{"gene":"STC2","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":1998,"finding":"STC2 (stanniocalcin-2) encodes a secreted glycoprotein with 34% identity to STC1; conditioned medium from STC2-transfected CHO cells inhibited the promoter activity of the Na-phosphate cotransporter (NaPi-3) and inhibited phosphate uptake in kidney OK cells, demonstrating an inhibitory function on renal phosphate transport opposite to STC1.","method":"Molecular cloning, CHO cell transfection, NaPi-3 promoter reporter assay, phosphate uptake assay in OK cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assays with two orthogonal readouts (promoter activity + transport assay), single lab","pmids":["9753616"],"is_preprint":false},{"year":2022,"finding":"STC2 forms a 2:2 heterotetramer with PAPP-A (pregnancy-associated plasma protein-A) via covalent interaction, revealed by cryo-EM structures. STC2 binds exosites on PAPP-A distal to its catalytic cleft, causing steric hindrance that prevents IGFBP substrate binding and cleavage, thus inhibiting PAPP-A protease activity toward IGFBPs.","method":"Cryo-EM structural determination of endogenous PAPP-A/STC2 complex; functional assays with IGFBP linker peptides","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with functional validation; exosite-competitive inhibition mechanism directly demonstrated","pmids":["36550107"],"is_preprint":false},{"year":2023,"finding":"STC2 physically interacts with PRMT5 and activates it, leading to increased symmetric dimethylation of histone H4 on Arg3 (H4R3me2s), which promotes DNA damage repair via homologous recombination and NHEJ pathways; STC2 also participates in SLC7A11-mediated ferroptosis suppression in a PRMT5-dependent manner, contributing to radioresistance in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation (STC2-PRMT5 interaction), Western blot for H4R3me2s, siRNA knockdown, in vivo xenograft experiments","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed, multiple downstream pathway readouts, single lab","pmids":["36764215"],"is_preprint":false},{"year":2019,"finding":"STC2 promotes AXL promoter activity by increasing phosphorylation of c-Jun, an indispensable transcription factor for AXL transactivation, thereby activating the JUN-AXL-ERK signaling axis and conferring acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.","method":"AXL promoter luciferase reporter assay, phospho-c-Jun Western blot, genetic silencing/overexpression of STC2, pharmacological inhibition of AXL-ERK, patient-derived resistant cell line validation","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay plus multiple orthogonal methods (KD/OE, pharmacological inhibition, patient-derived cells), single lab","pmids":["31162839"],"is_preprint":false},{"year":2016,"finding":"STC2 overexpression in colorectal cancer cells activates pERK, pAKT, PI3K and Ras signaling; blocking AKT-ERK signaling pathways attenuates STC2-activated EMT. Exogenous STC2 protein is sufficient to induce EMT characteristics in epithelial cells.","method":"STC2 plasmid transfection, exogenous STC2 protein treatment, Western blot for pathway markers, pharmacological pathway inhibition, mouse xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (OE, exogenous protein, inhibition rescue, in vivo), single lab","pmids":["27662663"],"is_preprint":false},{"year":2017,"finding":"STC2 upregulates phosphorylation of AKT and enhances HNSCC metastasis through Snail-mediated increase of vimentin and decrease of E-cadherin (EMT markers); these effects are blocked by silencing STC2/Snail or inhibiting pAKT activity, placing STC2 upstream of the PI3K/AKT/Snail axis.","method":"STC2 overexpression/silencing, pAKT Western blot, Snail/vimentin/E-cadherin Western blot, in vivo metastasis assay, pharmacological AKT inhibition","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double silencing), multiple orthogonal methods, single lab","pmids":["27863406"],"is_preprint":false},{"year":2015,"finding":"HMGA2 directly regulates STC2 transcription; overexpression of STC2 in ovarian cancer cells directly enhances cell migration and invasion in vitro.","method":"Transcriptional regulation assay (HMGA2→STC2), in vitro migration/invasion assays, gene expression correlation in three independent patient cohorts","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation demonstrated, functional OE assays, replicated across multiple cohorts for correlation","pmids":["26165228"],"is_preprint":false},{"year":2012,"finding":"STC2 regulates cyclin D1 expression and activates ERK1/2 signaling in hepatocellular carcinoma cells to promote G0/G1 to S-phase cell cycle progression and cell proliferation.","method":"STC2 ectopic expression and siRNA knockdown, flow cytometry cell cycle analysis, Western blot for cyclin D1 and pERK1/2, colony formation and Transwell migration assays","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with specific molecular readouts, single lab","pmids":["23187001"],"is_preprint":false},{"year":2016,"finding":"STC2 acts downstream of Mus81 to promote HCC cell proliferation and survival; Mus81 knockdown downregulates STC2, which in turn activates APAF1, APC, and PTEN pathways and inhibits the MAPK pathway; restoration of STC2 expression rescues proliferation and survival defects caused by Mus81 depletion.","method":"DNA microarray screening, high content screen, qRT-PCR, STC2 rescue expression, knockdown of Mus81 in vitro and in vivo","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment, multiple screening methods, single lab","pmids":["27939696"],"is_preprint":false},{"year":2019,"finding":"STC2 silencing in colorectal cancer SW480 cells activates the Wnt/β-catenin pathway (β-catenin expression suppressed by STC2 silencing and restored by Wnt activator SB216763), and STC2 silencing decreases MMP-2, MMP-9, and vimentin while increasing E-cadherin, indicating STC2 promotes EMT via Wnt/β-catenin signaling.","method":"STC2 siRNA knockdown, Western blot for β-catenin/E-cadherin/vimentin/MMP-2/MMP-9, pharmacological rescue with SB216763, wound healing/Transwell assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue establishes pathway placement, multiple molecular readouts, single lab","pmids":["31173256"],"is_preprint":false},{"year":2020,"finding":"STC2 overexpression in human mesenchymal stem cells suppresses adipogenic differentiation by increasing ERK1/2 phosphorylation and decreasing PPARγ and FABP4 expression; treatment with ERK inhibitor U0126 disrupts ERK1/2 phosphorylation and restores adipogenic differentiation, placing STC2 upstream of ERK1/2 in adipogenesis suppression.","method":"STC2 overexpression/knockdown, adipogenic differentiation assay, lipid droplet staining, Western blot for ERK1/2 phosphorylation/PPARγ/FABP4, ERK inhibitor (U0126) rescue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue establishes ERK