{"gene":"STC1","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2010,"finding":"Fission yeast Stc1 (a LIM domain protein) acts as a molecular bridge coupling RNAi to heterochromatin formation: it physically interacts with the RNAi effector Ago1 (via its N-terminal tandem zinc finger domain) and with the chromatin-modifying CLRC complex (via its non-conserved C-terminal region), thereby recruiting CLRC to RITS-bound centromeric transcripts and promoting H3K9 methylation. Tethering Stc1 to a euchromatic locus is sufficient to induce silencing independently of RNAi.","method":"Co-immunoprecipitation, genetic epistasis, tethering assay, ChIP for H3K9me, loss-of-function analysis in fission yeast","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, tethering experiment, and ChIP in a single rigorous study; findings subsequently confirmed structurally","pmids":["20211136"],"is_preprint":false},{"year":2013,"finding":"Structural analysis of fission yeast Stc1 revealed that its conserved N-terminal region forms an unusual tandem zinc finger domain (with similarities to LIM domains but lacking preferred relative orientation of the two zinc fingers) that mediates binding to Ago1, while the non-conserved C-terminal region mediates association with CLRC.","method":"NMR/structural analysis combined with in vivo functional validation (deletion/mutagenesis analysis, Co-IP)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination combined with mutagenesis and binding assays, confirming and extending mechanistic model from prior Cell paper","pmids":["23613586"],"is_preprint":false},{"year":2004,"finding":"Recombinant N-glycosylated STC1 protein specifically suppresses FSH-stimulated progesterone biosynthesis (including CYP11A transcripts and LH receptor induction) in rat granulosa cells while having minimal effect on estradiol and cAMP production; radiolabeled STC1 shows high-affinity specific receptor binding on granulosa cells, and STC1 acts downstream of adenylate cyclase, suggesting a follicular paracrine system in which theca-derived STC1 dampens granulosa cell differentiation.","method":"Recombinant protein treatment of primary granulosa cells, radioligand receptor binding assay, RT-PCR for CYP11A, RIA for steroid hormones","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein functional assay plus receptor binding, single lab with two orthogonal methods","pmids":["15131261"],"is_preprint":false},{"year":2006,"finding":"STC1 uncouples oxidative phosphorylation in intact mitochondria isolated from rat muscle and liver: exposure to 500 nM recombinant human STC1 increases respiration rate, significantly reduces ADP:O ratios, and enhances mitochondrial 45Ca uptake. These respiratory effects are attenuated or abolished by nucleotide triphosphates (ATP, GTP at 5 mM) through a four-fold decrease in receptor binding affinity.","method":"Mitochondrial respiration assay (oxygen consumption), ADP:O ratio measurement, 45Ca uptake assay, radioligand receptor binding assay with nucleotide competition","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution with purified mitochondria and receptor binding, single lab with multiple readouts","pmids":["17092635"],"is_preprint":false},{"year":2011,"finding":"MSC-derived STC1 promotes survival of lung cancer (A549) cells by upregulating uncoupling protein 2 (UCP2), which uncouples oxidative phosphorylation, reduces intracellular ROS, decreases mitochondrial membrane potential, and shifts metabolism toward glycolysis (increased lactate production). Knockdown of UCP2 abolishes the protective effects of both MSC conditioned medium and recombinant STC1.","method":"shRNA knockdown of UCP2, recombinant STC1 treatment, ROS measurement, mitochondrial membrane potential assay, lactate production assay","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus recombinant protein rescue, multiple mechanistic readouts, single lab","pmids":["22146344"],"is_preprint":false},{"year":2012,"finding":"PDGF-stimulated cancer-associated fibroblasts increase migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner; in an orthotopic mouse model, STC1-deficient fibroblasts produce tumors with reduced tumor cell intravasation and fewer/smaller distant metastases, identifying STC1 as a mediator of PDGF receptor-driven metastasis.","method":"Co-culture invasion/migration assay, STC1-deficient fibroblasts (genetic loss-of-function), orthotopic mouse model with intravasation quantification","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo orthotopic model with genetic loss-of-function plus in vitro mechanistic assays, single lab","pmids":["23243022"],"is_preprint":false},{"year":2018,"finding":"CAPG competes with the transcriptional repressor PRMT5 for binding to the STC1 promoter; when CAPG displaces PRMT5, histone H4R3 methylation at the STC1 promoter is reduced, leading to enhanced STC1 transcription and increased breast cancer cell metastasis.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, Co-IP, MS/MS, histone methyltransferase assay, xenograft model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, reporter assay, enzymatic assay) in single lab","pmids":["29721098"],"is_preprint":false},{"year":2020,"finding":"DROSHA interacts with β-Catenin to transactivate STC1 in an RNA cleavage-independent manner in breast cancer stem-like cells (BCSCs), promoting stemness. AURKA stabilizes METTL14 (by inhibiting its ubiquitylation/degradation) to promote m6A methylation of DROSHA mRNA, enhancing its stability; AURKA also directly binds the DROSHA transcript to strengthen IGF2BP2 binding and stabilization of m6A-modified DROSHA.","method":"Co-IP (DROSHA–β-Catenin interaction), m6A methylation analysis, ubiquitylation assay, RNA stability assay, luciferase reporter, m6A-deficient mutant rescue experiments","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RNA stability, mutant rescue), single lab","pmids":["32859993"],"is_preprint":false},{"year":2019,"finding":"STC1 ameliorates renal injury in diabetic nephropathy by inhibiting BNIP3 expression through activation of the AMPK/SIRT3 pathway in db/db mice and high-glucose-treated BUMPT cells.","method":"In vivo db/db mouse model, in vitro high-glucose cell model, Western blotting for AMPK/SIRT3/BNIP3 pathway components, siRNA knockdown","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by Western blot without biochemical reconstitution, single lab, single study","pmids":["30683904"],"is_preprint":false},{"year":2016,"finding":"Elevated STC1 increases invasiveness of triple-negative breast cancer cells through activation of the JNK/c-Jun signaling pathway, leading to increased MMP-9 expression; JNK inhibitor SP600125 suppresses both STC1-induced MMP-9 expression and cell invasion.","method":"Recombinant STC1 treatment, siRNA knockdown, Western blotting for phospho-JNK/c-Jun, MMP-9 expression, Transwell invasion assay","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor plus recombinant protein, single lab, single study with limited pathway resolution","pmids":["27459971"],"is_preprint":false},{"year":2017,"finding":"STC1 regulates glioblastoma migration and invasion via the TGF-β/SMAD4 signaling pathway: STC1 knockdown reduces SMAD2/3 and SMAD4 protein levels, and SMAD4 expression is suppressed by miR-34a (whose expression is also decreased by STC1 knockdown), with luciferase assay confirming SMAD4 3'UTR as miR-34a target.","method":"shRNA knockdown, lentiviral overexpression, Western blotting, luciferase 3'UTR reporter assay, EdU/Transwell assays","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway placement, single lab, correlative Western blots with limited mechanistic dissection","pmids":["31432189"],"is_preprint":false},{"year":2021,"finding":"STC1 inhibits airway smooth muscle (ASM) contraction and airway hyperresponsiveness by blocking store-operated Ca2+ entry (SOCE) through suppression of stromal interaction molecule 1 (STIM1), thereby inhibiting Ca2+-dependent myosin light chain (MLC) phosphorylation. IL-13 suppresses STC1 release from bronchial epithelial cells, whereas recombinant human STC1 reduces AHR and inflammation in OVA-challenged mice.","method":"Recombinant human STC1 (rhSTC1) treatment ex vivo and in vivo (intranasal), Ca2+ influx assay (SOCE measurement), STIM1/MLC phosphorylation Western blotting, mouse AHR model","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein with mechanistic readouts (SOCE, STIM1, MLC phosphorylation) plus in vivo model, single lab","pmids":["33378582"],"is_preprint":false},{"year":2015,"finding":"STC1 signals through inhibitory G-protein to modulate cAMP: STC1 inhibits forskolin-stimulated cAMP accumulation in HEK293 cells transfected with calcitonin receptor (CTR) but not in CALCRL/RAMP1-transfected HEK293 cells, indicating STC1's inhibitory action is specific to CTR and not CGRP receptor. STC1 also modifies plasma membrane spatial distribution of CALCRL/RAMP1 complex in pre-osteoblasts.","method":"cAMP accumulation assay in transfected HEK293 cells, immunofluorescence for receptor localization in osteoblastogenesis model","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-based cAMP assay in transfected cells, single lab, limited mechanistic depth","pmids":["25591908"],"is_preprint":false},{"year":2022,"finding":"STC1 upregulates SMAD7 in a UCP2-dependent manner in alveolar epithelial and fibroblast cells, induces demethylation of the SMAD7 promoter and acetylation of SMAD7 protein, and attenuates pulmonary fibrosis in a bleomycin mouse model. STC1 also stimulates glycolysis, acetyl-CoA synthesis, and the methionine/cysteine-glutathione pathway as shown by comprehensive metabolomics.","method":"Metabolomics (capillary electrophoresis-TOF MS), Western blotting, promoter methylation assay, UCP2-dependent knockdown rescue, bleomycin mouse model","journal":"American journal of respiratory cell and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway inferred from metabolomics and