by the UHRF1/DNMT1–MZF1 axis [PMID:41046946, PMID:35480112, PMID:37250150]. In keratinocytes, mesotrypsin processes pro-filaggrin and remodels cell junctions and the actin cytoskeleton, indicating physiological roles beyond cancer [PMID:38811772]."},"prefetch_data":{"uniprot":{"accession":"P35030","full_name":"Trypsin-3","aliases":["Brain trypsinogen","Mesotrypsin","Mesotrypsinogen","Serine protease 3","Serine protease 4","Trypsin III","Trypsin IV"],"length_aa":304,"mass_kda":32.5,"function":"Digestive protease that cleaves proteins preferentially after an Arg residue and has proteolytic activity toward Kunitz-type trypsin inhibitors","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P35030/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRSS3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRSS3","total_profiled":1310},"omim":[{"mim_id":"613578","title":"PROTEASE, SERINE, 3; PRSS3","url":"https://www.omim.org/entry/613578"},{"mim_id":"603722","title":"ELONGATOR COMPLEX PROTEIN 1; ELP1","url":"https://www.omim.org/entry/603722"},{"mim_id":"276000","title":"PROTEASE, SERINE, 1; PRSS1","url":"https://www.omim.org/entry/276000"},{"mim_id":"223900","title":"DYSAUTONOMIA, FAMILIAL; FD","url":"https://www.omim.org/entry/223900"},{"mim_id":"167800","title":"PANCREATITIS, HEREDITARY; PCTT","url":"https://www.omim.org/entry/167800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":29336.6}],"url":"https://www.proteinatlas.org/search/PRSS3"},"hgnc":{"alias_symbol":["TRY3","TRY4"],"prev_symbol":["PRSS4"]},"alphafold":{"accession":"P35030","domains":[{"cath_id":"2.40.10.10","chopping":"94-183_294-303","consensus_level":"medium","plddt":98.1876,"start":94,"end":303},{"cath_id":"2.40.10.10","chopping":"185-291","consensus_level":"medium","plddt":96.3169,"start":185,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35030","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35030-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35030-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRSS3","jax_strain_url":"https://www.jax.org/strain/search?query=PRSS3"},"sequence":{"accession":"P35030","fasta_url":"https://rest.uniprot.org/uniprotkb/P35030.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35030/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35030"}},"corpus_meta":[{"pmid":"20947888","id":"PMC_20947888","title":"PRSS3 promotes tumour growth and metastasis of human pancreatic cancer.","date":"2010","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/20947888","citation_count":81,"is_preprint":false},{"pmid":"23258495","id":"PMC_23258495","title":"PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer.","date":"2012","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/23258495","citation_count":57,"is_preprint":false},{"pmid":"31810373","id":"PMC_31810373","title":"Circular RNA ADAM9 facilitates the malignant behaviours of pancreatic cancer by sponging miR-217 and upregulating PRSS3 expression.","date":"2019","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31810373","citation_count":47,"is_preprint":false},{"pmid":"16013053","id":"PMC_16013053","title":"Epigenetic silencing of the PRSS3 putative tumor suppressor gene in non-small cell lung cancer.","date":"2005","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16013053","citation_count":28,"is_preprint":false},{"pmid":"15901841","id":"PMC_15901841","title":"Interchromosomal segmental duplications explain the unusual structure of PRSS3, the gene for an inhibitor-resistant trypsinogen.","date":"2005","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/15901841","citation_count":25,"is_preprint":false},{"pmid":"28844099","id":"PMC_28844099","title":"Epigenetic silencing of PRSS3 provides growth and metastasis advantage for human hepatocellular carcinoma.","date":"2017","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/28844099","citation_count":21,"is_preprint":false},{"pmid":"37250150","id":"PMC_37250150","title":"UHRF1/DNMT1-MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer.","date":"2023","source":"Acta pharmaceutica Sinica. 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[et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/20484962","citation_count":7,"is_preprint":false},{"pmid":"35480112","id":"PMC_35480112","title":"CpG Site-Specific Methylation-Modulated Divergent Expression of PRSS3 Transcript Variants Facilitates Nongenetic Intratumor Heterogeneity in Human Hepatocellular Carcinoma.