{"gene":"CGA","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"ADCYAP1 (PACAP) stimulates Cga promoter activity in gonadotroph LβT2 cells via two parallel pathways: cAMP/PKA (acting through a CRE element) and MAPK3/1 (ERK1/2, acting through an SRE element). Both pathways are required for full Cga induction, as shown by inhibition with H89 (PKA inhibitor) and U0126 (MEK inhibitor) separately and in combination, with additive but not complete inhibition when combined.","method":"Luciferase reporter assay with Cga promoter constructs, pharmacological inhibition of PKA (H89, PKI) and MEK (U0126), constitutively active PKA transfection, measurement of cAMP accumulation and MAPK3/1 activation in gonadotroph LβT2 cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, pharmacological inhibitors, activated kinase constructs) in a single lab","pmids":["17596563"],"is_preprint":false},{"year":2015,"finding":"Thyroid hormone T3 negatively regulates CGA at multiple steps: it down-regulates Cga mRNA expression, inhibits association of Cga mRNA with ribosomes, and inhibits CGA secretion from pituitary thyrotrophs and gonadotrophs. Hypothyroidism increased Cga mRNA and its ribosomal association but paradoxically decreased intracellular CGA protein content; all were reversed by acute or chronic T3 treatment.","method":"Rat hypothyroidism model with acute and chronic T3 treatment; qRT-PCR for Cga mRNA; polysome fractionation to assess mRNA-ribosome association; measurement of intracellular CGA content and secretion by RIA/ELISA","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (mRNA quantification, polysome fractionation, secretion assay) in a single lab using in vivo model","pmids":["25869399"],"is_preprint":false},{"year":2012,"finding":"POU5F1 (OCT4) silences the CGA promoter by squelching ETS2: POU5F1 forms a complex with ETS2 that prevents ETS2 from binding the CGA promoter. DLX3 and ETS2 synergistically activate the CGA promoter ~100-fold when both bind the promoter simultaneously. POU5F1 disrupts the DLX3/ETS2 synergy. In human embryonic stem cells, ETS2 is sequestered in a soluble complex with POU5F1 away from the CGA promoter; upon BMP4-induced differentiation, POU5F1 levels fall and ETS2 occupies the CGA promoter.","method":"Luciferase reporter assays with CGA promoter mutations; co-immunoprecipitation of POU5F1-ETS2 complex; chromatin immunoprecipitation (ChIP) of ETS2 binding to CGA promoter in ES cells before and after BMP4 differentiation; co-transfection of DLX3, ETS2, and POU5F1 expression constructs","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, reporter mutagenesis, and functional complementation across multiple cell systems in one study","pmids":["22446105"],"is_preprint":false},{"year":2022,"finding":"Secreted CGA protein directly binds EGFR and activates EGFR downstream signaling, conferring chemoresistance in gastric cancer cells. N-glycosylation of CGA at Asn52 and Asn78 is required for CGA stability, secretion, and interaction with EGFR. GATA2 transcriptionally activates CGA, and CGA in turn induces GATA2 expression and phosphorylation in an EGFR-dependent manner, forming a positive feedback circuit. Anti-EGFR therapy or CGA knockdown (via miR-708-3p and miR-761) restored chemotherapy sensitivity.","method":"Co-immunoprecipitation of CGA with EGFR; site-directed mutagenesis of N-glycosylation sites (Asn52 and Asn78); conditioned media experiments; EGFR phosphorylation assays; ChIP for GATA2 on CGA promoter; luciferase reporter assays; miRNA overexpression; xenograft mouse models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, mutagenesis of glycosylation sites, ChIP, reporter assays, and in vivo validation across multiple orthogonal methods in one study","pmids":["35289315"],"is_preprint":false},{"year":2022,"finding":"L3MBTL2 (a component of ncPRC1.6) transcriptionally represses CGA through an H2AK119ub1-dependent mechanism. The MGA/MAX heterodimer binds an E-box on the CGA promoter and is required for selective L3MBTL2-mediated repression of CGA. Glycosylated CGA-T1 (the major CGA transcript product) inhibits pancreatic ductal adenocarcinoma (PDAC) progression partly by suppressing autophagy through the PI3K/Akt/mTOR and TP53INP2 pathways; this tumor-suppressive function depends on CGA glycosylation.","method":"ChIP for L3MBTL2 and H2AK119ub1 at the CGA promoter; L3MBTL2 knockdown/overexpression with CGA expression readout; MGA/MAX complex