dependency, gain/loss-of-function, single lab","pmids":["31982135"],"is_preprint":false},{"year":2020,"finding":"STC2 is required for axon regeneration in sensory neurons; STC2 expression is upregulated after axotomy in dorsal root ganglion neurons, and loss of STC2 impairs axon regeneration both in vitro and in vivo; application of secreted STC2 protein to injured DRG neurons promotes regeneration; in vivo gene delivery of STC2 increases regenerative growth after peripheral nerve injury.","method":"Injury-responsive transcriptome analysis, STC2 loss-of-function in vitro/in vivo, exogenous STC2 protein application, in vivo AAV-mediated gene delivery in mice","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (KO, exogenous protein, gene delivery), in vivo validation, single lab","pmids":["33011858"],"is_preprint":false},{"year":2022,"finding":"HBV X protein (HBx) transcriptionally upregulates HMGA2, which in turn transcriptionally activates STC2; STC2 knockdown disrupts Bax/Bcl-2 balance, increases cytochrome c release and caspase 3/7 activity, abolishing HMGA2-driven growth promotion; STC2 acts as a cytoprotective downstream effector of the HBx/HMGA2 pathway to counteract oxidative stress-induced apoptosis.","method":"HBx overexpression, HMGA2 and STC2 siRNA knockdown, Western blot for Bax/Bcl-2/cytochrome c/caspase 3/7, ChIP or promoter assay implied by transcriptional regulation data, clinical correlation with serum samples","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (HBx→HMGA2→STC2 pathway), multiple apoptosis readouts, single lab","pmids":["35353897"],"is_preprint":false},{"year":2024,"finding":"STC2 knockdown in HCC cells inhibits glycolysis (reducing PKM2, GLUT1, HK2 expression), induces autophagy (increasing LC3II/LC3I and Beclin1), and reduces PI3K/AKT/mTOR phosphorylation; glycolysis inhibitor (2-DG) blocks STC2-driven HCC growth, and autophagy/PI3K pathway modulators (3-MA, IGF-1, Rap, LY294002) alter STC2 effects, placing STC2 upstream of PI3K/Akt/mTOR-mediated autophagy and glycolysis.","method":"STC2 siRNA knockdown and overexpression, Western blot for glycolytic enzymes and autophagy markers, pharmacological modulators (2-DG, 3-MA, IGF-1, Rap, LY294002), in vivo xenograft","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological rescues establish pathway placement, in vivo validation, single lab","pmids":["39271096"],"is_preprint":false},{"year":2025,"finding":"ATF4 transcription factor directly binds to the STC2 promoter region and upregulates STC2 transcription (along with OMD) in vascular smooth muscle cells; this ATF4→STC2 axis activates the PI3K/AKT signaling pathway, promoting osteogenic differentiation of HASMCs and vascular calcification; AAV-mediated ATF4 knockdown in vivo alleviates vascular calcification by suppressing STC2 expression.","method":"ChIP assay (ATF4 binding to STC2 promoter), luciferase promoter reporter assay, Western blot, in vitro osteogenic differentiation, in vivo AAV-SM22α-shATF4 mouse model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP and dual-luciferase confirm direct transcriptional regulation, in vivo validation, single lab","pmids":["41274065"],"is_preprint":false},{"year":2025,"finding":"In keloid fibroblasts, hypoxia induces STC2 expression via HIF-1α; STC2 silencing under hypoxia reduces fibroblast proliferation, migration and ECM remodeling (downregulating collagen I, α-SMA, MMP2, MMP9) and attenuates ERK and AKT signaling pathway activation.","method":"HIF-1α pathway analysis, STC2 siRNA silencing under hypoxic conditions, Western blot for fibrosis markers and pERK/pAKT, functional proliferation and migration assays","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic upstream (HIF-1α) and downstream (ERK/AKT) pathway placement, multiple molecular readouts, single lab","pmids":["41408929"],"is_preprint":false},{"year":2025,"finding":"METTL3 (m6A methyltransferase) upregulates STC2 mRNA stability through m6A modification (primarily in CDS region) via YTHDF2 binding; STC2 overexpression drives glycolysis-related enzyme expression, CRC cell proliferation and metastasis; METTL3 knockdown reduces 5-FU resistance and these effects are reversed by STC2 overexpression.","method":"MeRIP-seq, mRNA-seq, Western blot, EdU, CCK-8, Transwell assay, siRNA knockdown and overexpression, in vivo xenograft","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq establishes m6A modification of STC2, METTL3→STC2 epistasis via rescue, multiple methods, single lab","pmids":["40494964"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated m6A methylation of STC2 mRNA increases its stability via YTHDF2 binding in response to PM2.5 exposure; STC2 in turn increases SQSTM1 levels by inhibiting its proteasomal degradation, thereby enhancing mitophagy and asthma severity.","method":"Single-cell RNA sequencing, m6A methylation analysis, METTL3/STC2 knockdown, SQSTM1 protein stability assay, in vivo asthma mouse model","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A/YTHDF2/STC2/SQSTM1 pathway established with mechanistic experiments, single lab","pmids":["40499413"],"is_preprint":false},{"year":2026,"finding":"STC2 binds TGIF1 mRNA directly (via RNA immunoprecipitation) and stabilizes it by inhibiting its degradation; this mechanism enables STC2 to promote anoikis resistance in colorectal cancer cells through upregulation of TGIF1 expression.","method":"RNA immunoprecipitation (RIP), RNA stability assay, RNA sequencing, flow cytometry (anoikis), live/dead staining","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms direct RNA binding, stability assay shows functional mechanism, single lab","pmids":["41696444"],"is_preprint":false},{"year":2025,"finding":"STC2 interacts with ITGB2 (integrin beta-2) in glioma cells (confirmed by co-immunoprecipitation); STC2 knockdown inhibits glioma cell proliferation, invasion, migration, and glycolysis, and ITGB2 knockdown phenocopies these effects; the STC2/ITGB2 interaction is required for STC2-mediated regulation of these processes.","method":"Co-immunoprecipitation (STC2-ITGB2), GPIA database analysis, CCK-8, colony formation, Transwell, ELISA, Western blot","journal":"Metabolic brain disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited follow-up mechanistic detail, single lab","pmids":["40126711"],"is_preprint":false},{"year":2026,"finding":"STC2 promotes glycolysis and CRC progression through the PI3K/AKT/mTOR pathway, which enhances c-Myc activity; activated c-Myc directly occupies GLUT1 and LDHA promoters (shown by ChIP) to upregulate glycolytic flux; STC2 knockdown reduces c-Myc occupancy on these promoters.","method":"ChIP for c-Myc on GLUT1/LDHA promoters, glucose uptake and lactate production assays, Western blot, STC2 KD/OE, in vivo xenograft","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates c-Myc promoter occupancy as downstream