{"gene":"HPSE","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2012,"finding":"Knockdown of HPSE (heparanase) in melanoma cells using artificial miRNA reduced adhesion, migration, and invasion in vitro and in vivo, and suppressed expression of chemokines IL-8 and CXCL1 at both mRNA and protein levels. The downstream effect was correlated with reduced MAPK phosphorylation (p38 MAPK, JNK, ERK1/2), and could be rescued by re-expression of miRNA-incompatible HPSE cDNA, establishing HPSE as an upstream regulator of chemokine expression via MAPK signaling.","method":"Artificial miRNA knockdown, in vitro invasion/migration assays, in vivo xenograft, Western blot for MAPK phosphorylation, rescue experiment with mutant HPSE cDNA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement via rescue experiment, single lab with multiple orthogonal methods","pmids":["22719918"],"is_preprint":false},{"year":2016,"finding":"HMGB1 activates HPSE expression through its receptor RAGE, which activates NF-κB that binds to the HPSE promoter to drive transcription. The resulting elevated HPSE then cleaves heparan sulfate chains on myofibroblast ECM to release latent TGF-β, promoting bronchiolitis obliterans syndrome (BOS). Blockade of HMGB1 alone or combined with HPSE attenuated BOS development in a mouse tracheal transplant model.","method":"Mouse tracheal transplantation model, HMGB1 blockade, HPSE inhibition, promoter binding assay for NF-κB on HPSE promoter, TGF-β release assay from ECM","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with mechanistic pathway dissection (RAGE→NF-κB→HPSE promoter→HS cleavage→TGF-β release), single lab","pmids":["27347307"],"is_preprint":false},{"year":2015,"finding":"HPSE (heparanase) modulates autophagy in normal and malignant cells, conferring growth advantages and resistance to chemotherapy. This establishes a non-ECM-degradation role for heparanase in regulating intracellular autophagy pathways.","method":"Cell-based autophagy assays in normal and cancer cell lines with HPSE modulation (gain/loss of function)","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract provides only summary-level description of findings without specifying methods in detail; single lab","pmids":["26571129"],"is_preprint":false},{"year":2021,"finding":"Osteoblast-derived exosomes transfer miR-503-3p to osteoclast progenitor cells, where miR-503-3p directly targets HPSE (heparanase) mRNA to suppress its expression, thereby inhibiting osteoclast differentiation. Knockdown of Hpse phenocopied the inhibitory effect of miR-503-3p on osteoclastogenesis.","method":"Exosome isolation (TEM, NTA, Western blot), miRNA target validation, gain/loss-of-function of miR-503-3p and Hpse, osteoclast differentiation assay","journal":"Acta histochemica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods to establish miR-503-3p/Hpse axis in osteoclast differentiation, single lab","pmids":["34592492"],"is_preprint":false},{"year":2009,"finding":"HPSE gene SNPs rs4693608 and rs4364254 regulate heparanase expression at both mRNA and plasma protein levels, with an unexpected inverse correlation: low-risk genotype combinations associated with low mRNA but high plasma heparanase protein, and high-risk genotypes with high mRNA but low plasma protein, suggesting regulation at multiple levels (transcriptional and post-transcriptional/secretion).","method":"SNP genotyping of 11 HPSE SNPs in 108 healthy individuals, haplotype analysis, real-time RT-PCR for mRNA, ELISA for plasma protein","journal":"Journal of leukocyte biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association with expression data, single population cohort study, no direct functional manipulation","pmids":["19406828"],"is_preprint":false},{"year":2010,"finding":"HPSE expression precedes corneal neovascularization (detectable on day 1, before vessel ingrowth on day 3) across five different etiological models of corneal injury (alkaline burn, fungal infection, suturing, immunogen implantation, tumor implantation), suggesting HPSE acts as a pioneer factor enabling neovascular growth in the corneal stroma.","method":"Immunohistochemistry and double immunofluorescence staining in five mouse corneal neovascularization models; temporal co-expression analysis with MMP-2, MMP-9, and FAP","journal":"Current eye research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative expression/localization data without direct functional manipulation of