co-IP; CGA glycosylation mutants; autophagy flux assays; PI3K/Akt/mTOR pathway western blotting; PDAC cell proliferation and tumor growth assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, glycosylation mutagenesis, and pathway assays in a single lab","pmids":["35521536"],"is_preprint":false},{"year":2011,"finding":"A SNP (rs6631, T-to-A substitution) in the miR-1302 binding site within the 3' UTR of CGA reduces the binding affinity of miR-1302 and results in overexpression of CGA in vitro, as demonstrated by dual luciferase reporter assay. This SNP is associated with idiopathic male infertility (azoospermia/severe oligozoospermia).","method":"Dual luciferase reporter assay with wild-type and mutant CGA 3'UTR; case-control association study; computational miRNA binding site prediction","journal":"Fertility and sterility","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase reporter assay directly validating miR-1302 binding, single lab, single functional method","pmids":["21601192"],"is_preprint":false},{"year":2024,"finding":"miR-107 directly targets both CGA and GATA2 mRNAs, as validated by luciferase reporter assays. Overexpression of miR-107 in multidrug-resistant GC cells reduces CGA and GATA2 protein levels, inhibits EGFR downstream signaling (reduced ERK and AKT phosphorylation), and restores chemotherapy sensitivity in vitro and in vivo. This confirms CGA functions as an EGFR ligand upstream of ERK/AKT in the resistance circuit.","method":"Luciferase reporter assays with CGA and GATA2 3'UTR constructs; western blot for CGA, GATA2, p-ERK, p-AKT; cell viability assays with chemotherapeutic agents; intratumoral miR-107 injection in xenograft models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of miR-107 targeting, western blots, in vivo xenograft confirmation; single lab replicating and extending prior CGA/EGFR finding","pmids":["38960034"],"is_preprint":false}],"current_model":"CGA (glycoprotein hormone alpha subunit) is transcriptionally regulated by ERα, T3 (which represses Cga mRNA, its ribosomal loading, and its secretion), ADCYAP1/cAMP/PKA and MAPK3/1 signaling, and a POU5F1-squelching mechanism that sequesters the ETS2/DLX3 transcriptional activators; L3MBTL2 represses CGA via H2AK119ub1 in a MGA/MAX E-box-dependent manner. Beyond its classical role as a glycoprotein hormone subunit, secreted CGA acts as a direct ligand for EGFR (requiring N-glycosylation at Asn52/Asn78 for stability and interaction), activating EGFR/ERK/AKT signaling and forming a GATA2/CGA/EGFR positive feedback circuit that drives chemoresistance in gastric cancer; glycosylated CGA also suppresses autophagy via PI3K/Akt/mTOR and TP53INP2 pathways to inhibit pancreatic cancer progression."},"narrative":{"mechanistic_narrative":"CGA encodes the glycoprotein hormone alpha subunit, whose expression is integrated by multiple signaling and transcriptional inputs in pituitary gonadotrophs and thyrotrophs and is repurposed as a secreted signaling ligand in cancer [PMID:17596563, PMID:35289315]. In gonadotrophs, ADCYAP1 (PACAP) drives Cga promoter activity through two parallel and additive routes, cAMP/PKA acting via a CRE and MAPK3/1 (ERK1/2) acting via an SRE [PMID:17596563], while thyroid hormone T3 imposes negative control at several steps by lowering Cga mRNA, reducing its ribosomal loading, and suppressing CGA secretion [PMID:25869399]. Transcriptional activation requires DLX3 and ETS2 acting synergistically at the CGA promoter, an output that POU5F1 (OCT4) gates by sequestering ETS2 in a soluble complex away from the promoter until differentiation lowers POU5F1 and frees ETS2 to bind [PMID:22446105]; an opposing repressive arm operates through L3MBTL2 of ncPRC1.6, which deposits H2AK119ub1 at the CGA promoter in a manner dependent on MGA/MAX binding an E-box [PMID:35521536]. Beyond its classical hormone-subunit role, secreted CGA functions as a direct EGFR ligand: N-glycosylation at Asn52 and Asn78 is required for its stability, secretion, and EGFR binding, and CGA–EGFR engagement activates ERK and AKT signaling within a GATA2/CGA/EGFR positive-feedback circuit that drives chemoresistance in gastric cancer [PMID:35289315, PMID:38960034]. In pancreatic ductal adenocarcinoma, glycosylated CGA instead suppresses autophagy through PI3K/Akt/mTOR and TP53INP2 to restrain tumor progression, a function dependent on CGA glycosylation [PMID:35521536]. CGA expression is further tuned