effector, multiple methods, single lab","pmids":["41843816"],"is_preprint":false},{"year":2025,"finding":"Nicotine activates the JAK2/STAT3 signaling pathway through CHRNA5, causing direct STAT3 binding to the STC2 promoter and upregulating STC2 transcription; STC2 subsequently upregulates TGFBI, which interacts with ITGA5 on endothelial cells to regulate vascular permeability; STC2 knockdown alters F-actin cytoskeletal dynamics by modulating small GTPase signaling.","method":"Spatial transcriptomics, scRNA-seq, STAT3 promoter binding assay (STAT3→STC2), STC2 knockdown, F-actin cytoskeleton analysis","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomics-driven with some mechanistic follow-up, STAT3 binding assay not fully described in abstract, single lab","pmids":["41203580"],"is_preprint":false},{"year":2025,"finding":"In cancer-associated fibroblasts, STC2 depletion prevents CAF alignment and blocks multicellular calcium wave-driven neuronal mimicry, thereby reducing immune exclusion and allowing CD8+ T cell access to tumor cells.","method":"STC2 depletion (molecular intervention), CAF alignment assay, calcium imaging, CD8+ T cell localization analysis in tumor model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single depletion experiment with functional readout but mechanism of STC2 in calcium signaling not biochemically resolved","pmids":[],"is_preprint":true},{"year":2025,"finding":"A missense mutation A60P in the conserved region of STC2 (validated in gene-edited mouse models) results in homozygous carriers with approximately 11% increased average body weight, establishing that the STC2 protein influences mammalian body size/growth regulation.","method":"Gene-edited mouse models with STC2 A60P knock-in, body weight measurement","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene editing validates causal role of STC2 variant in growth regulation, replicated in multiple livestock species for convergent mutations","pmids":["40094447"],"is_preprint":false},{"year":2026,"finding":"HIF-1α directly binds to the STC2 promoter and activates STC2 transcription under hypoxic conditions in hepatocellular carcinoma cells (demonstrated by ChIP and dual-luciferase reporter assay); STC2 overexpression activates the PI3K-Akt and HIF-1α signaling pathways and is associated with M2-type macrophage polarization in the tumor microenvironment.","method":"ChIP assay and dual-luciferase reporter assay (HIF-1α→STC2 promoter), siRNA knockdown/overexpression, transcriptomic profiling, immune deconvolution (CIBERSORT)","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP + dual-luciferase directly demonstrate HIF-1α transcriptional activation of STC2, single lab","pmids":["42217552"],"is_preprint":false},{"year":2025,"finding":"FUT3-mediated fucosylation of GRP78 triggers downstream ER stress signaling and activates the PERK/ATF4/STC2 pathway, thereby enhancing CRC cell survival under glucose-deficient conditions; this places STC2 as a downstream effector of the PERK/ATF4 ER stress axis.","method":"MeRIP-seq context, co-IP (FUT3-GRP78), Western blot, pathway inhibition/activation experiments under glucose restriction, in vitro and in vivo assays","journal":"NPJ precision oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — STC2 placed as downstream of PERK/ATF4 based on pathway analysis with limited direct STC2-specific mechanistic data in the abstract","pmids":["41392296"],"is_preprint":false}],"current_model":"STC2 is a secreted homodimeric glycoprotein that functions as a covalent inhibitor of the PAPP-A metalloprotease (forming a 2:2 heterotetramer that sterically blocks IGFBP substrate binding), inhibits renal phosphate transport (opposing STC1), suppresses adipogenic differentiation and promotes axon regeneration in neurons; in cancer contexts STC2 activates multiple oncogenic pathways (PI3K/AKT, ERK/MAPK, Wnt/β-catenin, JUN-AXL-ERK) to promote EMT, glycolysis, drug/radiation resistance, and survival, with its expression directly regulated transcriptionally by HIF-1α, HMGA2, ATF4, and STAT3 (downstream of JAK2), and post-transcriptionally by METTL3-mediated m6A methylation, while acting upstream through interactions with PRMT5, ITGB2, and TGIF1 mRNA stabilization."},"narrative":{"mechanistic_narrative":"STC2 is a secreted glycoprotein that regulates extracellular growth-factor signaling, mineral handling, and tissue growth, and is repeatedly co-opted as a downstream oncogenic effector in multiple cancers [PMID:9753616, PMID:27662663, PMID:42217552]. Its best-resolved biochemical activity is as a covalent inhibitor of the metalloprotease PAPP-A: STC2 forms a 2:2 heterotetramer with PAPP-A by binding exosites distal to the catalytic cleft, sterically blocking IGFBP substrate engagement and cleavage [PMID:36550107]. Independently of this protease control, conditioned medium from STC2-expressing cells suppresses Na-phosphate cotransporter promoter activity and renal phosphate uptake, an activity opposite to STC1 [PMID:9753616], and a conserved A60P missense variant in gene-edited mice increases body weight, establishing a causal role in mammalian growth regulation [PMID:40094447]. In physiological contexts STC2 suppresses adipogenic differentiation of mesenchymal stem cells through ERK1/2 activation and PPARγ/FABP4 repression [PMID:31982135] and is required for sensory axon regeneration after injury [PMID:33011858]. Across cancers STC2 acts upstream of converging pro-tumorigenic pathways—PI3K/AKT/(mTOR), ERK/MAPK, Wnt/β-catenin, and the JUN–AXL–ERK axis—to drive EMT, glycolysis, proliferation, survival, and therapy resistance [PMID:27662663, PMID:27863406, PMID:31173256, PMID:31162839, PMID:39271096, PMID:41843816]. STC2 expression is itself directly transactivated by HIF-1α under hypoxia [PMID:42217552, PMID:41408929], by HMGA2 [PMID:26165228, PMID:35353897], by ATF4 [PMID:41274065], and by STAT3 [PMID:41203580], and is stabilized post-transcriptionally by METTL3-dependent m6A modification read by YTHDF2 [PMID:40494964, PMID:40499413]. STC2 also engages intracellular and RNA-level effectors: it interacts with and activates PRMT5 to increase H4R3me2s and promote DNA-damage repair and ferroptosis suppression [PMID:36764215], binds and stabilizes TGIF1 mRNA to promote anoikis resistance [PMID:41696444], and stabilizes SQSTM1 protein to enhance mitophagy [PMID:40499413].","teleology":[{"year":1998,"claim":"Established STC2 as a secreted glycoprotein with an endocrine-like activity on mineral handling, distinguishing it functionally from its paralog STC1.","evidence":"Molecular cloning with CHO conditioned-medium transfer onto kidney OK cells, NaPi-3 promoter reporter and phosphate-uptake assays","pmids":["9753616"],"confidence":"Medium","gaps":["No receptor or direct molecular target for the phosphate effect identified","Endogenous physiological context untested"]},{"year":2012,"claim":"Showed