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35480112","citation_count":6,"is_preprint":false},{"pmid":"37215724","id":"PMC_37215724","title":"Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis.","date":"2023","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37215724","citation_count":6,"is_preprint":false},{"pmid":"27161730","id":"PMC_27161730","title":"PO-44 - Tissue factor pathway inhibitor-2 (TFPI-2) is cleaved by PRSS3: implication for tumor endothelial cells migration.","date":"2016","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/27161730","citation_count":5,"is_preprint":false},{"pmid":"26662304","id":"PMC_26662304","title":"Clinical significance and expression of the PRSS3 and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 for the early detection of epithelial ovarian cancer.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26662304","citation_count":2,"is_preprint":false},{"pmid":"38811772","id":"PMC_38811772","title":"PRSS3/mesotrypsin as a putative regulator of the biophysical characteristics of epidermal keratinocytes in superficial layers.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38811772","citation_count":1,"is_preprint":false},{"pmid":"41046946","id":"PMC_41046946","title":"Targeting the PRSS3-PAR2-ERK1/2 axis inhibits malignancy and regulates chemosensitivity and resistance through ferroptosis in breast cancer.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41046946","citation_count":0,"is_preprint":false},{"pmid":"40569456","id":"PMC_40569456","title":"Therapeutic targeting of PRSS3 to alleviate kidney damage in DKD.","date":"2025","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40569456","citation_count":0,"is_preprint":false},{"pmid":"41163337","id":"PMC_41163337","title":"CpG Methylation-Driven Pleiotropic Spliced Isoforms of PRSS3 Facilitate Gastric Intratumor Heterogeneity and Metastasis.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/41163337","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.14.688538","title":"Colorectal cancer relies on an immunosuppressive cellular topography and genomic adaptations for establishing brain metastases","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688538","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12929,"output_tokens":3026,"usd":0.042089},"stage2":{"model":"claude-opus-4-6","input_tokens":6392,"output_tokens":2829,"usd":0.154028},"total_usd":0.196117,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway in pancreatic cancer cells, promoting proliferation, invasion, and metastasis.\",\n      \"method\": \"PRSS3 overexpression/silencing in cancer cell lines, VEGF ELISA, ERK inhibitor treatment, in vivo metastasis models\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement by gain/loss-of-function with defined molecular readouts, single lab\",\n      \"pmids\": [\"20947888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRSS3/mesotrypsin promotes prostate cancer invasion through its proteolytic activity; a catalytically inactive mesotrypsin mutant cannot drive the invasive phenotype, and recombinant active mesotrypsin is sufficient to promote invasion.\",\n      \"method\": \"Recombinant mesotrypsin treatment, catalytically inactive mutant comparison, Matrigel transwell invasion assay, 3D cell culture, mesotrypsin-specific inhibitor, orthotopic mouse model with bioluminescent imaging\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity requirement demonstrated by mutant rescue and specific inhibitor, multiple orthogonal assays\",\n      \"pmids\": [\"23258495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TFPI-2 (a Kunitz-type serine proteinase inhibitor) is a direct substrate of PRSS3; active PRSS3 cleaves TFPI-2 in a cell-free system and removes it from the extracellular matrix of tumor endothelial cells, thereby promoting their migration.\",\n      \"method\": \"Cell-free proteolytic assay (western blot), siRNA silencing of PRSS3 in tumor-derived endothelial cells, wound healing migration assay\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct substrate cleavage demonstrated in vitro with functional consequence shown by siRNA\",\n      \"pmids\": [\"27161730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"circ-ADAM9 acts as a ceRNA that sponges miR-217, thereby relieving miR-217-mediated suppression of PRSS3, which in turn activates the ERK/VEGF signalling pathway to promote pancreatic cancer progression.\",\n      \"method\": \"miR-217 and circ-ADAM9 overexpression/silencing in cell lines and xenograft models, luciferase reporter assays (implied by ceRNA analysis), in vivo tumor growth assays\",\n      \"journal\": \"Artificial cells, nanomedicine, and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ceRNA mechanism with functional readouts, single lab, confirms upstream regulation of PRSS3-ERK/VEGF axis\",\n      \"pmids\": [\"31810373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRSS3 variant 3 (brain trypsinogen isoform) physically interacts with Enterovirus A71 nonstructural 3A protein in human neuroblastoma cells, and PRSS3 facilitates EV-A71 replication.