post-transcriptionally by miRNAs targeting its 3' UTR, including miR-107 (which co-targets GATA2), miR-708-3p/miR-761, and miR-1302, whose binding is reduced by the rs6631 polymorphism associated with idiopathic male infertility [PMID:35289315, PMID:21601192, PMID:38960034].","teleology":[{"year":2007,"claim":"Established how an upstream neuropeptide signal is transduced into CGA gene activation, defining two convergent kinase pathways rather than a single route.","evidence":"Luciferase reporter assays with Cga promoter constructs, PKA/MEK pharmacological inhibition, and activated kinase constructs in gonadotroph LβT2 cells","pmids":["17596563"],"confidence":"Medium","gaps":["Does not identify the transcription factors binding the CRE and SRE in vivo","Restricted to a single gonadotroph cell line","Endogenous Cga transcription not assayed beyond reporter constructs"]},{"year":2011,"claim":"Showed that CGA is under post-transcriptional miRNA control, with a 3' UTR variant altering miRNA binding and linking CGA dysregulation to a reproductive phenotype.","evidence":"Dual luciferase reporter assay of wild-type/mutant CGA 3'UTR plus case-control association in idiopathic male infertility","pmids":["21601192"],"confidence":"Medium","gaps":["miR-1302 regulation of endogenous CGA not demonstrated","Causal link between the SNP and infertility is associative","No in vivo confirmation"]},{"year":2012,"claim":"Defined the activating transcription-factor logic of the CGA promoter and how a stem-cell factor gates it, explaining why CGA is silent in pluripotency and induced on differentiation.","evidence":"Reciprocal Co-IP of POU5F1-ETS2, ChIP of ETS2 at the CGA promoter before/after BMP4 differentiation, and reporter mutagenesis with DLX3/ETS2/POU5F1 across cell systems","pmids":["22446105"],"confidence":"High","gaps":["Does not connect the DLX3/ETS2 axis to the CRE/SRE signaling inputs","Squelching mechanism studied in ES-cell context only","Stoichiometry of the POU5F1-ETS2 complex not resolved"]},{"year":2015,"claim":"Demonstrated that CGA is negatively regulated by thyroid hormone at transcriptional, translational, and secretory levels, revealing multi-step control rather than simple transcriptional repression.","evidence":"Rat hypothyroidism model with T3 treatment, qRT-PCR, polysome fractionation, and CGA secretion/content assays","pmids":["25869399"],"confidence":"Medium","gaps":["Molecular mediators of T3 repression at each step not identified","Paradoxical drop in intracellular CGA in hypothyroidism unexplained mechanistically","Findings in rat pituitary not validated in human cells"]},{"year":2022,"claim":"Reframed secreted CGA as a direct EGFR ligand and uncovered a self-reinforcing transcriptional circuit driving chemoresistance, a function distinct from its classical hormone-subunit role.","evidence":"CGA-EGFR Co-IP, N-glycosylation site mutagenesis (Asn52/Asn78), conditioned media, GATA2 ChIP/reporter assays, miRNA knockdown, and xenografts in gastric cancer","pmids":["35289315"],"confidence":"High","gaps":["Structural basis of CGA-EGFR binding not resolved","Whether CGA acts as a monomer or with a beta partner in this context unaddressed","Generality across EGFR-driven cancers not established"]},{"year":2022,"claim":"Identified an epigenetic repressor of CGA and showed a context-dependent tumor-suppressive function, contrasting with the oncogenic gastric-cancer circuit.","evidence":"ChIP for L3MBTL2/H2AK119ub1 at the CGA promoter, MGA/MAX Co-IP, CGA glycosylation mutants, and autophagy/PI3K-Akt-mTOR assays in PDAC cells","pmids":["35521536"],"confidence":"Medium","gaps":["Why CGA is tumor-suppressive in PDAC yet oncogenic in gastric cancer not reconciled","Direct receptor for CGA in the autophagy-suppressing role not identified","Single-lab pathway evidence"]},{"year":2024,"claim":"Confirmed CGA's position upstream of ERK/AKT in the resistance circuit by identifying a single miRNA that co-targets CGA and GATA2 to dismantle the feedback loop.","evidence":"Luciferase validation of miR-107 targeting CGA and GATA2 3'UTRs, western blots for p-ERK/p-AKT, viability assays, and intratumoral miR-107 xenograft injection","pmids":["38960034"],"confidence":"Medium","gaps":["Does not establish endogenous miR-107 regulation under physiological conditions","Clinical translatability of miR-107 delivery not demonstrated","Relative contribution of CGA vs GATA2 targeting not dissected"]},{"year":null,"claim":"How