HPSE; single study","pmids":["20958185"],"is_preprint":false}],"current_model":"HPSE (heparanase) is an endo-β-D-glucuronidase that cleaves heparan sulfate chains on extracellular matrix proteoglycans, thereby releasing ECM-bound growth factors (e.g., latent TGF-β) and facilitating cancer cell invasion, angiogenesis, and inflammation; its expression is transcriptionally driven by NF-κB downstream of HMGB1/RAGE signaling, it promotes tumor invasion and metastasis by upregulating chemokines (IL-8, CXCL1) via MAPK (p38, JNK, ERK) signaling, it modulates osteoclast differentiation when targeted by miR-503-3p, and it induces autophagy in both normal and malignant cells to confer chemotherapy resistance."},"narrative":{"mechanistic_narrative":"HPSE (heparanase) is an endo-glucuronidase whose cleavage of heparan sulfate chains on extracellular matrix proteoglycans liberates ECM-sequestered factors and drives invasion, angiogenesis, and tissue remodeling [PMID:27347307]. In the lung, HMGB1 signaling through RAGE activates NF-κB, which binds the HPSE promoter to induce transcription; the resulting heparanase cleaves heparan sulfate on myofibroblast ECM to release latent TGF-β and promote bronchiolitis obliterans syndrome [PMID:27347307]. Beyond matrix degradation, HPSE acts as an upstream driver of tumor cell adhesion, migration, and invasion by upregulating the chemokines IL-8 and CXCL1 in a manner correlated with p38, JNK, and ERK1/2 MAPK activation [PMID:22719918], and its expression is post-transcriptionally restrained by miR-503-3p, an axis through which suppression of HPSE inhibits osteoclast differentiation [PMID:34592492]. Lower-confidence findings additionally link HPSE to autophagy-associated chemotherapy resistance [PMID:26571129] and to early corneal neovascularization [PMID:20958185].","teleology":[{"year":2009,"claim":"Addressed whether HPSE expression is genetically controlled, finding common SNPs that regulate heparanase at multiple levels and revealing a disconnect between mRNA and circulating protein.","evidence":"SNP genotyping with haplotype analysis, RT-PCR and plasma ELISA in a healthy cohort","pmids":["19406828"],"confidence":"Low","gaps":["Association only, no direct functional manipulation","Mechanism of the inverse mRNA/protein correlation (secretion vs translation) unresolved","Single small population cohort"]},{"year":2010,"claim":"Tested whether HPSE acts before angiogenesis, showing it appears prior to vessel ingrowth across diverse corneal injury models and positioning it as a pioneer factor for neovascularization.","evidence":"Immunohistochemistry and double immunofluorescence with temporal analysis in five mouse corneal neovascularization models","pmids":["20958185"],"confidence":"Low","gaps":["Correlative localization without HPSE loss/gain of function","Does not establish causality for vessel growth","Mechanism linking HPSE to endothelial recruitment unaddressed"]},{"year":2012,"claim":"Placed HPSE upstream of chemokine-driven invasion, showing it controls IL-8 and CXCL1 expression in correlation with MAPK signaling rather than acting solely through matrix degradation.","evidence":"Artificial miRNA knockdown with rescue, in vitro invasion/migration and xenograft assays, MAPK phosphorylation Western blot in melanoma cells","pmids":["22719918"],"confidence":"Medium","gaps":["Causal link between MAPK activation and chemokine induction is correlative","Whether enzymatic activity is required for chemokine regulation not resolved","Single cancer cell type"]},{"year":2015,"claim":"Proposed a non-canonical, intracellular role for HPSE in modulating autophagy to confer growth advantage and chemoresistance, distinct from its ECM-degrading function.","evidence":"Cell-based autophagy assays with HPSE gain/loss of function in normal and cancer cell lines","pmids":["26571129"],"confidence":"Low","gaps":["Methodological detail limited to summary-level","Molecular mechanism connecting HPSE to autophagy machinery undefined","Not independently confirmed"]},{"year":2016,"claim":"Dissected the transcriptional circuit driving HPSE in tissue remodeling, establishing the HMGB1/RAGE/NF-κB axis as inducer and latent TGF-β release as a key downstream consequence.","evidence":"Mouse tracheal transplant BOS model with HMGB1 blockade and HPSE inhibition, NF-κB promoter binding assay, TGF-β release assay","pmids":["27347307"],"confidence":"Medium","gaps":["Direct NF-κB occupancy of the HPSE promoter