STC2 drives cell-cycle progression and proliferation through cyclin D1 and ERK1/2, the first link to a proliferative cancer phenotype.","evidence":"Ectopic expression and siRNA in hepatocellular carcinoma cells with cell-cycle flow cytometry and pathway Western blots","pmids":["23187001"],"confidence":"Medium","gaps":["Mechanism by which secreted STC2 activates ERK1/2 not defined","No receptor identified"]},{"year":2015,"claim":"Identified an upstream transcriptional regulator (HMGA2) of STC2 and tied STC2 to invasion, beginning to map the regulatory circuitry controlling its expression.","evidence":"Transcriptional regulation assays plus migration/invasion assays, with correlation across three patient cohorts","pmids":["26165228"],"confidence":"Medium","gaps":["Direct promoter binding by HMGA2 not structurally mapped","Downstream effectors of invasion unresolved here"]},{"year":2016,"claim":"Placed STC2 upstream of PI3K/AKT and ERK signaling as a sufficient inducer of EMT, and as a downstream effector of Mus81, integrating it into proliferation/survival circuitry.","evidence":"Overexpression, exogenous protein, pharmacological pathway inhibition and Mus81 rescue in colorectal and HCC models with xenografts","pmids":["27662663","27939696"],"confidence":"Medium","gaps":["How extracellular STC2 transmits signal to intracellular kinases unresolved","Direct binding partners not identified"]},{"year":2019,"claim":"Extended STC2 oncogenic signaling to the JUN–AXL–ERK axis and Wnt/β-catenin, explaining its role in acquired EGFR-TKI resistance and EMT.","evidence":"AXL promoter luciferase, phospho-c-Jun blots, pharmacological rescue (SB216763) and patient-derived resistant cells","pmids":["31162839","31173256"],"confidence":"Medium","gaps":["Mechanism linking secreted STC2 to c-Jun phosphorylation unknown","Receptor mediating Wnt pathway control not defined"]},{"year":2020,"claim":"Defined non-cancer physiological roles—suppression of adipogenesis via ERK1/2 and a requirement in injury-induced axon regeneration—broadening STC2 beyond tumor biology.","evidence":"Gain/loss-of-function with ERK inhibitor rescue in hMSCs; axotomy transcriptomics, exogenous protein and AAV delivery in DRG neurons in vivo","pmids":["31982135","33011858"],"confidence":"Medium","gaps":["Receptor for secreted STC2 in either context unidentified","Signaling intermediates in neurons unmapped"]},{"year":2022,"claim":"Resolved the central biochemical mechanism: STC2 is an exosite-competitive covalent inhibitor of PAPP-A that blocks IGFBP cleavage, providing a structural basis for its growth-regulatory activity.","evidence":"Cryo-EM of the endogenous PAPP-A/STC2 heterotetramer with IGFBP linker peptide functional assays","pmids":["36550107"],"confidence":"High","gaps":["Links between this PAPP-A inhibition and the downstream oncogenic kinase signaling not established","In vivo consequences of inhibition not quantified here"]},{"year":2023,"claim":"Revealed an intracellular activity—STC2 binds and activates PRMT5 to increase H4R3me2s—coupling STC2 to DNA-damage repair, ferroptosis suppression and radioresistance.","evidence":"Reciprocal Co-IP, H4R3me2s blots, siRNA and xenografts in esophageal squamous cell carcinoma","pmids":["36764215"],"confidence":"Medium","gaps":["How a classically secreted protein accesses nuclear PRMT5 unresolved","Direct STC2-PRMT5 binding interface unmapped"]},{"year":2025,"claim":"Mapped the upstream transcriptional and post-transcriptional control of STC2—HIF-1α, ATF4, STAT3 and METTL3/YTHDF2 m6A—and a causal growth role via the A60P mouse variant, consolidating how STC2 levels are set across stress and disease states.","evidence":"ChIP/dual-luciferase for HIF-1α and ATF4 promoter binding, MeRIP-seq for m6A, gene-edited A60P knock-in mice, plus fibrosis, asthma, calcification and glioma models","pmids":["41408929","41274065","40494964","40499413","40094447","40126711","41203580"],"confidence":"Medium","gaps":["ITGB2 and STAT3 links rest on single Co-IP/transcriptomic evidence","Unifying receptor for STC2 signaling still unidentified"]},{"year":2026,"claim":"Detailed STC2's metabolic and RNA-stabilizing outputs—PI3K/AKT/mTOR-driven c-Myc activation of glycolytic gene promoters and direct stabilization of TGIF1 mRNA—linking it to glycolysis, M2 macrophage polarization and anoikis resistance.","evidence":"ChIP for c-Myc on GLUT1/LDHA promoters, RIP and RNA-stability assays, glucose/lactate assays and xenografts in CRC and HCC","pmids":["41843816","41696444","42217552"],"confidence":"Medium","gaps":["Whether STC2 directly binds RNA or acts via partners not fully resolved","Connection between extracellular and RNA-binding pools of STC2 unexplained"]},{"year":null,"claim":"The receptor or surface mechanism by which secreted STC2 transduces signals into PI3K/AKT and ERK pathways, and how a secreted protein reaches intracellular/nuclear targets (PRMT5, TGIF1 mRNA, SQSTM1), remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No STC2 signaling receptor identified in the corpus","Subcellular trafficking reconciling secreted and intracellular roles unknown","Causal link between PAPP-A inhibition and downstream kinase signaling untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,9,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,20,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[24,14,6]}],"complexes":["PAPP-A/STC2 heterotetramer"],"partners":["PAPPA","PRMT5","ITGB2","TGIF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O76061","full_name":"Stanniocalcin-2","aliases":["Stanniocalcin-related protein","STC-related protein","STCRP"],"length_aa":302,"mass_kda":33.2,"function":"Has an anti-hypocalcemic action on calcium and phosphate homeostasis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O76061/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STC2","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/STC2","total_profiled":1310},"omim":[{"mim_id":"606255","title":"STATURE AS A QUANTITATIVE TRAIT","url":"https://www.omim.org/entry/606255"},{"mim_id":"603665","title":"STANNIOCALCIN 2; STC2","url":"https://www.omim.org/entry/603665"},{"mim_id":"601185","title":"STANNIOCALCIN 1; STC1","url":"https://www.omim.org/entry/601185"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":135.0}],"url":"https://www.proteinatlas.org/search/STC2"},"hgnc":{"alias_symbol":["STC-2"],"prev_symbol":[]},"alphafold":{"accession":"O76061","domains":[{"cath_id":"-","chopping":"2-13_45-215","consensus_level":"medium","plddt":89.5625,"start":2,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O76061","model_url":"https://alphafold.ebi.ac.uk/files/AF-O76061-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O76061-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STC2","jax_strain_url":"https://www.jax.org/strain/search?query=STC2"},"sequence":{"accession":"O76061","fasta_url":"https://rest.uniprot.org/uniprotkb/O76061.