correlative Western blots, limited direct biochemical evidence for STC1–SMAD7 link, single lab","pmids":["35696344"],"is_preprint":false},{"year":2020,"finding":"In fibroblast-derived STC1 regulation of lung adenocarcinoma: STC1 secreted by tumor-associated fibroblasts (TAFs) suppresses tumor-associated macrophage (TAM) differentiation at least in part by sequestering GRP94 (an autocrine macrophage-differentiation-inducing factor) from binding to its cognate scavenger receptors; Stc1-deficient mouse lungs accumulate more mature TAMs, which secrete more TGF-β1 leading to increased TAF accumulation.","method":"Stc1 knockout mouse lung models (G12DKRAS, V600EBRAF), macrophage differentiation assays, GRP94-receptor binding competition (mechanistic inference from genetic model), TGF-β1 measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in two mouse models with defined cellular phenotype and proposed molecular mechanism (GRP94 sequestration), single lab","pmids":["32579928"],"is_preprint":false},{"year":2023,"finding":"CAF-derived STC1 directly binds Notch1 receptors (shown by Co-IP) to activate Notch signaling, promoting hepatocellular carcinoma stemness; STC1 is in turn a direct transcriptional target of CSL (a Notch transcriptional effector), forming a feedforward amplification loop. STC1 expression positively correlates with Notch1 expression in HCC tissue microarray.","method":"Co-immunoprecipitation (STC1–Notch1 binding), dual-luciferase reporter assay (CSL→STC1 promoter), sphere formation, sorafenib resistance assay, orthotopic xenograft","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for protein-protein interaction, reporter assay for transcriptional regulation; single lab, limited orthogonal validation","pmids":["37004088"],"is_preprint":false},{"year":2023,"finding":"A20 inhibits GSK3β-mediated phosphorylation of STC1 at Thr86, slowing STC1 protein degradation; elevated STC1 then binds calreticulin (CRT) and retains it in mitochondria, preventing CRT translocation to the cell membrane (the 'eat-me' signal), thereby promoting immune evasion in colorectal cancer.","method":"Co-IP (STC1–CRT interaction), Western blotting for phospho-STC1(Thr86), cell surface CRT assay, gain/loss-of-function studies, in vivo mouse model","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein-protein interaction, phosphorylation site identification, cell surface trafficking assay, in vivo validation; single lab with multiple orthogonal methods","pmids":["37607946"],"is_preprint":false},{"year":2024,"finding":"STC1 competes with YAP for binding to βPIX within its KER domain in melanoma cells; competitive binding displaces YAP from βPIX, leading to YAP nuclear translocation and activation, which drives CCL2 upregulation. CCL2-recruited M2 macrophages secrete VEGFA, which activates AKT signaling in melanoma cells to further increase STC1 expression, forming a pro-metastatic feedback loop. STC1-induced YAP activation also increases PD-L1 expression.","method":"Mass spectrometry, Co-immunoprecipitation (STC1–βPIX, YAP–βPIX), Dual-luciferase reporter assay (CCL2 promoter), ChIP (YAP at CCL2 promoter), in vivo lung metastasis model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP, ChIP, reporter assay, in vivo model), single lab","pmids":["38768671"],"is_preprint":false},{"year":2012,"finding":"STC1 overexpression in cervical cancer cells activates NF-κB p65, inhibiting cell proliferation and invasion; NF-κB p65 protein directly binds the STC1 promoter and activates STC1 expression (as confirmed by ChIP and reporter assay), establishing a regulatory loop.","method":"shRNA knockdown, STC1 overexpression, ChIP (NF-κB p65 at STC1 promoter), luciferase reporter assay, cell proliferation and invasion assays","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assay performed but mechanistic dissection is limited; single lab, single study","pmids":["23382863"],"is_preprint":false},{"year":2017,"finding":"STC1 overexpression in hepatocellular carcinoma cells inhibits the p70S6K/phospho-rpS6 signaling pathway, reduces cellular ATP levels, activates AMPK, and shifts cellular energy metabolism toward lower glycolysis and oxygen consumption rates, thereby reducing tumor growth in a xenograft model.","method":"Lentiviral STC1 overexpression, Western blotting (p-rpS6, p70S6K, p-AMPK), ATP measurement, Seahorse metabolic flux analysis (glycolysis/OCR), xenograft model","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative Western blots with metabolic readouts; no direct biochemical link between STC1 and p70S6K established; single lab","pmids":["29467934"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A methylation increases the mRNA stability of STC1 (and GDF6) in dental pulp stem cells, promoting dentinogenesis differentiation; METTL3 knockdown impairs differentiation while overexpression promotes it.","method":"MeRIP-seq, RNA stability assay (actinomycin D chase), lentiviral METTL3 knockdown/overexpression, ALP/alizarin red staining, direct pulp capping rat model","journal":"BMC oral health","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MeRIP-seq identifies m6A on STC1 mRNA and stability assay confirms effect, but the downstream mechanism of STC1 in dentinogenesis is not resolved; single lab","pmids":["37041485"],"is_preprint":false},{"year":2012,"finding":"PACAP induces STC1 gene expression in rat cortical neurons through cAMP and ERK1/2 signaling but not through canonical cAMP-dependent PKA; PACAP-mediated ERK1/2 activation occurs downstream of cAMP but independently of PKA, distinguishing this neuroprotective pathway from the canonical PKA-dependent cAMP pathway used for BDNF induction.","method":"PACAP receptor activation, pharmacological inhibitors (MEK/ERK inhibitor, PKA inhibitor H-89), cAMP and Ca2+ second messenger assays, STC1 mRNA quantification in cultured cortical neurons","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor-based pathway dissection, single lab, single study","pmids":["21975601"],"is_preprint":false}],"current_model":"STC1 (stanniocalcin-1) is a secreted glycoprotein that functions through multiple mechanisms: in fission yeast, the ortholog Stc1 physically bridges the RNAi effector Ago1 (via an N-terminal tandem zinc finger domain) and the CLRC histone methyltransferase complex (via its C-terminal region) to couple RNAi to H3K9 methylation and heterochromatin formation; in mammalian systems, STC1 acts on mitochondria to uncouple oxidative phosphorylation (increasing respiration while reducing ADP:O ratios) through a mechanism sensitive to nucleotide triphosphates and involving UCP2 upregulation, thereby reducing ROS and shifting metabolism toward glycolysis; extracellularly, STC1 binds specific high-affinity receptors on target cells (e.g., granulosa cells) to modulate steroidogenesis, and signals via inhibitory G-protein to suppress cAMP; in cancer contexts STC1 promotes metastasis through PDGF-dependent CAF activation, competes with YAP for βPIX binding to drive YAP nuclear translocation and downstream CCL2/VEGFA signaling, sequesters calreticulin in mitochondria to block immunogenic 'eat-me' signals, and binds Notch1 receptors to activate Notch-dependent stemness programs, while its own transcription is regulated epigenetically by CAPG/PRMT5 competition at its promoter and by m6A modification of upstream regulators."},"narrative":{"mechanistic_narrative":"STC1 is a secreted glycoprotein that acts at the cell surface and on mitochondria to modulate energy metabolism, calcium handling, and intercellular signaling, with prominent roles in the tumor microenvironment [PMID:17092635, PMID:22146344, PMID:23243022]. Through high-affinity cell-surface receptors it engages inhibitory G-protein signaling to suppress cAMP and dampens FSH-stimulated steroidogenesis in granulosa cells, acting downstream of adenylate cyclase [PMID:15131261, PMID:25591908]. On isolated mitochondria STC1 uncouples oxidative phosphorylation—raising respiration while lowering ADP:O ratios and increasing Ca2+ uptake in a nucleotide-sensitive manner [PMID:17092635]—and in cells it drives this effect by upregulating UCP2, thereby lowering ROS and shifting metabolism toward glycolysis [PMID:22146344]. In cancer, stromal- and CAF-derived STC1 promotes metastasis downstream of PDGF receptor signaling [PMID:23243022], and within tumor cells STC1 acts as a protein-protein competitor and scaffold: it competes with YAP for βPIX binding to drive YAP nuclear translocation and CCL2/VEGFA signaling [PMID:38768671], sequesters calreticulin in mitochondria to block the surface 'eat-me' signal and enable immune evasion (a function stabilized when A20 blocks GSK3β-mediated phosphorylation at Thr86) [PMID:37607946], and shapes macrophage differentiation by sequestering GRP94 [PMID:32579928]. STC1's own expression is set transcriptionally and post-transcriptionally, including CAPG/PRMT5 competition at its promoter and m6A-dependent control of upstream regulators [PMID:29721098, PMID:32859993]. A mechanistically distinct activity is seen in fission yeast, where the Stc1 ortholog bridges the RNAi effector Ago1 to the CLRC histone methyltransferase complex to couple RNAi to H3K9 methylation and heterochromatin formation [PMID:20211136, PMID:23613586].","teleology":[{"year":2004,"claim":"Established that STC1 is a secreted paracrine factor acting through specific cell-surface receptors, answering whether it signals on target endocrine cells; it suppresses FSH-stimulated steroidogenesis downstream of adenylate cyclase.","evidence":"Recombinant STC1 treatment of primary rat granulosa cells with radioligand receptor binding and steroid/cAMP readouts","pmids":["15131261"],"confidence":"Medium","gaps":["Receptor identity not molecularly defined","Signaling step downstream of adenylate cyclase not resolved"]},{"year":2006,"claim":"Defined a direct mitochondrial action for STC1, showing it uncouples oxidative phosphorylation and enhances Ca2+ uptake in a