shown by binding assay but not by genetic dissection of the site","Generalizability beyond the BOS model untested","Single lab"]},{"year":2021,"claim":"Identified a post-transcriptional brake on HPSE, showing osteoblast exosome-delivered miR-503-3p directly targets HPSE mRNA to suppress osteoclast differentiation.","evidence":"Exosome isolation, miRNA target validation, miR-503-3p and Hpse gain/loss of function, osteoclast differentiation assays","pmids":["34592492"],"confidence":"Medium","gaps":["Whether HPSE enzymatic activity drives osteoclastogenesis not addressed","Direct miR-503-3p binding to HPSE 3'UTR confirmation context limited","Single lab"]},{"year":null,"claim":"How HPSE's enzymatic heparan sulfate cleavage is mechanistically coupled to its intracellular signaling roles (MAPK/chemokine induction, autophagy) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or catalytic dissection distinguishing enzymatic vs non-enzymatic functions in the corpus","Direct substrates beyond ECM heparan sulfate not enumerated","Mechanism linking HS cleavage to signaling output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y251","full_name":"Heparanase","aliases":["Endo-glucoronidase","Heparanase-1","Hpa1"],"length_aa":543,"mass_kda":61.1,"function":"Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as a procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extracellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis","subcellular_location":"Lysosome membrane; Secreted; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y251/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HPSE","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HPSE","total_profiled":1310},"omim":[{"mim_id":"616473","title":"MICRO RNA 558; MIR558","url":"https://www.omim.org/entry/616473"},{"mim_id":"614488","title":"MICRO RNA 1258; MIR1258","url":"https://www.omim.org/entry/614488"},{"mim_id":"613469","title":"HEPARANASE 2; HPSE2","url":"https://www.omim.org/entry/613469"},{"mim_id":"607360","title":"LACRITIN; LACRT","url":"https://www.omim.org/entry/607360"},{"mim_id":"604724","title":"HEPARANASE; HPSE","url":"https://www.omim.org/entry/604724"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HPSE"},"hgnc":{"alias_symbol":["HPA","HSE1","HPSE1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y251","domains":[{"cath_id":"2.60.40.1180","chopping":"36-51_420-543","consensus_level":"medium","plddt":97.5339,"start":36,"end":543},{"cath_id":"3.20.20.80","chopping":"53-112_143-417","consensus_level":"high","plddt":98.3018,"start":53,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y251","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y251-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y251-F1-predicted_aligned_error_v6.png","plddt_mean":94.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HPSE","jax_strain_url":"https://www.jax.org/strain/search?query=HPSE"},"sequence":{"accession":"Q9Y251","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y251.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y251/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y251"}},"corpus_meta":[{"pmid":"27528460","id":"PMC_27528460","title":"HPA 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The hidden links between insulinotropic peptides and the HPA axis.","date":"2016","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27325244","citation_count":37,"is_preprint":false},{"pmid":"30086534","id":"PMC_30086534","title":"Childhood trauma dependent anxious depression sensitizes HPA axis function.","date":"2018","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30086534","citation_count":36,"is_preprint":false},{"pmid":"33422640","id":"PMC_33422640","title":"Stress impairs response to antidepressants via HPA axis and immune system activation.","date":"2021","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/33422640","citation_count":36,"is_preprint":false},{"pmid":"27347307","id":"PMC_27347307","title":"HMGB1 exacerbates bronchiolitis obliterans syndrome via RAGE/NF-κB/HPSE signaling to enhance latent TGF-β release from ECM.","date":"2016","source":"American journal of translational 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psychopathology","url":"https://pubmed.ncbi.nlm.nih.gov/30394263","citation_count":35,"is_preprint":false},{"pmid":"31106715","id":"PMC_31106715","title":"Gene-environment interactions between HPA-axis genes and stressful life events in depression: a systematic review.","date":"2019","source":"Acta neuropsychiatrica","url":"https://pubmed.ncbi.nlm.nih.gov/31106715","citation_count":34,"is_preprint":false},{"pmid":"27147943","id":"PMC_27147943","title":"Neuroendocrinological and Epigenetic Mechanisms Subserving Autonomic Imbalance and HPA Dysfunction in the Metabolic Syndrome.","date":"2016","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27147943","citation_count":33,"is_preprint":false},{"pmid":"26571129","id":"PMC_26571129","title":"Function from within: Autophagy induction by HPSE/heparanase--new possibilities for intervention.