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O76061/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O76061"}},"corpus_meta":[{"pmid":"9753616","id":"PMC_9753616","title":"Molecular 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conditioned medium from STC2-transfected CHO cells inhibited the promoter activity of the Na-phosphate cotransporter (NaPi-3) and inhibited phosphate uptake in kidney OK cells, demonstrating an inhibitory function on renal phosphate transport opposite to STC1.\",\n      \"method\": \"Molecular cloning, CHO cell transfection, NaPi-3 promoter reporter assay, phosphate uptake assay in OK cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assays with two orthogonal readouts (promoter activity + transport assay), single lab\",\n      \"pmids\": [\"9753616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STC2 forms a 2:2 heterotetramer with PAPP-A (pregnancy-associated plasma protein-A) via covalent interaction, revealed by cryo-EM structures. STC2 binds exosites on PAPP-A distal to its catalytic cleft, causing steric hindrance that prevents IGFBP substrate binding and cleavage, thus inhibiting PAPP-A protease activity toward IGFBPs.\",\n      \"method\": \"Cryo-EM structural determination of endogenous PAPP-A/STC2 complex; functional assays with IGFBP linker peptides\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with functional validation; exosite-competitive inhibition mechanism directly demonstrated\",\n      \"pmids\": [\"36550107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STC2 physically interacts with PRMT5 and activates it, leading to increased symmetric dimethylation of histone H4 on Arg3 (H4R3me2s), which promotes DNA damage repair via homologous recombination and NHEJ pathways; STC2 also participates in SLC7A11-mediated ferroptosis suppression in a PRMT5-dependent manner, contributing to radioresistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (STC2-PRMT5 interaction), Western blot for H4R3me2s, siRNA knockdown, in vivo xenograft experiments\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed, multiple downstream pathway readouts, single lab\",\n      \"pmids\": [\"36764215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STC2 promotes AXL promoter activity by increasing phosphorylation of c-Jun, an indispensable transcription factor for AXL transactivation, thereby activating the JUN-AXL-ERK signaling axis and conferring acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells.\",\n      \"method\": \"AXL promoter luciferase reporter assay, phospho-c-Jun Western blot, genetic silencing/overexpression of STC2, pharmacological inhibition of AXL-ERK, patient-derived resistant cell line validation\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay plus multiple orthogonal methods (KD/OE, pharmacological inhibition, patient-derived cells), single lab\",\n      \"pmids\": [\"31162839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STC2 overexpression in colorectal cancer cells activates pERK, pAKT, PI3K and Ras signaling; blocking AKT-ERK signaling pathways attenuates STC2-activated EMT. Exogenous STC2 protein is sufficient to induce EMT characteristics in epithelial cells.\",\n      \"method\": \"STC2 plasmid transfection, exogenous STC2 protein treatment, Western blot for pathway markers, pharmacological pathway inhibition, mouse xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (OE, exogenous protein, inhibition rescue, in vivo), single lab\",\n      \"pmids\": [\"27662663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STC2 upregulates phosphorylation of AKT and enhances HNSCC metastasis through Snail-mediated increase of vimentin and decrease of E-cadherin (EMT markers); these effects are blocked by silencing STC2/Snail or inhibiting pAKT activity, placing STC2 upstream of the PI3K/AKT/Snail axis.\",\n      \"method\": \"STC2 overexpression/silencing, pAKT Western blot, Snail/vimentin/E-cadherin Western blot, in vivo metastasis assay, pharmacological AKT inhibition\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double silencing), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"27863406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGA2 directly regulates STC2 transcription; overexpression of STC2 in ovarian cancer cells directly enhances cell migration and invasion in vitro.\",\n      \"method\": \"Transcriptional regulation assay (HMGA2→STC2), in vitro migration/invasion assays, gene expression correlation in three independent patient cohorts\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation demonstrated, functional OE assays, replicated across multiple cohorts for correlation\",\n      \"pmids\": [\"26165228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STC2 regulates cyclin D1 expression and activates ERK1/2 signaling in hepatocellular carcinoma cells to promote G0/G1 to S-phase cell cycle progression and cell proliferation.\",\n      \"method\": \"STC2 ectopic expression and siRNA knockdown, flow cytometry cell cycle analysis, Western blot for cyclin D1 and pERK1/2, colony formation and Transwell migration assays\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with specific molecular readouts, single lab\",\n      \"pmids\": [\"23187001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STC2 acts downstream of Mus81 to promote HCC cell proliferation and survival; Mus81 knockdown downregulates STC2, which in turn activates APAF1, APC, and PTEN pathways and inhibits the MAPK pathway; restoration of STC2 expression rescues proliferation and survival defects caused by Mus81 depletion.\",\n      \"method\": \"DNA microarray screening, high content screen, qRT-PCR, STC2 rescue expression, knockdown of Mus81 in vitro and in vivo\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment, multiple screening methods, single lab\",\n      \"pmids\": [\"27939696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STC2 silencing in colorectal cancer SW480 cells activates the Wnt/β-catenin pathway (β-catenin expression suppressed by STC2 silencing and restored by Wnt activator SB216763), and STC2 silencing decreases MMP-2, MMP-9, and vimentin while increasing E-cadherin, indicating STC2 promotes EMT via Wnt/β-catenin signaling.\",\n      \"method\": \"STC2 siRNA knockdown, Western blot for β-catenin/E-cadherin/vimentin/MMP-2/MMP-9, pharmacological rescue with SB216763, wound healing/Transwell assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue establishes pathway placement, multiple molecular readouts, single lab\",\n      \"pmids\": [\"31173256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STC2 overexpression in human mesenchymal stem cells suppresses adipogenic differentiation by increasing ERK1/2 phosphorylation and decreasing PPARγ and FABP4 expression; treatment with ERK inhibitor U0126 disrupts ERK1/2 phosphorylation and restores adipogenic differentiation, placing STC2 upstream of ERK1/2 in adipogenesis suppression.