the divergent CGA functions—classical glycoprotein hormone subunit versus secreted EGFR ligand versus autophagy-modulating tumor suppressor—are partitioned across tissues and what determines this context dependence remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking transcriptional inputs to functional output","Structural determinants of CGA-EGFR engagement uncharacterized","Tissue-specific glycosylation requirements not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,6]}],"complexes":[],"partners":["EGFR","GATA2","ETS2","DLX3","POU5F1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P01215","full_name":"Glycoprotein hormones alpha chain","aliases":["Anterior pituitary glycoprotein hormones common subunit alpha","Choriogonadotropin alpha chain","Chorionic gonadotrophin subunit alpha","CG-alpha","Follicle-stimulating hormone alpha chain","FSH-alpha","Follitropin alpha chain","Luteinizing hormone alpha chain","LSH-alpha","Lutropin alpha chain","Thyroid-stimulating hormone alpha chain","TSH-alpha","Thyrotropin alpha chain"],"length_aa":116,"mass_kda":13.1,"function":"Shared alpha chain of the active heterodimeric glycoprotein hormones thyrotropin/thyroid stimulating hormone/TSH, lutropin/luteinizing hormone/LH, follitropin/follicle stimulating hormone/FSH and choriogonadotropin/CG. These hormones bind specific receptors on target cells that in turn activate downstream signaling pathways","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P01215/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CGA","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/CGA","total_profiled":1310},"omim":[{"mim_id":"618412","title":"GLOBAL DEVELOPMENTAL DELAY, PROGRESSIVE ATAXIA, AND ELEVATED GLUTAMINE; GDPAG","url":"https://www.omim.org/entry/618412"},{"mim_id":"614873","title":"PEROXISOME BIOGENESIS DISORDER 7B; PBD7B","url":"https://www.omim.org/entry/614873"},{"mim_id":"614872","title":"PEROXISOME BIOGENESIS DISORDER 7A (ZELLWEGER); PBD7A","url":"https://www.omim.org/entry/614872"},{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"613890","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 2; HSD3B2","url":"https://www.omim.org/entry/613890"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pituitary gland","ntpm":6387.3}],"url":"https://www.proteinatlas.org/search/CGA"},"hgnc":{"alias_symbol":["HCG","GPHa","GPHA1","FSHA","LHA","TSHA","GPA1"],"prev_symbol":[]},"alphafold":{"accession":"P01215","domains":[{"cath_id":"2.10.90.10","chopping":"29-116","consensus_level":"medium","plddt":94.7077,"start":29,"end":116}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01215","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01215-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01215-F1-predicted_aligned_error_v6.png","plddt_mean":91.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CGA","jax_strain_url":"https://www.jax.org/strain/search?query=CGA"},"sequence":{"accession":"P01215","fasta_url":"https://rest.uniprot.org/uniprotkb/P01215.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01215/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01215"}},"corpus_meta":[{"pmid":"11245479","id":"PMC_11245479","title":"Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11245479","citation_count":128,"is_preprint":false},{"pmid":"23160006","id":"PMC_23160006","title":"Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients.","date":"2012","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/23160006","citation_count":108,"is_preprint":false},{"pmid":"21669946","id":"PMC_21669946","title":"National survey of Escherichia coli causing extraintestinal infections reveals the spread of drug-resistant clonal groups O25b:H4-B2-ST131, O15:H1-D-ST393 and CGA-D-ST69 with high virulence gene content in Spain.","date":"2011","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/21669946","citation_count":107,"is_preprint":false},{"pmid":"23825054","id":"PMC_23825054","title":"Translation of CGA codon repeats in yeast involves quality control components and ribosomal protein L1.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23825054","citation_count":102,"is_preprint":false},{"pmid":"2877960","id":"PMC_2877960","title":"Chromogranin A (CGA) in the gastro-entero-pancreatic (GEP) endocrine system. 