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26571129","citation_count":33,"is_preprint":false},{"pmid":"27507764","id":"PMC_27507764","title":"HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome.","date":"2016","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/27507764","citation_count":32,"is_preprint":false},{"pmid":"21387128","id":"PMC_21387128","title":"Effects of kisspeptin on parameters of the HPA axis.","date":"2011","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/21387128","citation_count":32,"is_preprint":false},{"pmid":"16132204","id":"PMC_16132204","title":"Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome.","date":"2004","source":"Pituitary","url":"https://pubmed.ncbi.nlm.nih.gov/16132204","citation_count":30,"is_preprint":false},{"pmid":"19038456","id":"PMC_19038456","title":"HPA-1a alloantibodies reduce endothelial cell spreading and monolayer integrity.","date":"2008","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19038456","citation_count":30,"is_preprint":false},{"pmid":"32472381","id":"PMC_32472381","title":"Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood.","date":"2020","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32472381","citation_count":30,"is_preprint":false},{"pmid":"28825666","id":"PMC_28825666","title":"NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28825666","citation_count":28,"is_preprint":false},{"pmid":"20958185","id":"PMC_20958185","title":"Expression of MMP, HPSE, and FAP in stroma promoted corneal neovascularization induced by different etiological factors.","date":"2010","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/20958185","citation_count":26,"is_preprint":false},{"pmid":"29704202","id":"PMC_29704202","title":"Role of HPA and the HPG Axis Interaction in Testosterone-Mediated Learned Helpless Behavior.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29704202","citation_count":25,"is_preprint":false},{"pmid":"36481932","id":"PMC_36481932","title":"Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36481932","citation_count":25,"is_preprint":false},{"pmid":"33293624","id":"PMC_33293624","title":"Ethanol affects behavior and HPA axis activity during development in zebrafish larvae.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33293624","citation_count":24,"is_preprint":false},{"pmid":"34635736","id":"PMC_34635736","title":"HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34635736","citation_count":24,"is_preprint":false},{"pmid":"31466501","id":"PMC_31466501","title":"Female HPA axis displays heightened sensitivity to pre-pubertal stress.","date":"2019","source":"Stress (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/31466501","citation_count":23,"is_preprint":false},{"pmid":"27061711","id":"PMC_27061711","title":"Differentiation of Keratinocytes Modulates Skin HPA Analog.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27061711","citation_count":22,"is_preprint":false},{"pmid":"30367959","id":"PMC_30367959","title":"Role of corticosterone in anxiety- and depressive-like behavior and HPA regulation following prenatal alcohol exposure.","date":"2018","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30367959","citation_count":22,"is_preprint":false},{"pmid":"18383324","id":"PMC_18383324","title":"Polymorphisms of the human platelet alloantigens HPA-1, HPA-2, HPA-3, and HPA-4 in ischemic stroke.","date":"2008","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/18383324","citation_count":22,"is_preprint":false},{"pmid":"32271938","id":"PMC_32271938","title":"New effects of caffeine on corticotropin-releasing hormone (CRH)-induced stress along the intrafollicular classical hypothalamic-pituitary-adrenal (HPA) axis (CRH-R1/2, IP3 -R, ACTH, MC-R2) and the neurogenic non-HPA axis (substance P, p75NTR and TrkA) in ex vivo human male androgenetic scalp hair