\",\n      \"method\": \"STC2 overexpression/knockdown, adipogenic differentiation assay, lipid droplet staining, Western blot for ERK1/2 phosphorylation/PPARγ/FABP4, ERK inhibitor (U0126) rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue establishes ERK dependency, gain/loss-of-function, single lab\",\n      \"pmids\": [\"31982135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STC2 is required for axon regeneration in sensory neurons; STC2 expression is upregulated after axotomy in dorsal root ganglion neurons, and loss of STC2 impairs axon regeneration both in vitro and in vivo; application of secreted STC2 protein to injured DRG neurons promotes regeneration; in vivo gene delivery of STC2 increases regenerative growth after peripheral nerve injury.\",\n      \"method\": \"Injury-responsive transcriptome analysis, STC2 loss-of-function in vitro/in vivo, exogenous STC2 protein application, in vivo AAV-mediated gene delivery in mice\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (KO, exogenous protein, gene delivery), in vivo validation, single lab\",\n      \"pmids\": [\"33011858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBV X protein (HBx) transcriptionally upregulates HMGA2, which in turn transcriptionally activates STC2; STC2 knockdown disrupts Bax/Bcl-2 balance, increases cytochrome c release and caspase 3/7 activity, abolishing HMGA2-driven growth promotion; STC2 acts as a cytoprotective downstream effector of the HBx/HMGA2 pathway to counteract oxidative stress-induced apoptosis.\",\n      \"method\": \"HBx overexpression, HMGA2 and STC2 siRNA knockdown, Western blot for Bax/Bcl-2/cytochrome c/caspase 3/7, ChIP or promoter assay implied by transcriptional regulation data, clinical correlation with serum samples\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (HBx→HMGA2→STC2 pathway), multiple apoptosis readouts, single lab\",\n      \"pmids\": [\"35353897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STC2 knockdown in HCC cells inhibits glycolysis (reducing PKM2, GLUT1, HK2 expression), induces autophagy (increasing LC3II/LC3I and Beclin1), and reduces PI3K/AKT/mTOR phosphorylation; glycolysis inhibitor (2-DG) blocks STC2-driven HCC growth, and autophagy/PI3K pathway modulators (3-MA, IGF-1, Rap, LY294002) alter STC2 effects, placing STC2 upstream of PI3K/Akt/mTOR-mediated autophagy and glycolysis.\",\n      \"method\": \"STC2 siRNA knockdown and overexpression, Western blot for glycolytic enzymes and autophagy markers, pharmacological modulators (2-DG, 3-MA, IGF-1, Rap, LY294002), in vivo xenograft\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological rescues establish pathway placement, in vivo validation, single lab\",\n      \"pmids\": [\"39271096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4 transcription factor directly binds to the STC2 promoter region and upregulates STC2 transcription (along with OMD) in vascular smooth muscle cells; this ATF4→STC2 axis activates the PI3K/AKT signaling pathway, promoting osteogenic differentiation of HASMCs and vascular calcification; AAV-mediated ATF4 knockdown in vivo alleviates vascular calcification by suppressing STC2 expression.\",\n      \"method\": \"ChIP assay (ATF4 binding to STC2 promoter), luciferase promoter reporter assay, Western blot, in vitro osteogenic differentiation, in vivo AAV-SM22α-shATF4 mouse model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP and dual-luciferase confirm direct transcriptional regulation, in vivo validation, single lab\",\n      \"pmids\": [\"41274065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In keloid fibroblasts, hypoxia induces STC2 expression via HIF-1α; STC2 silencing under hypoxia reduces fibroblast proliferation, migration and ECM remodeling (downregulating collagen I, α-SMA, MMP2, MMP9) and attenuates ERK and AKT signaling pathway activation.\",\n      \"method\": \"HIF-1α pathway analysis, STC2 siRNA silencing under hypoxic conditions, Western blot for fibrosis markers and pERK/pAKT, functional proliferation and migration assays\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic upstream (HIF-1α) and downstream (ERK/AKT) pathway placement, multiple molecular readouts, single lab\",\n      \"pmids\": [\"41408929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 (m6A methyltransferase) upregulates STC2 mRNA stability through m6A modification (primarily in CDS region) via YTHDF2 binding; STC2 overexpression drives glycolysis-related enzyme expression, CRC cell proliferation and metastasis; METTL3 knockdown reduces 5-FU resistance and these effects are reversed by STC2 overexpression.\",\n      \"method\": \"MeRIP-seq, mRNA-seq, Western blot, EdU, CCK-8, Transwell assay, siRNA knockdown and overexpression, in vivo xenograft\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq establishes m6A modification of STC2, METTL3→STC2 epistasis via rescue, multiple methods, single lab\",\n      \"pmids\": [\"40494964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated m6A methylation of STC2 mRNA increases its stability via YTHDF2 binding in response to PM2.5 exposure; STC2 in turn increases SQSTM1 levels by inhibiting its proteasomal degradation, thereby enhancing mitophagy and asthma severity.\",\n      \"method\": \"Single-cell RNA sequencing, m6A methylation analysis, METTL3/STC2 knockdown, SQSTM1 protein stability assay, in vivo asthma mouse model\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A/YTHDF2/STC2/SQSTM1 pathway established with mechanistic experiments, single lab\",\n      \"pmids\": [\"40499413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STC2 binds TGIF1 mRNA directly (via RNA immunoprecipitation) and stabilizes it by inhibiting its degradation; this mechanism enables STC2 to promote anoikis resistance in colorectal cancer cells through upregulation of TGIF1 expression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA stability assay, RNA sequencing, flow cytometry (anoikis), live/dead staining\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms direct RNA binding, stability assay shows functional mechanism, single lab\",\n      \"pmids\": [\"41696444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STC2 interacts with ITGB2 (integrin beta-2) in glioma cells (confirmed by co-immunoprecipitation); STC2 knockdown inhibits glioma cell proliferation, invasion, migration, and glycolysis, and ITGB2 knockdown phenocopies these effects; the STC2/ITGB2 interaction is required for STC2-mediated regulation of these processes.