nucleotide-regulated manner, locating part of its function at the organelle.","evidence":"Respiration and ADP:O assays plus 45Ca uptake and nucleotide-competition receptor binding on isolated rat mitochondria","pmids":["17092635"],"confidence":"Medium","gaps":["Molecular target on/in mitochondria not identified","Link between surface receptor binding and mitochondrial entry unresolved"]},{"year":2010,"claim":"Resolved how RNAi is coupled to heterochromatin in fission yeast by showing the Stc1 ortholog physically bridges Ago1 and the CLRC complex, with tethering sufficient to silence.","evidence":"Co-IP, genetic epistasis, tethering assay, and H3K9me ChIP in fission yeast","pmids":["20211136"],"confidence":"High","gaps":["Relationship of this nuclear chromatin role to mammalian secreted STC1 unclear","Does not address mammalian function"]},{"year":2011,"claim":"Connected STC1's mitochondrial uncoupling activity to a cellular effector, showing UCP2 upregulation mediates ROS reduction and a glycolytic shift that promotes cancer cell survival.","evidence":"UCP2 shRNA knockdown with recombinant STC1 rescue, ROS, membrane potential, and lactate assays in A549 cells","pmids":["22146344"],"confidence":"Medium","gaps":["Mechanism linking STC1 receptor engagement to UCP2 transcription not defined"]},{"year":2012,"claim":"Demonstrated a stromal pro-metastatic role, placing STC1 downstream of PDGF receptor signaling in cancer-associated fibroblasts that drive tumor cell intravasation.","evidence":"Coculture invasion assays and STC1-deficient fibroblasts in an orthotopic mouse model","pmids":["23243022"],"confidence":"Medium","gaps":["Receptor on tumor cells mediating the effect not identified","Direct STC1 effector in invasion unresolved"]},{"year":2013,"claim":"Provided the structural basis for the Stc1 bridge, showing an unusual N-terminal tandem zinc finger binds Ago1 while the C-terminus binds CLRC.","evidence":"NMR/structural analysis with deletion/mutagenesis and Co-IP in fission yeast","pmids":["23613586"],"confidence":"High","gaps":["Structure pertains to the yeast ortholog, not mammalian STC1"]},{"year":2015,"claim":"Began to define STC1's proximal signaling, indicating it acts through inhibitory G-protein to suppress cAMP in a receptor-specific manner.","evidence":"cAMP accumulation assays in calcitonin-receptor- vs CALCRL/RAMP1-transfected HEK293 cells and receptor immunofluorescence","pmids":["25591908"],"confidence":"Low","gaps":["Cell-based assay in transfected cells without direct STC1-receptor binding demonstration","Endogenous receptor not established"]},{"year":2018,"claim":"Explained how STC1 transcription is set epigenetically, showing CAPG displaces the repressor PRMT5 at the STC1 promoter to lower H4R3 methylation and boost expression.","evidence":"ChIP, luciferase reporter, Co-IP, HMT assay, and xenograft in breast cancer","pmids":["29721098"],"confidence":"Medium","gaps":["Generality across tissues not tested"]},{"year":2020,"claim":"Extended STC1 regulation to the m6A/RNA axis, showing AURKA-stabilized METTL14 promotes m6A of DROSHA, which with β-Catenin transactivates STC1 to drive stemness.","evidence":"Co-IP, m6A analysis, RNA stability, ubiquitylation, and mutant rescue in breast cancer stem-like cells","pmids":["32859993"],"confidence":"Medium","gaps":["Direct STC1 contribution to stemness phenotype only inferred from upstream regulators"]},{"year":2020,"claim":"Identified a sequestration mechanism by which fibroblast STC1 suppresses macrophage maturation, proposing GRP94 sequestration to limit autocrine differentiation signals.","evidence":"Stc1 knockout mouse lung tumor models with macrophage differentiation assays and TGF-β1 measurement","pmids":["32579928"],"confidence":"Medium","gaps":["GRP94 sequestration inferred rather than directly demonstrated biochemically"]},{"year":2023,"claim":"Defined a calreticulin-sequestration mechanism of immune evasion, with STC1 retaining CRT in mitochondria, and a phospho-regulatory node (A20→GSK3β→Thr86) controlling STC1 stability.","evidence":"Co-IP, phospho-STC1(Thr86) Western blots, cell-surface CRT assays, and in vivo colorectal cancer models","pmids":["37607946"],"confidence":"Medium","gaps":["How STC1 enters/retains CRT in mitochondria mechanistically unresolved"]},{"year":2024,"claim":"Revealed STC1 as a competitive scaffold, displacing YAP from βPIX to drive YAP nuclear activation, CCL2/VEGFA signaling, and a pro-metastatic feedback loop with PD-L1 induction.","evidence":"MS, Co-IP (STC1–βPIX, YAP–βPIX), CCL2 reporter/ChIP, and in vivo lung metastasis model in melanoma","pmids":["38768671"],"confidence":"Medium","gaps":["Whether secreted vs intracellular STC1 mediates βPIX competition not clarified"]},{"year":null,"claim":"The identity of the mammalian STC1 cell-surface receptor and the molecular link between extracellular receptor engagement and its intracellular/mitochondrial activities remain unresolved.","evidence":"No discovery in the corpus molecularly identifies the high-affinity STC1 receptor","pmids":[],"confidence":"Low","gaps":["Receptor not cloned","Mechanism of mitochondrial localization of a secreted protein undefined","Reconciliation of yeast chromatin role with mammalian secreted roles absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[14,16,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,12,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,12]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,16,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["AGO1","CRT","ARHGEF7","YAP1","NOTCH1","HSP90B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52823","full_name":"Stanniocalcin-1","aliases":[],"length_aa":247,"mass_kda":27.6,"function":"Stimulates renal phosphate reabsorption, and could therefore prevent hypercalcemia","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P52823/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STC1","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/STC1","total_profiled":1310},"omim":[{"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":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STC1"},"hgnc":{"alias_symbol":[],"prev_symbol":["STC"]},"alphafold":{"accession":"P52823","domains":[{"cath_id":"-","chopping":"38-198","consensus_level":"medium","plddt":93.0474,"start":38,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52823","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52823-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52823-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STC1","jax_strain_url":"https://www.jax.org/strain/search?query=STC1"},"sequence":{"accession":"P52823","fasta_url":"https://rest.uniprot.org/uniprotkb/P52823.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52823/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52823"}},"corpus_meta":[{"pmid":"15721318","id":"PMC_15721318","title":"Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15721318","citation_count":640,"is_preprint":false},{"pmid":"11854532","id":"PMC_11854532","title":"Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11854532","citation_count":385,"is_preprint":false},{"pmid":"20211136","id":"PMC_20211136","title":"Stc1: a critical link between RNAi and chromatin modification required for heterochromatin integrity.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/20211136","citation_count":180,"is_preprint":false},{"pmid":"16707556","id":"PMC_16707556","title":"Bitter stimuli induce Ca2+ signaling and CCK release in enteroendocrine STC-1 cells: role of L-type voltage-sensitive Ca2+ channels.","date":"2006","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16707556","citation_count":171,"is_preprint":false},{"pmid":"23922312","id":"PMC_23922312","title":"Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1).","date":"2013","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/23922312","citation_count":160,"is_preprint":false},{"pmid":"15774482","id":"PMC_15774482","title":"Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15774482","citation_count":157,"is_preprint":false},{"pmid":"23243022","id":"PMC_23243022","title":"STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23243022","citation_count":152,"is_preprint":false},{"pmid":"32859993","id":"PMC_32859993","title":"Oncogenic AURKA-enhanced N6-methyladenosine modification increases DROSHA mRNA stability to transactivate STC1 in breast cancer stem-like cells.","date":"2020","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32859993","citation_count":109,"is_preprint":false},{"pmid":"22146344","id":"PMC_22146344","title":"Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1.","date":"2011","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22146344","citation_count":105,"is_preprint":false},{"pmid":"17290006","id":"PMC_17290006","title":"GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells.","date":"2007","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17290006","citation_count":98,"is_preprint":false},{"pmid":"10645957","id":"PMC_10645957","title":"A deep-coverage tomato BAC library and prospects toward development of an STC framework for genome sequencing.","date":"2000","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/10645957","citation_count":92,"is_preprint":false},{"pmid":"25391215","id":"PMC_25391215","title":"STC1 expression is associated with tumor growth and metastasis in breast cancer.","date":"2014","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/25391215","citation_count":88,"is_preprint":false},{"pmid":"26819328","id":"PMC_26819328","title":"Peptide production and secretion in GLUTag, NCI-H716, and STC-1 cells: a comparison to native L-cells.","date":"2016","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26819328","citation_count":86,"is_preprint":false},{"pmid":"18691347","id":"PMC_18691347","title":"Calcium-sensing receptor mediates phenylalanine-induced cholecystokinin secretion in enteroendocrine STC-1 cells.","date":"2008","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18691347","citation_count":77,"is_preprint":false},{"pmid":"11018115","id":"PMC_11018115","title":"Fatty acid-induced cholecystokinin secretion and changes in intracellular Ca2+ in two enteroendocrine cell lines, STC-1 and GLUTag.","date":"2000","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11018115","citation_count":76,"is_preprint":false},{"pmid":"9048620","id":"PMC_9048620","title":"Peptones stimulate cholecystokinin secretion and gene transcription in the intestinal cell line STC-1.