follicles.","date":"2020","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/32271938","citation_count":22,"is_preprint":false},{"pmid":"41155288","id":"PMC_41155288","title":"Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41155288","citation_count":21,"is_preprint":false},{"pmid":"30923048","id":"PMC_30923048","title":"HLA-DRB3*01:01 exhibits a dose-dependent impact on HPA-1a antibody levels in HPA-1a-immunized women.","date":"2019","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/30923048","citation_count":21,"is_preprint":false},{"pmid":"19406828","id":"PMC_19406828","title":"Inverse correlation between HPSE gene single nucleotide polymorphisms and heparanase expression: possibility of multiple levels of heparanase regulation.","date":"2009","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/19406828","citation_count":20,"is_preprint":false},{"pmid":"29223280","id":"PMC_29223280","title":"Circadian and ultradian patterns of HPA-axis activity in rodents: Significance for brain functionality.","date":"2017","source":"Best practice & research. Clinical endocrinology & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29223280","citation_count":20,"is_preprint":false},{"pmid":"12029532","id":"PMC_12029532","title":"Gene frequencies of the HPA-1 to HPA-8w platelet antigen alleles in Taiwanese, Indonesian, and Thai.","date":"2002","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12029532","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49854,"output_tokens":2184,"usd":0.091161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8579,"output_tokens":2354,"usd":0.050873,"stage2_stop_reason":"end_turn"},"total_usd":0.142034,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical HPSE gene (heparanase, the endo-β-D-glucuronidase). The vast majority of papers are about the HPA axis (hypothalamic-pituitary-adrenal axis), HPA-1 platelet antigens, or Hse1 (the yeast ESCRT component). Let me identify the relevant HPSE papers:\n\n- Papers 18, 46, 49: These are about yeast Hse1 (ESCRT pathway component) — this is a different protein (yeast ortholog of STAM, not heparanase). NOT the canonical HPSE.\n- Paper 35: HPSE eRNA (non-coding RNA product) — exclude per rules.\n- Paper 55: HPSE (heparanase) knockdown in melanoma — INCLUDE.\n- Paper 57: HPSE gene SNPs and GVHD — mostly genetic association, but mentions heparanase in inflammation/autoimmunity context.\n- Paper 64: miR-503-3p/Hpse axis in osteoclast differentiation — INCLUDE (Hpse as target gene).\n- Paper 69: HPSE SNPs and hematological malignancies — expression data, mostly association.\n- Paper 73: HMGB1/RAGE/NF-κB/HPSE signaling in BOS — INCLUDE.\n- Paper 79: HPSE and autophagy — INCLUDE.\n- Paper 86: HPSE expression in corneal neovascularization — localization/expression.\n- Paper 98: HPSE SNPs and expression regulation — INCLUDE (mechanistic regulation).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of HPSE (heparanase) in melanoma cells using artificial miRNA reduced adhesion, migration, and invasion in vitro and in vivo, and suppressed expression of chemokines IL-8 and CXCL1 at both mRNA and protein levels. The downstream effect was correlated with reduced MAPK phosphorylation (p38 MAPK, JNK, ERK1/2), and could be rescued by re-expression of miRNA-incompatible HPSE cDNA, establishing HPSE as an upstream regulator of chemokine expression via MAPK signaling.\",\n      \"method\": \"Artificial miRNA knockdown, in vitro invasion/migration assays, in vivo xenograft, Western blot for MAPK phosphorylation, rescue experiment with mutant HPSE cDNA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement via rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22719918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HMGB1 activates HPSE expression through its receptor RAGE, which activates NF-κB that binds to the HPSE promoter to drive transcription. The resulting elevated HPSE then cleaves heparan sulfate chains on myofibroblast ECM to release latent TGF-β, promoting bronchiolitis obliterans syndrome (BOS). Blockade of HMGB1 alone or combined with HPSE attenuated BOS development in a mouse tracheal transplant model.\",\n      \"method\": \"Mouse tracheal transplantation model, HMGB1 blockade, HPSE inhibition, promoter binding assay for NF-κB on HPSE promoter, TGF-β release assay from ECM\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with mechanistic pathway dissection (RAGE→NF-κB→HPSE promoter→HS cleavage→TGF-β release), single lab\",\n      \"pmids\": [\"27347307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HPSE (heparanase) modulates autophagy in normal and malignant cells, conferring growth advantages and resistance to chemotherapy. This establishes a non-ECM-degradation role for heparanase in regulating intracellular autophagy pathways.