\",\n      \"method\": \"Co-immunoprecipitation (STC2-ITGB2), GPIA database analysis, CCK-8, colony formation, Transwell, ELISA, Western blot\",\n      \"journal\": \"Metabolic brain disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited follow-up mechanistic detail, single lab\",\n      \"pmids\": [\"40126711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STC2 promotes glycolysis and CRC progression through the PI3K/AKT/mTOR pathway, which enhances c-Myc activity; activated c-Myc directly occupies GLUT1 and LDHA promoters (shown by ChIP) to upregulate glycolytic flux; STC2 knockdown reduces c-Myc occupancy on these promoters.\",\n      \"method\": \"ChIP for c-Myc on GLUT1/LDHA promoters, glucose uptake and lactate production assays, Western blot, STC2 KD/OE, in vivo xenograft\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates c-Myc promoter occupancy as downstream effector, multiple methods, single lab\",\n      \"pmids\": [\"41843816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nicotine activates the JAK2/STAT3 signaling pathway through CHRNA5, causing direct STAT3 binding to the STC2 promoter and upregulating STC2 transcription; STC2 subsequently upregulates TGFBI, which interacts with ITGA5 on endothelial cells to regulate vascular permeability; STC2 knockdown alters F-actin cytoskeletal dynamics by modulating small GTPase signaling.\",\n      \"method\": \"Spatial transcriptomics, scRNA-seq, STAT3 promoter binding assay (STAT3→STC2), STC2 knockdown, F-actin cytoskeleton analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomics-driven with some mechanistic follow-up, STAT3 binding assay not fully described in abstract, single lab\",\n      \"pmids\": [\"41203580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cancer-associated fibroblasts, STC2 depletion prevents CAF alignment and blocks multicellular calcium wave-driven neuronal mimicry, thereby reducing immune exclusion and allowing CD8+ T cell access to tumor cells.\",\n      \"method\": \"STC2 depletion (molecular intervention), CAF alignment assay, calcium imaging, CD8+ T cell localization analysis in tumor model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single depletion experiment with functional readout but mechanism of STC2 in calcium signaling not biochemically resolved\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A missense mutation A60P in the conserved region of STC2 (validated in gene-edited mouse models) results in homozygous carriers with approximately 11% increased average body weight, establishing that the STC2 protein influences mammalian body size/growth regulation.\",\n      \"method\": \"Gene-edited mouse models with STC2 A60P knock-in, body weight measurement\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene editing validates causal role of STC2 variant in growth regulation, replicated in multiple livestock species for convergent mutations\",\n      \"pmids\": [\"40094447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HIF-1α directly binds to the STC2 promoter and activates STC2 transcription under hypoxic conditions in hepatocellular carcinoma cells (demonstrated by ChIP and dual-luciferase reporter assay); STC2 overexpression activates the PI3K-Akt and HIF-1α signaling pathways and is associated with M2-type macrophage polarization in the tumor microenvironment.\",\n      \"method\": \"ChIP assay and dual-luciferase reporter assay (HIF-1α→STC2 promoter), siRNA knockdown/overexpression, transcriptomic profiling, immune deconvolution (CIBERSORT)\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP + dual-luciferase directly demonstrate HIF-1α transcriptional activation of STC2, single lab\",\n      \"pmids\": [\"42217552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT3-mediated fucosylation of GRP78 triggers downstream ER stress signaling and activates the PERK/ATF4/STC2 pathway, thereby enhancing CRC cell survival under glucose-deficient conditions; this places STC2 as a downstream effector of the PERK/ATF4 ER stress axis.\",\n      \"method\": \"MeRIP-seq context, co-IP (FUT3-GRP78), Western blot, pathway inhibition/activation experiments under glucose restriction, in vitro and in vivo assays\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — STC2 placed as downstream of PERK/ATF4 based on pathway analysis with limited direct STC2-specific mechanistic data in the abstract\",\n      \"pmids\": [\"41392296\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STC2 is a secreted homodimeric glycoprotein that functions as a covalent inhibitor of the PAPP-A metalloprotease (forming a 2:2 heterotetramer that sterically blocks IGFBP substrate binding), inhibits renal phosphate transport (opposing STC1), suppresses adipogenic differentiation and promotes axon regeneration in neurons; in cancer contexts STC2 activates multiple oncogenic pathways (PI3K/AKT, ERK/MAPK, Wnt/β-catenin, JUN-AXL-ERK) to promote EMT, glycolysis, drug/radiation resistance, and survival, with its expression directly regulated transcriptionally by HIF-1α, HMGA2, ATF4, and STAT3 (downstream of JAK2), and post-transcriptionally by METTL3-mediated m6A methylation, while acting upstream through interactions with PRMT5, ITGB2, and TGIF1 mRNA stabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STC2 is a secreted glycoprotein that regulates extracellular growth-factor signaling, mineral handling, and tissue growth, and is repeatedly co-opted as a downstream oncogenic effector in multiple cancers [#0, #4, #24]. Its best-resolved biochemical activity is as a covalent inhibitor of the metalloprotease PAPP-A: STC2 forms a 2:2 heterotetramer with PAPP-A by binding exosites distal to the catalytic cleft, sterically blocking IGFBP substrate engagement and cleavage [#1]. Independently of this protease control, conditioned medium from STC2-expressing cells suppresses Na-phosphate cotransporter promoter activity and renal phosphate uptake, an activity opposite to STC1 [#0], and a conserved A60P missense variant in gene-edited mice increases body weight, establishing a causal role in mammalian growth regulation [#23]. In physiological contexts STC2 suppresses adipogenic differentiation of mesenchymal stem cells through ERK1/2 activation and PPARγ/FABP4 repression [#10] and is required for sensory axon regeneration after injury [#11]. Across cancers STC2 acts upstream of converging pro-tumorigenic pathways—PI3K/AKT/(mTOR), ERK/MAPK, Wnt/β-catenin, and the JUN–AXL–ERK axis—to drive EMT, glycolysis, proliferation, survival, and therapy resistance [#4, #5, #9, #3, #13, #20]. STC2 expression is itself directly transactivated by HIF-1α under hypoxia [#24, #15], by HMGA2 [#6, #12], by ATF4 [#14], and by STAT3 [#21], and is stabilized post-transcriptionally by METTL3-dependent m6A modification read by YTHDF2 [#16, #17]. STC2 also engages intracellular and RNA-level effectors: it interacts with and activates PRMT5 to increase H4R3me2s and promote DNA-damage repair and ferroptosis suppression [#2], binds and stabilizes TGIF1 mRNA to promote anoikis resistance [#18], and stabilizes SQSTM1 protein to enhance mitophagy [#17].