\",\n      \"method\": \"Pull-down assay with LC-MS/MS identification, siRNA-mediated PRSS3 knockdown and overexpression in SH-SY5Y cells, viral replication assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by pull-down/MS and functional role by KD/OE, single lab\",\n      \"pmids\": [\"35896602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Individual PRSS3 splice variants (V1–V4) have distinct and opposing functions in hepatocellular carcinoma: PRSS3-V2 is oncogenic while PRSS3-V1, -V3, and -V4 are tumor-suppressive; their expression is controlled by site-specific CpG methylation at the PRSS3 promoter.\",\n      \"method\": \"CRISPR/Cas9 deletion of PRSS3 followed by re-expression of individual isoform constructs, gain/loss-of-function cell models, qPCR, methylation analysis of public datasets\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific function established with CRISPR and isoform re-expression, single lab\",\n      \"pmids\": [\"35480112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Shear stress triggers PRSS3 to cleave the N-terminal inhibitory domain of PAR2 within 2 hours; activated PAR2 then signals via Gαi to the Src-ERK/p38/JNK-FRA1/cJUN axis, upregulating EMT markers and further PRSS3 expression, promoting metastasis of circulating lung cancer cells.\",\n      \"method\": \"Microfluidic circulatory system generating arteriosus shear stress, transcriptome profiling, PAR2 cleavage assay, Gαi signaling pathway analysis, in vivo metastasis assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct cleavage of PAR2 by PRSS3 demonstrated with temporal resolution, downstream pathway mapped by multiple methods\",\n      \"pmids\": [\"37395651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UHRF1/DNMT1 complex mediates intragenic CpG island methylation at the PRSS3 locus by interfering with binding of MZF1 transcription factor, leading to isoform-specific silencing (particularly PRSS3-V3) and divergent oncogenic vs. tumor-suppressive outputs in lung cancer.\",\n      \"method\": \"Site-specific methylation analysis (BALF and tumor tissues), ChIP/MZF1 binding assays, UHRF1/DNMT1 complex characterization, 5-aza-2'-deoxycytidine and diallyl trisulfide treatment, isoform-specific qPCR\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic writer complex (UHRF1/DNMT1) and reader (MZF1) identified with functional isoform consequences, single lab\",\n      \"pmids\": [\"37250150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mesotrypsin (PRSS3) processes pro-filaggrin in keratinocytes and, when expressed in HaCaT cells, causes a flattened phenotype, reduced proliferation, altered F-actin assembly, enhanced E-cadherin adhesion, and facilitated tight junction formation without overtly affecting epidermal differentiation.\",\n      \"method\": \"Venus-mesotrypsin fusion expression in HaCaT keratinocytes, immunofluorescence for F-actin, E-cadherin and tight junction markers, proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — defined cellular phenotypes with specific molecular readouts from gain-of-function, single lab\",\n      \"pmids\": [\"38811772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRSS3-V1 (splice isoform 1) interacts with protease-activated receptor 2 (PAR2) and enhances ERK1/2 phosphorylation in breast cancer cells; PRSS3 silencing induces ferroptosis via downregulation of SLC7A11 and GPX4, accumulation of labile iron, ROS, lipid peroxidation, and NLRP3 inflammasome activation, which can be rescued by PAR2 agonist or TfR1 inhibitor ferrostatin II.\",\n      \"method\": \"Gain/loss-of-function cell models, co-immunoprecipitation (PRSS3-V1 and PAR2), ERK1/2 phosphorylation western blot, ferroptosis markers (MDA, LDH, ROS), mitochondrial membrane potential assay, NLRP3 inflammasome activation, in vivo xenograft\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing PRSS3-V1/PAR2/ERK axis and ferroptosis mechanism, single lab\",\n      \"pmids\": [\"41046946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRSS3 overexpression in hepatocellular carcinoma cells suppresses proliferation by arresting the cell cycle at G1/S phase, accompanied by downregulation of CCND1/CDK4 and CCNE1/CDK2 complexes, and inhibits migration/invasion via downregulation of MMP2 and reduced MEK1/2 and ERK1/2 phosphorylation; these effects are reversed by PRSS3 knockdown.\",\n      \"method\": \"PRSS3 overexpression and siRNA knockdown in HCC cell lines, cell cycle analysis, western blot for cyclins/CDKs/MMP2/pMEK/pERK, proliferation and invasion assays\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with defined molecular pathway readouts, single lab\",\n      \"pmids\": [\"28844099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The PRSS3 T167A variant shows normal secretion and trypsin activity in functional assays, indicating this amino acid position is not critical for mesotrypsin catalytic function.