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esophagus.","date":"2017","source":"Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus","url":"https://pubmed.ncbi.nlm.nih.gov/28575250","citation_count":13,"is_preprint":false},{"pmid":"10490503","id":"PMC_10490503","title":"Implications of cytosine methylation on (+)-anti-Benzo[a]pyrene 7, 8-dihydrodiol 9,10-epoxide N(2)-dG adduct formation in 5'-d(CGT), 5'-d(CGA), and 5'-d(CGC) sequence contexts of single- and double-stranded oligonucleotides.","date":"1999","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/10490503","citation_count":12,"is_preprint":false},{"pmid":"17242462","id":"PMC_17242462","title":"Granulogenesis in non-neuroendocrine COS-7 cells induced by EGFP-tagged chromogranin A gene transfection: identical and distinct distribution of CgA and EGFP.","date":"2007","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/30269676","citation_count":10,"is_preprint":false},{"pmid":"30471181","id":"PMC_30471181","title":"Misdecoding of rare CGA codon by translation termination factors, eRF1/eRF3, suggests novel class of ribosome rescue pathway in S. cerevisiae.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30471181","citation_count":10,"is_preprint":false},{"pmid":"32380199","id":"PMC_32380199","title":"Chromogranin A (CGA)-derived polypeptide (CGA47-66) inhibits TNF-α-induced vascular endothelial hyper-permeability through SOC-related Ca2+ signaling.","date":"2020","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/32380199","citation_count":9,"is_preprint":false},{"pmid":"29627965","id":"PMC_29627965","title":"Association of T/A polymorphism in miR-1302 binding site in CGA gene with male infertility in Isfahan population.","date":"2018","source":"Molecular biology 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B, Analytical technologies in the biomedical and life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16891165","citation_count":7,"is_preprint":false},{"pmid":"37108287","id":"PMC_37108287","title":"Reduction in CgA-Derived CST Protein Level in HTR-8/SVneo and BeWo Trophoblastic Cell Lines Caused by the Preeclamptic Environment.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37108287","citation_count":6,"is_preprint":false},{"pmid":"31485132","id":"PMC_31485132","title":"Molecular modelling and docking of Mus musculus HMGB1 inflammatory protein with CGA.","date":"2019","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/31485132","citation_count":6,"is_preprint":false},{"pmid":"32169638","id":"PMC_32169638","title":"Assessing the cyto-genotoxic potential of model zinc oxide nanoparticles in the presence of humic-acid-like-polycondensate (HALP) and the leonardite HA (LHA).","date":"2020","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/32169638","citation_count":6,"is_preprint":false},{"pmid":"32348458","id":"PMC_32348458","title":"Effects of CGA-N12 on the membrane structure of Candida tropicalis cells.","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32348458","citation_count":6,"is_preprint":false},{"pmid":"1511524","id":"PMC_1511524","title":"Delayed changes of chromogranin A immunoreactivity (CgA ir) in human striate cortex during postnatal development.","date":"1992","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/1511524","citation_count":6,"is_preprint":false},{"pmid":"40147263","id":"PMC_40147263","title":"CGA protects against experimental colitis by modulating host purine metabolism through the gut microbiota.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40147263","citation_count":5,"is_preprint":false},{"pmid":"1724699","id":"PMC_1724699","title":"Influence of litter size on the RNA content of VMH and LHA in preweaning rats.","date":"1991","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/1724699","citation_count":5,"is_preprint":false},{"pmid":"36806932","id":"PMC_36806932","title":"The CGA codon decoding through tRNAArg (ICG) supply governed by Tad2/Tad3 in Saccharomyces cerevisiae.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36806932","citation_count":5,"is_preprint":false},{"pmid":"26215060","id":"PMC_26215060","title":"Increased plasma CgA levels associated with nonalcoholic fatty liver disease.","date":"2015","source":"The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26215060","citation_count":5,"is_preprint":false},{"pmid":"11004500","id":"PMC_11004500","title":"Identification of a novel human tRNA(Ser(CGA)) functional in murine leukemia virus replication.