\",\n      \"method\": \"Cell-based autophagy assays in normal and cancer cell lines with HPSE modulation (gain/loss of function)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract provides only summary-level description of findings without specifying methods in detail; single lab\",\n      \"pmids\": [\"26571129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Osteoblast-derived exosomes transfer miR-503-3p to osteoclast progenitor cells, where miR-503-3p directly targets HPSE (heparanase) mRNA to suppress its expression, thereby inhibiting osteoclast differentiation. Knockdown of Hpse phenocopied the inhibitory effect of miR-503-3p on osteoclastogenesis.\",\n      \"method\": \"Exosome isolation (TEM, NTA, Western blot), miRNA target validation, gain/loss-of-function of miR-503-3p and Hpse, osteoclast differentiation assay\",\n      \"journal\": \"Acta histochemica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods to establish miR-503-3p/Hpse axis in osteoclast differentiation, single lab\",\n      \"pmids\": [\"34592492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HPSE gene SNPs rs4693608 and rs4364254 regulate heparanase expression at both mRNA and plasma protein levels, with an unexpected inverse correlation: low-risk genotype combinations associated with low mRNA but high plasma heparanase protein, and high-risk genotypes with high mRNA but low plasma protein, suggesting regulation at multiple levels (transcriptional and post-transcriptional/secretion).\",\n      \"method\": \"SNP genotyping of 11 HPSE SNPs in 108 healthy individuals, haplotype analysis, real-time RT-PCR for mRNA, ELISA for plasma protein\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association with expression data, single population cohort study, no direct functional manipulation\",\n      \"pmids\": [\"19406828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HPSE expression precedes corneal neovascularization (detectable on day 1, before vessel ingrowth on day 3) across five different etiological models of corneal injury (alkaline burn, fungal infection, suturing, immunogen implantation, tumor implantation), suggesting HPSE acts as a pioneer factor enabling neovascular growth in the corneal stroma.\",\n      \"method\": \"Immunohistochemistry and double immunofluorescence staining in five mouse corneal neovascularization models; temporal co-expression analysis with MMP-2, MMP-9, and FAP\",\n      \"journal\": \"Current eye research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative expression/localization data without direct functional manipulation of HPSE; single study\",\n      \"pmids\": [\"20958185\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HPSE (heparanase) is an endo-β-D-glucuronidase that cleaves heparan sulfate chains on extracellular matrix proteoglycans, thereby releasing ECM-bound growth factors (e.g., latent TGF-β) and facilitating cancer cell invasion, angiogenesis, and inflammation; its expression is transcriptionally driven by NF-κB downstream of HMGB1/RAGE signaling, it promotes tumor invasion and metastasis by upregulating chemokines (IL-8, CXCL1) via MAPK (p38, JNK, ERK) signaling, it modulates osteoclast differentiation when targeted by miR-503-3p, and it induces autophagy in both normal and malignant cells to confer chemotherapy resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HPSE (heparanase) is an endo-glucuronidase whose cleavage of heparan sulfate chains on extracellular matrix proteoglycans liberates ECM-sequestered factors and drives invasion, angiogenesis, and tissue remodeling [#1]. In the lung, HMGB1 signaling through RAGE activates NF-\\u03baB, which binds the HPSE promoter to induce transcription; the resulting heparanase cleaves heparan sulfate on myofibroblast ECM to release latent TGF-\\u03b2 and promote bronchiolitis obliterans syndrome [#1]. Beyond matrix degradation, HPSE acts as an upstream driver of tumor cell adhesion, migration, and invasion by upregulating the chemokines IL-8 and CXCL1 in a manner correlated with p38, JNK, and ERK1/2 MAPK activation [#0], and its expression is post-transcriptionally restrained by miR-503-3p, an axis through which suppression of HPSE inhibits osteoclast differentiation [#3]. Lower-confidence findings additionally link HPSE to autophagy-associated chemotherapy resistance [#2] and to early corneal neovascularization [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Addressed whether HPSE expression is genetically controlled, finding common SNPs that regulate heparanase at multiple levels and revealing a disconnect between mRNA and circulating protein.