\",\n      \"method\": \"Transient transfection of HEK 293T cells, secretion assay, enzymatic activity assay\",\n      \"journal\": \"Pancreatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with specific variant, single lab\",\n      \"pmids\": [\"20484962\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRSS3/mesotrypsin is a serine protease with isoform-specific functions: its proteolytic activity drives cancer invasion and metastasis primarily by cleaving and activating protease-activated receptors (PAR1, PAR2) to engage ERK/VEGF signaling, by directly degrading extracellular inhibitors such as TFPI-2, and by interacting with PAR2 to inhibit ferroptosis via SLC7A11/GPX4 downregulation; its expression is controlled by isoform-specific intragenic CpG methylation regulated by the UHRF1/DNMT1–MZF1 axis, with distinct splice variants (V1–V4) exerting opposing oncogenic or tumor-suppressive functions depending on cellular context.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRSS3 (mesotrypsin) is a serine protease that drives tumor cell invasion, metastasis, and survival primarily through proteolytic activation of protease-activated receptors and degradation of extracellular inhibitors. Its catalytic activity is required for invasion: active PRSS3 cleaves PAR1 and PAR2, engaging ERK/VEGF signaling to promote proliferation and metastasis, and directly degrades the Kunitz-type inhibitor TFPI-2 to facilitate endothelial cell migration [PMID:20947888, PMID:23258495, PMID:27161730, PMID:37395651]. PRSS3-V1 interaction with PAR2 suppresses ferroptosis through maintenance of SLC7A11/GPX4, while the opposing isoform PRSS3-V2 is oncogenic and PRSS3-V1/-V3/-V4 are tumor-suppressive in hepatocellular carcinoma, with isoform-specific expression governed by intragenic CpG methylation controlled by the UHRF1/DNMT1–MZF1 axis [PMID:41046946, PMID:35480112, PMID:37250150]. In keratinocytes, mesotrypsin processes pro-filaggrin and remodels cell junctions and the actin cytoskeleton, indicating physiological roles beyond cancer [PMID:38811772].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that PRSS3 promotes pancreatic cancer through a defined signaling axis answered how a secreted trypsin isoform could drive metastasis: PRSS3 upregulates VEGF via PAR1-mediated ERK activation.\",\n      \"evidence\": \"PRSS3 overexpression/silencing in pancreatic cancer cells with VEGF ELISA, ERK inhibitor treatment, and in vivo metastasis models\",\n      \"pmids\": [\"20947888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PRSS3 directly cleaves PAR1 or acts indirectly was not resolved\",\n        \"Contribution of individual PRSS3 splice variants was not examined\",\n        \"In vivo specificity of the PAR1-ERK-VEGF axis was not validated with receptor-null models\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that catalytic activity is required for PRSS3-driven invasion resolved whether the protease acts enzymatically or as a scaffold: a catalytically dead mutant failed to promote invasion, and a mesotrypsin-specific inhibitor blocked it.\",\n      \"evidence\": \"Catalytically inactive mutant, recombinant active mesotrypsin, mesotrypsin-specific inhibitor, Matrigel invasion and 3D culture in prostate cancer cells, orthotopic mouse model\",\n      \"pmids\": [\"23258495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct proteolytic substrate mediating invasion was not identified\",\n        \"Whether the same catalytic requirement applies in other cancer types was untested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of TFPI-2 as a direct substrate revealed how PRSS3 remodels the tumor microenvironment: cleavage of this extracellular matrix-associated inhibitor liberates endothelial cell migration.\",\n      \"evidence\": \"Cell-free proteolytic cleavage assay plus PRSS3 siRNA in tumor-derived endothelial cells with wound healing migration readout\",\n      \"pmids\": [\"27161730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cleavage site on TFPI-2 was not mapped\",\n        \"In vivo relevance of TFPI-2 degradation to angiogenesis was not tested\",\n        \"Other extracellular substrates were not surveyed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Paradoxically, PRSS3 overexpression in hepatocellular carcinoma suppressed proliferation and invasion via G1/S arrest and MEK/ERK inhibition, raising the question of context-dependent or isoform-dependent function.