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9048620","citation_count":75,"is_preprint":false},{"pmid":"15131261","id":"PMC_15131261","title":"Paracrine regulation of ovarian granulosa cell differentiation by stanniocalcin (STC) 1: mediation through specific STC1 receptors.","date":"2004","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/15131261","citation_count":68,"is_preprint":false},{"pmid":"17092635","id":"PMC_17092635","title":"The respiratory effects of stanniocalcin-1 (STC-1) on intact mitochondria and cells: STC-1 uncouples oxidative phosphorylation and its actions are modulated by nucleotide triphosphates.","date":"2006","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17092635","citation_count":68,"is_preprint":false},{"pmid":"21998136","id":"PMC_21998136","title":"TRPM5 is critical for linoleic acid-induced CCK secretion from the enteroendocrine cell line, STC-1.","date":"2011","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21998136","citation_count":60,"is_preprint":false},{"pmid":"8167157","id":"PMC_8167157","title":"Characterization of the release of cholecystokinin from a murine neuroendocrine tumor cell line, STC-1.","date":"1994","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8167157","citation_count":59,"is_preprint":false},{"pmid":"21890837","id":"PMC_21890837","title":"Green tea polyphenol epigallocatechin gallate activates TRPA1 in an intestinal enteroendocrine cell line, STC-1.","date":"2011","source":"Chemical senses","url":"https://pubmed.ncbi.nlm.nih.gov/21890837","citation_count":56,"is_preprint":false},{"pmid":"22648622","id":"PMC_22648622","title":"Calcium-sensing receptor mediates dietary peptide-induced CCK secretion in enteroendocrine STC-1 cells.","date":"2012","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/22648622","citation_count":50,"is_preprint":false},{"pmid":"10511551","id":"PMC_10511551","title":"Aspergillus nidulans mutants defective in stc gene cluster regulation.","date":"1999","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10511551","citation_count":49,"is_preprint":false},{"pmid":"29721098","id":"PMC_29721098","title":"CAPG enhances breast cancer metastasis by competing with PRMT5 to modulate STC-1 transcription.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/29721098","citation_count":49,"is_preprint":false},{"pmid":"9492022","id":"PMC_9492022","title":"Regulation of cholecystokinin secretion by peptones and peptidomimetic antibiotics in STC-1 cells.","date":"1998","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9492022","citation_count":48,"is_preprint":false},{"pmid":"25787141","id":"PMC_25787141","title":"Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel.","date":"2015","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/25787141","citation_count":47,"is_preprint":false},{"pmid":"33072314","id":"PMC_33072314","title":"Effects of miR-101-3p on goat granulosa cells in vitro and ovarian development in vivo via STC1.","date":"2020","source":"Journal of animal science and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33072314","citation_count":46,"is_preprint":false},{"pmid":"29363059","id":"PMC_29363059","title":"Berberine activates bitter taste responses of enteroendocrine STC-1 cells.","date":"2018","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29363059","citation_count":45,"is_preprint":false},{"pmid":"16452456","id":"PMC_16452456","title":"Stanniocalcin (STC) in the endometrial glands of the ovine uterus: regulation by progesterone and placental hormones.","date":"2006","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16452456","citation_count":45,"is_preprint":false},{"pmid":"30683904","id":"PMC_30683904","title":"STC-1 ameliorates renal injury in diabetic nephropathy by inhibiting the expression of BNIP3 through the AMPK/SIRT3 pathway.","date":"2019","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30683904","citation_count":44,"is_preprint":false},{"pmid":"9660895","id":"PMC_9660895","title":"Expression of functional GABAA receptors in cholecystokinin-secreting gut neuroendocrine murine STC-1 cells.","date":"1998","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9660895","citation_count":42,"is_preprint":false},{"pmid":"23382863","id":"PMC_23382863","title":"Stanniocalcin1 (STC1) Inhibits Cell Proliferation and Invasion of Cervical Cancer Cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23382863","citation_count":41,"is_preprint":false},{"pmid":"37607946","id":"PMC_37607946","title":"A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block \"eat-me\" signal.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37607946","citation_count":39,"is_preprint":false},{"pmid":"29119787","id":"PMC_29119787","title":"Cysteine Linkages Accelerate Electron Flow through Tetra-Heme Protein STC.","date":"2017","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/29119787","citation_count":38,"is_preprint":false},{"pmid":"30091426","id":"PMC_30091426","title":"Stimulation of CCK and GLP-1 secretion and expression in STC-1 cells by human jejunal contents and in vitro gastrointestinal digests from casein and whey proteins.","date":"2018","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/30091426","citation_count":37,"is_preprint":false},{"pmid":"27459971","id":"PMC_27459971","title":"Elevated STC‑1 augments the invasiveness of triple‑negative breast cancer cells through activation of the JNK/c‑Jun signaling pathway.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27459971","citation_count":37,"is_preprint":false},{"pmid":"36795484","id":"PMC_36795484","title":"Cancer-associated mesothelial cell-derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36795484","citation_count":36,"is_preprint":false},{"pmid":"11897801","id":"PMC_11897801","title":"Stanniocalcin 1 (STC1) protein and mRNA are developmentally regulated during embryonic mouse osteogenesis: the potential of stc1 as an autocrine/paracrine factor for osteoblast development and bone formation.","date":"2002","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/11897801","citation_count":34,"is_preprint":false},{"pmid":"15741596","id":"PMC_15741596","title":"Characterization of bitter taste responses of intestinal STC-1 cells.","date":"2005","source":"Chemical senses","url":"https://pubmed.ncbi.nlm.nih.gov/15741596","citation_count":34,"is_preprint":false},{"pmid":"25930999","id":"PMC_25930999","title":"Nesfatin-1 stimulates glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide secretion from STC-1 cells in vitro.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25930999","citation_count":34,"is_preprint":false},{"pmid":"28545028","id":"PMC_28545028","title":"STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28545028","citation_count":32,"is_preprint":false},{"pmid":"9480753","id":"PMC_9480753","title":"Human stanniocalcin (STC): genomic structure, chromosomal localization, and the presence of CAG trinucleotide repeats.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9480753","citation_count":31,"is_preprint":false},{"pmid":"20352619","id":"PMC_20352619","title":"Acute and chronic effects of dietary fatty acids on cholecystokinin expression, storage and secretion in enteroendocrine STC-1 cells.","date":"2010","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/20352619","citation_count":29,"is_preprint":false},{"pmid":"32579928","id":"PMC_32579928","title":"Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32579928","citation_count":28,"is_preprint":false},{"pmid":"33543830","id":"PMC_33543830","title":"Circ-UBAP2 functions as sponges of miR-1205 and miR-382 to promote glioma progression by modulating STC1 expression.","date":"2021","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33543830","citation_count":27,"is_preprint":false},{"pmid":"9275044","id":"PMC_9275044","title":"Prohormone convertase 2 is necessary for the formation of cholecystokinin-22, but not cholecystokinin-8, in RIN5F and STC-1 cells.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9275044","citation_count":27,"is_preprint":false},{"pmid":"31432189","id":"PMC_31432189","title":"STC1 regulates glioblastoma migration and invasion via the TGF‑β/SMAD4 signaling pathway.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31432189","citation_count":26,"is_preprint":false},{"pmid":"33142290","id":"PMC_33142290","title":"Trichostatin A Induces Autophagy in Cervical Cancer Cells by Regulating the PRMT5-STC1-TRPV6-JNK Pathway.","date":"2020","source":"Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33142290","citation_count":26,"is_preprint":false},{"pmid":"20219951","id":"PMC_20219951","title":"Amino acid sensing by enteroendocrine STC-1 cells: role of the Na+-coupled neutral amino acid transporter 2.","date":"2010","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20219951","citation_count":26,"is_preprint":false},{"pmid":"34800749","id":"PMC_34800749","title":"MiR-144-3p targets STC1 to activate PI3K/AKT pathway to induce cell apoptosis and cell cycle arrest in selenium deficiency broilers.","date":"2021","source":"Journal of inorganic biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34800749","citation_count":25,"is_preprint":false},{"pmid":"12943684","id":"PMC_12943684","title":"The STC-1 cells express functional orexin-A receptors coupled to CCK release.