\",\n      \"evidence\": \"SNP genotyping with haplotype analysis, RT-PCR and plasma ELISA in a healthy cohort\",\n      \"pmids\": [\"19406828\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association only, no direct functional manipulation\", \"Mechanism of the inverse mRNA/protein correlation (secretion vs translation) unresolved\", \"Single small population cohort\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tested whether HPSE acts before angiogenesis, showing it appears prior to vessel ingrowth across diverse corneal injury models and positioning it as a pioneer factor for neovascularization.\",\n      \"evidence\": \"Immunohistochemistry and double immunofluorescence with temporal analysis in five mouse corneal neovascularization models\",\n      \"pmids\": [\"20958185\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative localization without HPSE loss/gain of function\", \"Does not establish causality for vessel growth\", \"Mechanism linking HPSE to endothelial recruitment unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed HPSE upstream of chemokine-driven invasion, showing it controls IL-8 and CXCL1 expression in correlation with MAPK signaling rather than acting solely through matrix degradation.\",\n      \"evidence\": \"Artificial miRNA knockdown with rescue, in vitro invasion/migration and xenograft assays, MAPK phosphorylation Western blot in melanoma cells\",\n      \"pmids\": [\"22719918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between MAPK activation and chemokine induction is correlative\", \"Whether enzymatic activity is required for chemokine regulation not resolved\", \"Single cancer cell type\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Proposed a non-canonical, intracellular role for HPSE in modulating autophagy to confer growth advantage and chemoresistance, distinct from its ECM-degrading function.\",\n      \"evidence\": \"Cell-based autophagy assays with HPSE gain/loss of function in normal and cancer cell lines\",\n      \"pmids\": [\"26571129\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Methodological detail limited to summary-level\", \"Molecular mechanism connecting HPSE to autophagy machinery undefined\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected the transcriptional circuit driving HPSE in tissue remodeling, establishing the HMGB1/RAGE/NF-\\u03baB axis as inducer and latent TGF-\\u03b2 release as a key downstream consequence.\",\n      \"evidence\": \"Mouse tracheal transplant BOS model with HMGB1 blockade and HPSE inhibition, NF-\\u03baB promoter binding assay, TGF-\\u03b2 release assay\",\n      \"pmids\": [\"27347307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NF-\\u03baB occupancy of the HPSE promoter shown by binding assay but not by genetic dissection of the site\", \"Generalizability beyond the BOS model untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a post-transcriptional brake on HPSE, showing osteoblast exosome-delivered miR-503-3p directly targets HPSE mRNA to suppress osteoclast differentiation.\",\n      \"evidence\": \"Exosome isolation, miRNA target validation, miR-503-3p and Hpse gain/loss of function, osteoclast differentiation assays\",\n      \"pmids\": [\"34592492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HPSE enzymatic activity drives osteoclastogenesis not addressed\", \"Direct miR-503-3p binding to HPSE 3'UTR confirmation context limited\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HPSE's enzymatic heparan sulfate cleavage is mechanistically coupled to its intracellular signaling roles (MAPK/chemokine induction, autophagy) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or catalytic dissection distinguishing enzymatic vs non-enzymatic functions in the corpus\", \"Direct substrates beyond ECM heparan sulfate not enumerated\", \"Mechanism linking HS cleavage to signaling output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":4,"faith_total":4,"faith_pct":100.0}}