\",\n      \"evidence\": \"PRSS3 overexpression and siRNA knockdown in HCC cell lines with cell cycle, cyclin/CDK, MMP2, and pERK western blot readouts\",\n      \"pmids\": [\"28844099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which PRSS3 isoform(s) mediated tumor suppression was not delineated\",\n        \"How PRSS3 both activates and suppresses ERK in different contexts was unexplained\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolution of the oncogene-versus-tumor-suppressor paradox came from dissecting individual splice variants: PRSS3-V2 is oncogenic while V1/V3/V4 are tumor-suppressive, with expression governed by site-specific CpG methylation at the PRSS3 promoter.\",\n      \"evidence\": \"CRISPR/Cas9 deletion of PRSS3 followed by individual isoform re-expression in HCC cells, methylation analysis\",\n      \"pmids\": [\"35480112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for opposing isoform functions was not determined\",\n        \"Whether isoform-specific methylation patterns hold across cancer types was untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The epigenetic machinery controlling isoform-specific expression was mapped: UHRF1/DNMT1-mediated intragenic CpG methylation blocks MZF1 binding, selectively silencing tumor-suppressive PRSS3-V3 in lung cancer.\",\n      \"evidence\": \"Site-specific methylation in BALF and tumor tissues, ChIP for MZF1 binding, UHRF1/DNMT1 complex characterization, demethylating agent treatment with isoform-specific qPCR\",\n      \"pmids\": [\"37250150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether other transcription factors co-regulate isoform expression was not explored\",\n        \"In vivo rescue of V3 expression by demethylation and its effect on tumor growth was not shown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Direct cleavage of PAR2 by PRSS3 was demonstrated with temporal resolution, connecting mechanical shear stress to a PRSS3→PAR2→Gαi→Src-ERK/p38/JNK→EMT positive feedback loop in circulating tumor cells.\",\n      \"evidence\": \"Microfluidic shear stress system, PAR2 N-terminal cleavage assay, transcriptomics, Gαi pathway dissection, in vivo metastasis assays in lung cancer\",\n      \"pmids\": [\"37395651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise PAR2 cleavage site for PRSS3 versus other trypsin-like proteases was not compared\",\n        \"Whether PAR1 and PAR2 are cleaved with different kinetics or specificity by PRSS3 was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A non-cancer physiological role emerged: mesotrypsin processes pro-filaggrin in keratinocytes, remodeling the actin cytoskeleton, enhancing E-cadherin adhesion, and promoting tight junction formation.\",\n      \"evidence\": \"Venus-mesotrypsin fusion expression in HaCaT keratinocytes, immunofluorescence for junctional markers, proliferation assays\",\n      \"pmids\": [\"38811772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether filaggrin processing is the primary substrate event or a bystander cleavage is unclear\",\n        \"Relevance to in vivo epidermal barrier function was not tested\",\n        \"Catalytic requirement was not confirmed with an inactive mutant in this system\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The PRSS3-V1/PAR2 interaction was shown to suppress ferroptosis by maintaining SLC7A11 and GPX4 levels, linking protease-activated receptor signaling to redox homeostasis and iron metabolism in breast cancer.\",\n      \"evidence\": \"Co-immunoprecipitation of PRSS3-V1 and PAR2, ferroptosis markers (MDA, ROS, lipid peroxidation, labile iron), rescue by PAR2 agonist and ferrostatin, NLRP3 inflammasome activation, in vivo xenograft\",\n      \"pmids\": [\"41046946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PRSS3-V1 cleaves PAR2 or signals through a non-catalytic interaction was not resolved\",\n        \"The mechanism linking PAR2/ERK to SLC7A11/GPX4 transcription or stability was not dissected\",\n        \"Whether other PRSS3 isoforms similarly regulate ferroptosis was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full substrate repertoire of mesotrypsin, the structural basis for opposing isoform functions, and whether PRSS3's physiological role in epithelial barrier maintenance connects to its tumor biology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unbiased substrate profiling (e.g., TAILS, N-terminomics) has been performed\",\n        \"Structural models for individual PRSS3 splice variants are lacking\",\n        \"Genetic models (PRSS3-knockout mice) with phenotypic characterization have not been reported in this timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 5, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"F2R\",\n      \"F2RL1\",\n      \"TFPI2\",\n      \"MZF1\",\n      \"SLC7A11\",\n      \"GPX4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}