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12943684","citation_count":25,"is_preprint":false},{"pmid":"31889892","id":"PMC_31889892","title":"Sevoflurane inhibits the progression of ovarian cancer through down-regulating stanniocalcin 1 (STC1).","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31889892","citation_count":24,"is_preprint":false},{"pmid":"33378582","id":"PMC_33378582","title":"Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation.","date":"2021","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/33378582","citation_count":23,"is_preprint":false},{"pmid":"8216272","id":"PMC_8216272","title":"Potassium channels regulate cholecystokinin secretion in STC-1 cells.","date":"1993","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8216272","citation_count":22,"is_preprint":false},{"pmid":"19323755","id":"PMC_19323755","title":"Peptide-YY is released by the intestinal cell line STC-1.","date":"2009","source":"Journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/19323755","citation_count":22,"is_preprint":false},{"pmid":"38768671","id":"PMC_38768671","title":"STC1 competitively binding βPIX enhances melanoma progression via YAP nuclear translocation and M2 macrophage recruitment through the YAP/CCL2/VEGFA/AKT feedback loop.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/38768671","citation_count":21,"is_preprint":false},{"pmid":"34220309","id":"PMC_34220309","title":"Abnormal proinflammatory and stressor environmental with increased the regulatory cellular IGF-1/PAPP-A/STC and Wnt-1/β-Catenin canonical pathway in placenta of women with Chronic venous Disease during Pregnancy.","date":"2021","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34220309","citation_count":21,"is_preprint":false},{"pmid":"8843778","id":"PMC_8843778","title":"Pituitary adenylate cyclase-activating polypeptide stimulates cholecystokinin secretion in STC-1 cells.","date":"1996","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8843778","citation_count":21,"is_preprint":false},{"pmid":"27156337","id":"PMC_27156337","title":"STC1 and NF-κB p65 (Rel A) is Constitutively Activated in Colorectal Cancer.","date":"2016","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/27156337","citation_count":20,"is_preprint":false},{"pmid":"31379744","id":"PMC_31379744","title":"A Possible Mechanism: Genistein Improves Metabolism and Induces White Fat Browning Through Modulating Hypothalamic Expression of Ucn3, Depp, and Stc1.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31379744","citation_count":20,"is_preprint":false},{"pmid":"37004088","id":"PMC_37004088","title":"The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37004088","citation_count":19,"is_preprint":false},{"pmid":"33716265","id":"PMC_33716265","title":"Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction.","date":"2021","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/33716265","citation_count":19,"is_preprint":false},{"pmid":"34797444","id":"PMC_34797444","title":"Bacillus Subtilis Promotes the Release of 5-HT to Regulate Intestinal Peristalsis in STC Mice via Bile Acid and Its Receptor TGR5 Pathway.","date":"2021","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34797444","citation_count":19,"is_preprint":false},{"pmid":"24357536","id":"PMC_24357536","title":"Unsaturated aldehydes induce CCK secretion via TRPA1 in STC-1 cells.","date":"2013","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/24357536","citation_count":19,"is_preprint":false},{"pmid":"32379497","id":"PMC_32379497","title":"MEG3 Induces Cervical Carcinoma Cells' Apoptosis Through Endoplasmic Reticulum Stress by miR-7-5p/STC1 Axis.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/32379497","citation_count":19,"is_preprint":false},{"pmid":"32998057","id":"PMC_32998057","title":"Dipeptidyl peptidase-4 and GLP-1 interplay in STC-1 and GLUTag cell lines.","date":"2020","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/32998057","citation_count":18,"is_preprint":false},{"pmid":"35587126","id":"PMC_35587126","title":"Digestion characteristics of quinoa, barley and mungbean proteins and the effects of their simulated gastrointestinal digests on CCK secretion in enteroendocrine STC-1 cells.","date":"2022","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/35587126","citation_count":18,"is_preprint":false},{"pmid":"27496247","id":"PMC_27496247","title":"Flavonoids stimulate cholecystokinin peptide secretion from the enteroendocrine STC-1 cells.","date":"2016","source":"Fitoterapia","url":"https://pubmed.ncbi.nlm.nih.gov/27496247","citation_count":18,"is_preprint":false},{"pmid":"9512470","id":"PMC_9512470","title":"Bombesin stimulates cholecystokinin secretion through mitogen-activated protein-kinase-dependent and -independent mechanisms in the enteroendocrine STC-1 cell line.","date":"1998","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9512470","citation_count":18,"is_preprint":false},{"pmid":"10070046","id":"PMC_10070046","title":"Diazepam-binding inhibitor33-50 elicits Ca2+ oscillation and CCK secretion in STC-1 cells via L-type Ca2+ channels.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10070046","citation_count":18,"is_preprint":false},{"pmid":"29938900","id":"PMC_29938900","title":"Novel Mechanism of Fatty Acid Sensing in Enteroendocrine Cells: Specific Structures in Oxo-Fatty Acids Produced by Gut Bacteria Are Responsible for CCK Secretion in STC-1 Cells via GPR40.","date":"2018","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/29938900","citation_count":18,"is_preprint":false},{"pmid":"35927233","id":"PMC_35927233","title":"Circular RNA circPOSTN promotes neovascularization by regulating miR-219a-2-3p/STC1 axis and stimulating the secretion of VEGFA in glioblastoma.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35927233","citation_count":17,"is_preprint":false},{"pmid":"27846263","id":"PMC_27846263","title":"Nicotine-Induced Effects on Nicotinic Acetylcholine Receptors (nAChRs), Ca2+ and Brain-Derived Neurotrophic Factor (BDNF) in STC-1 Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27846263","citation_count":17,"is_preprint":false},{"pmid":"23613586","id":"PMC_23613586","title":"Structural analysis of Stc1 provides insights into the coupling of RNAi and chromatin modification.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23613586","citation_count":16,"is_preprint":false},{"pmid":"10960361","id":"PMC_10960361","title":"Control of CCK gene transcription by PACAP in STC-1 cells.","date":"2000","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10960361","citation_count":16,"is_preprint":false},{"pmid":"32431516","id":"PMC_32431516","title":"Long Noncoding RNA MALAT1 Promotes the Development of Colon Cancer by Regulating miR-101-3p/STC1 Axis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32431516","citation_count":15,"is_preprint":false},{"pmid":"35603999","id":"PMC_35603999","title":"NF-κB-upregulated miR-155-5p promotes hepatocyte mitochondrial dysfunction to accelerate the development of nonalcoholic fatty liver disease through downregulation of STC1.","date":"2022","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35603999","citation_count":15,"is_preprint":false},{"pmid":"8333529","id":"PMC_8333529","title":"Calcium-dependent regulation of cholecystokinin secretion and potassium currents in STC-1 cells.","date":"1993","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8333529","citation_count":15,"is_preprint":false},{"pmid":"28905106","id":"PMC_28905106","title":"Recombinant Mouse Osteocalcin Secreted by Lactococcus lactis Promotes Glucagon-Like Peptide-1 Induction in STC-1 Cells.","date":"2017","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28905106","citation_count":15,"is_preprint":false},{"pmid":"27461417","id":"PMC_27461417","title":"STC-1 expression is upregulated through an Akt/NF-κB-dependent pathway in triple-negative breast cancer cells.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27461417","citation_count":14,"is_preprint":false},{"pmid":"21975601","id":"PMC_21975601","title":"STC1 induction by PACAP is mediated through cAMP and ERK1/2 but not PKA in cultured cortical neurons.","date":"2012","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/21975601","citation_count":14,"is_preprint":false},{"pmid":"33784880","id":"PMC_33784880","title":"Knockdown of lncRNA HOTTIP Inhibits Retinoblastoma Progression by Modulating the miR-101-3p/STC1 Axis.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33784880","citation_count":14,"is_preprint":false},{"pmid":"18007200","id":"PMC_18007200","title":"Intestinal STC-1 cells respond to five basic taste stimuli.","date":"2007","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/18007200","citation_count":14,"is_preprint":false},{"pmid":"21139325","id":"PMC_21139325","title":"Production of calcium maintenance factor Stanniocalcin-1 (STC1) by the equine endometrium during the early pregnant period.","date":"2010","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/21139325","citation_count":14,"is_preprint":false},{"pmid":"29467934","id":"PMC_29467934","title":"Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29467934","citation_count":13,"is_preprint":false},{"pmid":"36318610","id":"PMC_36318610","title":"Synergistic Effect of Kokumi-Active γ-Glutamyl Peptides and l-Glutamate on Enhancing Umami Sensation and Stimulating Cholecystokinin Secretion via T1R1/T1R3 Activation in STC-1 Cells.","date":"2022","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36318610","citation_count":13,"is_preprint":false},{"pmid":"7488089","id":"PMC_7488089","title":"Galanin inhibits cholecystokinin secretion in STC-1 cells.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7488089","citation_count":13,"is_preprint":false},{"pmid":"29857240","id":"PMC_29857240","title":"MSCs protect endothelial cells from inflammatory injury partially by secreting STC1.","date":"2018","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29857240","citation_count":13,"is_preprint":false},{"pmid":"27474567","id":"PMC_27474567","title":"Effects of abalone (Haliotis discus hannai Ino) gonad polysaccharides on cholecystokinin release in STC-1 cells and its signaling mechanism.","date":"2016","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/27474567","citation_count":13,"is_preprint":false},{"pmid":"32140959","id":"PMC_32140959","title":"Multifactor dimensionality reduction reveals a strong gene-gene interaction between STC1 and COL11A1 genes as a possible risk factor of knee osteoarthritis.