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established STC2 as a secreted glycoprotein with an endocrine-like activity on mineral handling, distinguishing it functionally from its paralog STC1.\",\n      \"evidence\": \"Molecular cloning with CHO conditioned-medium transfer onto kidney OK cells, NaPi-3 promoter reporter and phosphate-uptake assays\",\n      \"pmids\": [\"9753616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or direct molecular target for the phosphate effect identified\", \"Endogenous physiological context untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed STC2 drives cell-cycle progression and proliferation through cyclin D1 and ERK1/2, the first link to a proliferative cancer phenotype.\",\n      \"evidence\": \"Ectopic expression and siRNA in hepatocellular carcinoma cells with cell-cycle flow cytometry and pathway Western blots\",\n      \"pmids\": [\"23187001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which secreted STC2 activates ERK1/2 not defined\", \"No receptor identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an upstream transcriptional regulator (HMGA2) of STC2 and tied STC2 to invasion, beginning to map the regulatory circuitry controlling its expression.\",\n      \"evidence\": \"Transcriptional regulation assays plus migration/invasion assays, with correlation across three patient cohorts\",\n      \"pmids\": [\"26165228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding by HMGA2 not structurally mapped\", \"Downstream effectors of invasion unresolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed STC2 upstream of PI3K/AKT and ERK signaling as a sufficient inducer of EMT, and as a downstream effector of Mus81, integrating it into proliferation/survival circuitry.\",\n      \"evidence\": \"Overexpression, exogenous protein, pharmacological pathway inhibition and Mus81 rescue in colorectal and HCC models with xenografts\",\n      \"pmids\": [\"27662663\", \"27939696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How extracellular STC2 transmits signal to intracellular kinases unresolved\", \"Direct binding partners not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended STC2 oncogenic signaling to the JUN–AXL–ERK axis and Wnt/β-catenin, explaining its role in acquired EGFR-TKI resistance and EMT.\",\n      \"evidence\": \"AXL promoter luciferase, phospho-c-Jun blots, pharmacological rescue (SB216763) and patient-derived resistant cells\",\n      \"pmids\": [\"31162839\", \"31173256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking secreted STC2 to c-Jun phosphorylation unknown\", \"Receptor mediating Wnt pathway control not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined non-cancer physiological roles—suppression of adipogenesis via ERK1/2 and a requirement in injury-induced axon regeneration—broadening STC2 beyond tumor biology.\",\n      \"evidence\": \"Gain/loss-of-function with ERK inhibitor rescue in hMSCs; axotomy transcriptomics, exogenous protein and AAV delivery in DRG neurons in vivo\",\n      \"pmids\": [\"31982135\", \"33011858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor for secreted STC2 in either context unidentified\", \"Signaling intermediates in neurons unmapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the central biochemical mechanism: STC2 is an exosite-competitive covalent inhibitor of PAPP-A that blocks IGFBP cleavage, providing a structural basis for its growth-regulatory activity.\",\n      \"evidence\": \"Cryo-EM of the endogenous PAPP-A/STC2 heterotetramer with IGFBP linker peptide functional assays\",\n      \"pmids\": [\"36550107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Links between this PAPP-A inhibition and the downstream oncogenic kinase signaling not established\", \"In vivo consequences of inhibition not quantified here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an intracellular activity—STC2 binds and activates PRMT5 to increase H4R3me2s—coupling STC2 to DNA-damage repair, ferroptosis suppression and radioresistance.\",\n      \"evidence\": \"Reciprocal Co-IP, H4R3me2s blots, siRNA and xenografts in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"36764215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a classically secreted protein accesses nuclear PRMT5 unresolved\", \"Direct STC2-PRMT5 binding interface unmapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the upstream transcriptional and post-transcriptional control of STC2—HIF-1α, ATF4, STAT3 and METTL3/YTHDF2 m6A—and a causal growth role via the A60P mouse variant, consolidating how STC2 levels are set across stress and disease states.\",\n      \"evidence\": \"ChIP/dual-luciferase for HIF-1α and ATF4 promoter binding, MeRIP-seq for m6A, gene-edited A60P knock-in mice, plus fibrosis, asthma, calcification and glioma models\",\n      \"pmids\": [\"41408929\", \"41274065\", \"40494964\", \"40499413\", \"40094447\", \"40126711\", \"41203580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ITGB2 and STAT3 links rest on single Co-IP/transcriptomic evidence\", \"Unifying receptor for STC2 signaling still unidentified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Detailed STC2's metabolic and RNA-stabilizing outputs—PI3K/AKT/mTOR-driven c-Myc activation of glycolytic gene promoters and direct stabilization of TGIF1 mRNA—linking it to glycolysis, M2 macrophage polarization and anoikis resistance.\",\n      \"evidence\": \"ChIP for c-Myc on GLUT1/LDHA promoters, RIP and RNA-stability assays, glucose/lactate assays and xenografts in CRC and HCC\",\n      \"pmids\": [\"41843816\", \"41696444\", \"42217552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STC2 directly binds RNA or acts via partners not fully resolved\", \"Connection between extracellular and RNA-binding pools of STC2 unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor or surface mechanism by which secreted STC2 transduces signals into PI3K/AKT and ERK pathways, and how a secreted protein reaches intracellular/nuclear targets (PRMT5, TGIF1 mRNA, SQSTM1), remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No STC2 signaling receptor identified in the corpus\", \"Subcellular trafficking reconciling secreted and intracellular roles unknown\", \"Causal link between PAPP-A inhibition and downstream kinase signaling untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 9, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 20, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [24, 14, 6]}\n    ],\n    \"complexes\": [\"PAPP-A/STC2 heterotetramer\"],\n    \"partners\": [\"PAPPA\", \"PRMT5\", \"ITGB2\", \"TGIF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"STC2","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"sparse","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 41843816"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}