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32140959","citation_count":12,"is_preprint":false},{"pmid":"38397496","id":"PMC_38397496","title":"In Vitro Hypoglycemic Activities of Lactobacilli and Bifidobacterium Strains from Healthy Children's Sources and Their Effect on Stimulating GLP-1 Secretion in STC-1 Cells.","date":"2024","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38397496","citation_count":12,"is_preprint":false},{"pmid":"8779971","id":"PMC_8779971","title":"Beta-adrenergic regulation of cholecystokinin secretion in STC-1 cells.","date":"1996","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8779971","citation_count":12,"is_preprint":false},{"pmid":"9920804","id":"PMC_9920804","title":"Activation of calcium channels by cAMP in STC-1 cells is dependent upon Ca2+ calmodulin-dependent protein kinase II.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9920804","citation_count":12,"is_preprint":false},{"pmid":"35696344","id":"PMC_35696344","title":"Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis.","date":"2022","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35696344","citation_count":11,"is_preprint":false},{"pmid":"38851516","id":"PMC_38851516","title":"Effects and mechanisms of sciadonic acid on colonic transit function through regulating 5-HT4/cAMP/PKA/AQP4 signaling pathway in STC model mice.","date":"2024","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38851516","citation_count":11,"is_preprint":false},{"pmid":"33946970","id":"PMC_33946970","title":"Circ-140/chi-miR-8516/STC1-MMP1 Regulates αs1-/β-Casein Secretion and Lipid Formation in Goat Mammary Epithelial Cells.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33946970","citation_count":11,"is_preprint":false},{"pmid":"25591908","id":"PMC_25591908","title":"STC1 interference on calcitonin family of receptors signaling during osteoblastogenesis via adenylate cyclase inhibition.","date":"2015","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25591908","citation_count":11,"is_preprint":false},{"pmid":"22768997","id":"PMC_22768997","title":"Hormone profiling in a novel enteroendocrine cell line pGIP/neo: STC-1.","date":"2012","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/22768997","citation_count":11,"is_preprint":false},{"pmid":"27224272","id":"PMC_27224272","title":"Pregnane Glycosides from Cynanchum marnierianum Stimulate GLP-1 Secretion in STC-1 Cells.","date":"2016","source":"Planta medica","url":"https://pubmed.ncbi.nlm.nih.gov/27224272","citation_count":11,"is_preprint":false},{"pmid":"37041485","id":"PMC_37041485","title":"METTL3 enhances dentinogenesis differentiation of dental pulp stem cells via increasing GDF6 and STC1 mRNA stability.","date":"2023","source":"BMC oral health","url":"https://pubmed.ncbi.nlm.nih.gov/37041485","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54891,"output_tokens":6126,"usd":0.128281,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14895,"output_tokens":4061,"usd":0.088,"stage2_stop_reason":"end_turn"},"total_usd":0.216281,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Fission yeast Stc1 (a LIM domain protein) acts as a molecular bridge coupling RNAi to heterochromatin formation: it physically interacts with the RNAi effector Ago1 (via its N-terminal tandem zinc finger domain) and with the chromatin-modifying CLRC complex (via its non-conserved C-terminal region), thereby recruiting CLRC to RITS-bound centromeric transcripts and promoting H3K9 methylation. Tethering Stc1 to a euchromatic locus is sufficient to induce silencing independently of RNAi.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis, tethering assay, ChIP for H3K9me, loss-of-function analysis in fission yeast\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, tethering experiment, and ChIP in a single rigorous study; findings subsequently confirmed structurally\",\n      \"pmids\": [\"20211136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Structural analysis of fission yeast Stc1 revealed that its conserved N-terminal region forms an unusual tandem zinc finger domain (with similarities to LIM domains but lacking preferred relative orientation of the two zinc fingers) that mediates binding to Ago1, while the non-conserved C-terminal region mediates association with CLRC.\",\n      \"method\": \"NMR/structural analysis combined with in vivo functional validation (deletion/mutagenesis analysis, Co-IP)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination combined with mutagenesis and binding assays, confirming and extending mechanistic model from prior Cell paper\",\n      \"pmids\": [\"23613586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Recombinant N-glycosylated STC1 protein specifically suppresses FSH-stimulated progesterone biosynthesis (including CYP11A transcripts and LH receptor induction) in rat granulosa cells while having minimal effect on estradiol and cAMP production; radiolabeled STC1 shows high-affinity specific receptor binding on granulosa cells, and STC1 acts downstream of adenylate cyclase, suggesting a follicular paracrine system in which theca-derived STC1 dampens granulosa cell differentiation.\",\n      \"method\": \"Recombinant protein treatment of primary granulosa cells, radioligand receptor binding assay, RT-PCR for CYP11A, RIA for steroid hormones\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein functional assay plus receptor binding, single lab with two orthogonal methods\",\n      \"pmids\": [\"15131261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STC1 uncouples oxidative phosphorylation in intact mitochondria isolated from rat muscle and liver: exposure to 500 nM recombinant human STC1 increases respiration rate, significantly reduces ADP:O ratios, and enhances mitochondrial 45Ca uptake. These respiratory effects are attenuated or abolished by nucleotide triphosphates (ATP, GTP at 5 mM) through a four-fold decrease in receptor binding affinity.\",\n      \"method\": \"Mitochondrial respiration assay (oxygen consumption), ADP:O ratio measurement, 45Ca uptake assay, radioligand receptor binding assay with nucleotide competition\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution with purified mitochondria and receptor binding, single lab with multiple readouts\",\n      \"pmids\": [\"17092635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MSC-derived STC1 promotes survival of lung cancer (A549) cells by upregulating uncoupling protein 2 (UCP2), which uncouples oxidative phosphorylation, reduces intracellular ROS, decreases mitochondrial membrane potential, and shifts metabolism toward glycolysis (increased lactate production). Knockdown of UCP2 abolishes the protective effects of both MSC conditioned medium and recombinant STC1.\",\n      \"method\": \"shRNA knockdown of UCP2, recombinant STC1 treatment, ROS measurement, mitochondrial membrane potential assay, lactate production assay\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus recombinant protein rescue, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"22146344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDGF-stimulated cancer-associated fibroblasts increase migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner; in an orthotopic mouse model, STC1-deficient fibroblasts produce tumors with reduced tumor cell intravasation and fewer/smaller distant metastases, identifying STC1 as a mediator of PDGF receptor-driven metastasis.\",\n      \"method\": \"Co-culture invasion/migration assay, STC1-deficient fibroblasts (genetic loss-of-function), orthotopic mouse model with intravasation quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo orthotopic model with genetic loss-of-function plus in vitro mechanistic assays, single lab\",\n      \"pmids\": [\"23243022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAPG competes with the transcriptional repressor PRMT5 for binding to the STC1 promoter; when CAPG displaces PRMT5, histone H4R3 methylation at the STC1 promoter is reduced, leading to enhanced STC1 transcription and increased breast cancer cell metastasis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, Co-IP, MS/MS, histone methyltransferase assay, xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, reporter assay, enzymatic assay) in single lab\",\n      \"pmids\": [\"29721098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DROSHA interacts with β-Catenin to transactivate STC1 in an RNA cleavage-independent manner in breast cancer stem-like cells (BCSCs), promoting stemness. AURKA stabilizes METTL14 (by inhibiting its ubiquitylation/degradation) to promote m6A methylation of DROSHA mRNA, enhancing its stability; AURKA also directly binds the DROSHA transcript to strengthen IGF2BP2 binding and stabilization of m6A-modified DROSHA.\",\n      \"method\": \"Co-IP (DROSHA–β-Catenin interaction), m6A methylation analysis, ubiquitylation assay, RNA stability assay, luciferase reporter, m6A-deficient mutant rescue experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RNA stability, mutant rescue), single lab\",\n      \"pmids\": [\"32859993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STC1 ameliorates renal injury in diabetic nephropathy by inhibiting BNIP3 expression through activation of the AMPK/SIRT3 pathway in db/db mice and high-glucose-treated BUMPT cells.\",\n      \"method\": \"In vivo db/db mouse model, in vitro high-glucose cell model, Western blotting for AMPK/SIRT3/BNIP3 pathway components, siRNA knockdown\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by Western blot without biochemical reconstitution, single lab, single study\",\n      \"pmids\": [\"30683904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elevated STC1 increases invasiveness of triple-negative breast cancer cells through activation of the JNK/c-Jun signaling pathway, leading to increased MMP-9 expression; JNK inhibitor SP600125 suppresses both STC1-induced MMP-9 expression and cell invasion.\",\n      \"method\": \"Recombinant STC1 treatment, siRNA knockdown, Western blotting for phospho-JNK/c-Jun, MMP-9 expression, Transwell invasion assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor plus recombinant protein, single lab, single study with limited pathway resolution\",\n      \"pmids\": [\"27459971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STC1 regulates glioblastoma migration and invasion via the TGF-β/SMAD4 signaling pathway: STC1 knockdown reduces SMAD2/3 and SMAD4 protein levels, and SMAD4 expression is suppressed by miR-34a (whose expression is also decreased by STC1 knockdown), with luciferase assay confirming SMAD4 3'UTR as miR-34a target.\",\n      \"method\": \"shRNA knockdown, lentiviral overexpression, Western blotting, luciferase 3'UTR reporter assay, EdU/Transwell assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway placement, single lab, correlative Western blots with limited mechanistic dissection\",\n      \"pmids\": [\"31432189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STC1 inhibits airway smooth muscle (ASM) contraction and airway hyperresponsiveness by blocking store-operated Ca2+ entry (SOCE) through suppression of stromal interaction molecule 1 (STIM1), thereby inhibiting Ca2+-dependent myosin light chain (MLC) phosphorylation. IL-13 suppresses STC1 release from bronchial epithelial cells, whereas recombinant human STC1 reduces AHR and inflammation in OVA-challenged mice.\",\n      \"method\": \"Recombinant human STC1 (rhSTC1) treatment ex vivo and in vivo (intranasal), Ca2+ influx assay (SOCE measurement), STIM1/MLC phosphorylation Western blotting, mouse AHR model\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein with mechanistic readouts (SOCE, STIM1, MLC phosphorylation) plus in vivo model, single lab\",\n      \"pmids\": [\"33378582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STC1 signals through inhibitory G-protein to modulate cAMP: STC1 inhibits forskolin-stimulated cAMP accumulation in HEK293 cells transfected with calcitonin receptor (CTR) but not in CALCRL/RAMP1-transfected HEK293 cells, indicating STC1's inhibitory action is specific to CTR and not CGRP receptor. STC1 also modifies plasma membrane spatial distribution of CALCRL/RAMP1 complex in pre-osteoblasts.\",\n      \"method\": \"cAMP accumulation assay in transfected HEK293 cells, immunofluorescence for receptor localization in osteoblastogenesis model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-based cAMP assay in transfected cells, single lab, limited mechanistic depth\",\n      \"pmids\": [\"25591908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STC1 upregulates SMAD7 in a UCP2-dependent manner in alveolar epithelial and fibroblast cells, induces demethylation of the SMAD7 promoter and acetylation of SMAD7 protein, and attenuates pulmonary fibrosis in a bleomycin mouse model. STC1 also stimulates glycolysis, acetyl-CoA synthesis, and the methionine/cysteine-glutathione pathway as shown by comprehensive metabolomics.\",\n      \"method\": \"Metabolomics (capillary electrophoresis-TOF MS), Western blotting, promoter methylation assay, UCP2-dependent knockdown rescue, bleomycin mouse model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway inferred from metabolomics and correlative Western blots, limited direct biochemical evidence for STC1–SMAD7 link, single lab\",\n      \"pmids\": [\"35696344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In fibroblast-derived STC1 regulation of lung adenocarcinoma: STC1 secreted by tumor-associated fibroblasts (TAFs) suppresses tumor-associated macrophage (TAM) differentiation at least in part by sequestering GRP94 (an autocrine macrophage-differentiation-inducing factor) from binding to its cognate scavenger receptors; Stc1-deficient mouse lungs accumulate more mature TAMs, which secrete more TGF-β1 leading to increased TAF accumulation.\",\n      \"method\": \"Stc1 knockout mouse lung models (G12DKRAS, V600EBRAF), macrophage differentiation assays, GRP94-receptor binding competition (mechanistic inference from genetic model), TGF-β1 measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in two mouse models with defined cellular phenotype and proposed molecular mechanism (GRP94 sequestration), single lab\",\n      \"pmids\": [\"32579928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAF-derived STC1 directly binds Notch1 receptors (shown by Co-IP) to activate Notch signaling, promoting hepatocellular carcinoma stemness; STC1 is in turn a direct transcriptional target of CSL (a Notch transcriptional effector), forming a feedforward amplification loop. STC1 expression positively correlates with Notch1 expression in HCC tissue microarray.\",\n      \"method\": \"Co-immunoprecipitation (STC1–Notch1 binding), dual-luciferase reporter assay (CSL→STC1 promoter), sphere formation, sorafenib resistance assay, orthotopic xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for protein-protein interaction, reporter assay for transcriptional regulation; single lab, limited orthogonal validation\",\n      \"pmids\": [\"37004088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A20 inhibits GSK3β-mediated phosphorylation of STC1 at Thr86, slowing STC1 protein degradation; elevated STC1 then binds calreticulin (CRT) and retains it in mitochondria, preventing CRT translocation to the cell membrane (the 'eat-me' signal), thereby promoting immune evasion in colorectal cancer.\",\n      \"method\": \"Co-IP (STC1–CRT interaction), Western blotting for phospho-STC1(Thr86), cell surface CRT assay, gain/loss-of-function studies, in vivo mouse model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein-protein interaction, phosphorylation site identification, cell surface trafficking assay, in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37607946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STC1 competes with YAP for binding to βPIX within its KER domain in melanoma cells; competitive binding displaces YAP from βPIX, leading to YAP nuclear translocation and activation, which drives CCL2 upregulation. CCL2-recruited M2 macrophages secrete VEGFA, which activates AKT signaling in melanoma cells to further increase STC1 expression, forming a pro-metastatic feedback loop. STC1-induced YAP activation also increases PD-L1 expression.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation (STC1–βPIX, YAP–βPIX), Dual-luciferase reporter assay (CCL2 promoter), ChIP (YAP at CCL2 promoter), in vivo lung metastasis model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, Co-IP, ChIP, reporter assay, in vivo model), single lab\",\n      \"pmids\": [\"38768671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STC1 overexpression in cervical cancer cells activates NF-κB p65, inhibiting cell proliferation and invasion; NF-κB p65 protein directly binds the STC1 promoter and activates STC1 expression (as confirmed by ChIP and reporter assay), establishing a regulatory loop.\",\n      \"method\": \"shRNA knockdown, STC1 overexpression, ChIP (NF-κB p65 at STC1 promoter), luciferase reporter assay, cell proliferation and invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assay performed but mechanistic dissection is limited; single lab, single study\",\n      \"pmids\": [\"23382863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STC1 overexpression in hepatocellular carcinoma cells inhibits the p70S6K/phospho-rpS6 signaling pathway, reduces cellular ATP levels, activates AMPK, and shifts cellular energy metabolism toward lower glycolysis and oxygen consumption rates, thereby reducing tumor growth in a xenograft model.\",\n      \"method\": \"Lentiviral STC1 overexpression, Western blotting (p-rpS6, p70S6K, p-AMPK), ATP measurement, Seahorse metabolic flux analysis (glycolysis/OCR), xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative Western blots with metabolic readouts; no direct biochemical link between STC1 and p70S6K established; single lab\",\n      \"pmids\": [\"29467934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A methylation increases the mRNA stability of STC1 (and GDF6) in dental pulp stem cells, promoting dentinogenesis differentiation; METTL3 knockdown impairs differentiation while overexpression promotes it.\",\n      \"method\": \"MeRIP-seq, RNA stability assay (actinomycin D chase), lentiviral METTL3 knockdown/overexpression, ALP/alizarin red staining, direct pulp capping rat model\",\n      \"journal\": \"BMC oral health\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MeRIP-seq identifies m6A on STC1 mRNA and stability assay confirms effect, but the downstream mechanism of STC1 in dentinogenesis is not resolved; single lab\",\n      \"pmids\": [\"37041485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PACAP induces STC1 gene expression in rat cortical neurons through cAMP and ERK1/2 signaling but not through canonical cAMP-dependent PKA; PACAP-mediated ERK1/2 activation occurs downstream of cAMP but independently of PKA, distinguishing this neuroprotective pathway from the canonical PKA-dependent cAMP pathway used for BDNF induction.\",\n      \"method\": \"PACAP receptor activation, pharmacological inhibitors (MEK/ERK inhibitor, PKA inhibitor H-89), cAMP and Ca2+ second messenger assays, STC1 mRNA quantification in cultured cortical neurons\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor-based pathway dissection, single lab, single study\",\n      \"pmids\": [\"21975601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STC1 (stanniocalcin-1) is a secreted glycoprotein that functions through multiple mechanisms: in fission yeast, the ortholog Stc1 physically bridges the RNAi effector Ago1 (via an N-terminal tandem zinc finger domain) and the CLRC histone methyltransferase complex (via its C-terminal region) to couple RNAi to H3K9 methylation and heterochromatin formation; in mammalian systems, STC1 acts on mitochondria to uncouple oxidative phosphorylation (increasing respiration while reducing ADP:O ratios) through a mechanism sensitive to nucleotide triphosphates and involving UCP2 upregulation, thereby reducing ROS and shifting metabolism toward glycolysis; extracellularly, STC1 binds specific high-affinity receptors on target cells (e.g., granulosa cells) to modulate steroidogenesis, and signals via inhibitory G-protein to suppress cAMP; in cancer contexts STC1 promotes metastasis through PDGF-dependent CAF activation, competes with YAP for βPIX binding to drive YAP nuclear translocation and downstream CCL2/VEGFA signaling, sequesters calreticulin in mitochondria to block immunogenic 'eat-me' signals, and binds Notch1 receptors to activate Notch-dependent stemness programs, while its own transcription is regulated epigenetically by CAPG/PRMT5 competition at its promoter and by m6A modification of upstream regulators.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STC1 is a secreted glycoprotein that acts at the cell surface and on mitochondria to modulate energy metabolism, calcium handling, and intercellular signaling, with prominent roles in the tumor microenvironment [#3, #4, #5]. Through high-affinity cell-surface receptors it engages inhibitory G-protein signaling to suppress cAMP and dampens FSH-stimulated steroidogenesis in granulosa cells, acting downstream of adenylate cyclase [#2, #12]. On isolated mitochondria STC1 uncouples oxidative phosphorylation\\u2014raising respiration while lowering ADP:O ratios and increasing Ca2+ uptake in a nucleotide-sensitive manner [#3]\\u2014and in cells it drives this effect by upregulating UCP2, thereby lowering ROS and shifting metabolism toward glycolysis [#4]. In cancer, stromal- and CAF-derived STC1 promotes metastasis downstream of PDGF receptor signaling [#5], and within tumor cells STC1 acts as a protein-protein competitor and scaffold: it competes with YAP for \\u03b2PIX binding to drive YAP nuclear translocation and CCL2/VEGFA signaling [#17], sequesters calreticulin in mitochondria to block the surface 'eat-me' signal and enable immune evasion (a function stabilized when A20 blocks GSK3\\u03b2-mediated phosphorylation at Thr86) [#16], and shapes macrophage differentiation by sequestering GRP94 [#14]. STC1's own expression is set transcriptionally and post-transcriptionally, including CAPG/PRMT5 competition at its promoter and m6A-dependent control of upstream regulators [#6, #7]. A mechanistically distinct activity is seen in fission yeast, where the Stc1 ortholog bridges the RNAi effector Ago1 to the CLRC histone methyltransferase complex to couple RNAi to H3K9 methylation and heterochromatin formation [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that STC1 is a secreted paracrine factor acting through specific cell-surface receptors, answering whether it signals on target endocrine cells; it suppresses FSH-stimulated steroidogenesis downstream of adenylate cyclase.\",\n      \"evidence\": \"Recombinant STC1 treatment of primary rat granulosa cells with radioligand receptor binding and steroid/cAMP readouts\",\n      \"pmids\": [\"15131261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor identity not molecularly defined\", \"Signaling step downstream of adenylate cyclase not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a direct mitochondrial action for STC1, showing it uncouples oxidative phosphorylation and enhances Ca2+ uptake in a nucleotide-regulated manner, locating part of its function at the organelle.\",\n      \"evidence\": \"Respiration and ADP:O assays plus 45Ca uptake and nucleotide-competition receptor binding on isolated rat mitochondria\",\n      \"pmids\": [\"17092635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target on/in mitochondria not identified\", \"Link between surface receptor binding and mitochondrial entry unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how RNAi is coupled to heterochromatin in fission yeast by showing the Stc1 ortholog physically bridges Ago1 and the CLRC complex, with tethering sufficient to silence.\",\n      \"evidence\": \"Co-IP, genetic epistasis, tethering assay, and H3K9me ChIP in fission yeast\",\n      \"pmids\": [\"20211136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of this nuclear chromatin role to mammalian secreted STC1 unclear\", \"Does not address mammalian function\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected STC1's mitochondrial uncoupling activity to a cellular effector, showing UCP2 upregulation mediates ROS reduction and a glycolytic shift that promotes cancer cell survival.\",\n      \"evidence\": \"UCP2 shRNA knockdown with recombinant STC1 rescue, ROS, membrane potential, and lactate assays in A549 cells\",\n      \"pmids\": [\"22146344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking STC1 receptor engagement to UCP2 transcription not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a stromal pro-metastatic role, placing STC1 downstream of PDGF receptor signaling in cancer-associated fibroblasts that drive tumor cell intravasation.\",\n      \"evidence\": \"Coculture invasion assays and STC1-deficient fibroblasts in an orthotopic mouse model\",\n      \"pmids\": [\"23243022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on tumor cells mediating the effect not identified\", \"Direct STC1 effector in invasion unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for the Stc1 bridge, showing an unusual N-terminal tandem zinc finger binds Ago1 while the C-terminus binds CLRC.\",\n      \"evidence\": \"NMR/structural analysis with deletion/mutagenesis and Co-IP in fission yeast\",\n      \"pmids\": [\"23613586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure pertains to the yeast ortholog, not mammalian STC1\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Began to define STC1's proximal signaling, indicating it acts through inhibitory G-protein to suppress cAMP in a receptor-specific manner.\",\n      \"evidence\": \"cAMP accumulation assays in calcitonin-receptor- vs CALCRL/RAMP1-transfected HEK293 cells and receptor immunofluorescence\",\n      \"pmids\": [\"25591908\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cell-based assay in transfected cells without direct STC1-receptor binding demonstration\", \"Endogenous receptor not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Explained how STC1 transcription is set epigenetically, showing CAPG displaces the repressor PRMT5 at the STC1 promoter to lower H4R3 methylation and boost expression.\",\n      \"evidence\": \"ChIP, luciferase reporter, Co-IP, HMT assay, and xenograft in breast cancer\",\n      \"pmids\": [\"29721098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across tissues not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended STC1 regulation to the m6A/RNA axis, showing AURKA-stabilized METTL14 promotes m6A of DROSHA, which with \\u03b2-Catenin transactivates STC1 to drive stemness.\",\n      \"evidence\": \"Co-IP, m6A analysis, RNA stability, ubiquitylation, and mutant rescue in breast cancer stem-like cells\",\n      \"pmids\": [\"32859993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STC1 contribution to stemness phenotype only inferred from upstream regulators\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a sequestration mechanism by which fibroblast STC1 suppresses macrophage maturation, proposing GRP94 sequestration to limit autocrine differentiation signals.\",\n      \"evidence\": \"Stc1 knockout mouse lung tumor models with macrophage differentiation assays and TGF-\\u03b21 measurement\",\n      \"pmids\": [\"32579928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GRP94 sequestration inferred rather than directly demonstrated biochemically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a calreticulin-sequestration mechanism of immune evasion, with STC1 retaining CRT in mitochondria, and a phospho-regulatory node (A20\\u2192GSK3\\u03b2\\u2192Thr86) controlling STC1 stability.\",\n      \"evidence\": \"Co-IP, phospho-STC1(Thr86) Western blots, cell-surface CRT assays, and in vivo colorectal cancer models\",\n      \"pmids\": [\"37607946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How STC1 enters/retains CRT in mitochondria mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed STC1 as a competitive scaffold, displacing YAP from \\u03b2PIX to drive YAP nuclear activation, CCL2/VEGFA signaling, and a pro-metastatic feedback loop with PD-L1 induction.\",\n      \"evidence\": \"MS, Co-IP (STC1\\u2013\\u03b2PIX, YAP\\u2013\\u03b2PIX), CCL2 reporter/ChIP, and in vivo lung metastasis model in melanoma\",\n      \"pmids\": [\"38768671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether secreted vs intracellular STC1 mediates \\u03b2PIX competition not clarified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the mammalian STC1 cell-surface receptor and the molecular link between extracellular receptor engagement and its intracellular/mitochondrial activities remain unresolved.\",\n      \"evidence\": \"No discovery in the corpus molecularly identifies the high-affinity STC1 receptor\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Receptor not cloned\", \"Mechanism of mitochondrial localization of a secreted protein undefined\", \"Reconciliation of yeast chromatin role with mammalian secreted roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [14, 16, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 12, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AGO1\", \"CRT\", \"ARHGEF7\", \"YAP1\", \"NOTCH1\", \"HSP90B1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}