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11004500","citation_count":5,"is_preprint":false},{"pmid":"3625448","id":"PMC_3625448","title":"Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate.","date":"1987","source":"Journal of pharmacobio-dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/3625448","citation_count":5,"is_preprint":false},{"pmid":"7894031","id":"PMC_7894031","title":"Protein C deficiency found in a patient with acute myocardial infarction: a single base mutation 157 Arg (CGA) to stop codon (TGA).","date":"1994","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/7894031","citation_count":5,"is_preprint":false},{"pmid":"33955460","id":"PMC_33955460","title":"Internalization and membrane activity of the antimicrobial peptide CGA-N12.","date":"2021","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/33955460","citation_count":4,"is_preprint":false},{"pmid":"34171261","id":"PMC_34171261","title":"Establishing novel roles of bifidocin LHA, antibacterial, antibiofilm and immunomodulator against Pseudomonas aeruginosa corneal infection model.","date":"2021","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34171261","citation_count":4,"is_preprint":false},{"pmid":"38960034","id":"PMC_38960034","title":"miR-107 reverses the multidrug resistance of gastric cancer by targeting the CGA/EGFR/GATA2 positive feedback circuit.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38960034","citation_count":4,"is_preprint":false},{"pmid":"15293942","id":"PMC_15293942","title":"Two-triplet CGA repeats impede DNA replication in bacteriophage M13 in Escherichia coli.","date":"2004","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/15293942","citation_count":4,"is_preprint":false},{"pmid":"16398409","id":"PMC_16398409","title":"An Italian program of external quality control for chromogranin A (CgA) assay: state of the art of CgA measurement.","date":"2005","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/16398409","citation_count":4,"is_preprint":false},{"pmid":"35234144","id":"PMC_35234144","title":"The parallel-stranded d(CGA) duplex is a highly predictable structural motif with two conformationally distinct strands.","date":"2022","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/35234144","citation_count":4,"is_preprint":false},{"pmid":"8526863","id":"PMC_8526863","title":"Two different isoschizomers of the type-II restriction endonuclease Taq I (T/CGA) within the same Thermus isolate: Tsp32 I, an enzyme with similar heat stability properties to the prototype enzyme Taq I, and Tsp32 II, a hyperthermostable isoschizomer of Taq I.","date":"1995","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8526863","citation_count":4,"is_preprint":false},{"pmid":"35283254","id":"PMC_35283254","title":"The distribution of Dlx1-2 and glutamic acid decarboxylase in the embryonic and adult hypothalamus reveals three differentiated LHA subdivisions in rodents.","date":"2022","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/35283254","citation_count":3,"is_preprint":false},{"pmid":"30225006","id":"PMC_30225006","title":"5'-(CGA)  sequence-assisted pH-controlled assembly of supramolecular DNA nanostructure.","date":"2018","source":"Royal Society open science","url":"https://pubmed.ncbi.nlm.nih.gov/30225006","citation_count":3,"is_preprint":false},{"pmid":"8703976","id":"PMC_8703976","title":"Isolation of mitochondrial porin of the fly Protophormia: porin modification by the pesticide CGA 140'408 studied in lipid bilayer membranes.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8703976","citation_count":3,"is_preprint":false},{"pmid":"37206015","id":"PMC_37206015","title":"Preparation and characterization of FsHA/FsCol beads: Cell attachment and cytotoxicity studies.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37206015","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50364,"output_tokens":3229,"usd":0.099764,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9649,"output_tokens":3221,"usd":0.064385,"stage2_stop_reason":"end_turn"},"total_usd":0.164149,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical CGA gene (HGNC: CGA, encoding the alpha subunit of glycoprotein hormones, also known as GPHa/GPHA1/FSHA/LHA/TSHA/GPA1).\n\nLet me classify each paper:\n- Papers about CGA = glycoprotein hormone alpha subunit: PMIDs 11245479, 23160006 (no - CGA=comprehensive geriatric assessment), 2877960 (chromogranin A - different gene CHGA), 11342539 (chromogranin A - CHGA), 17596563, 25869399, 22446105, 35289315, 38960034, 521535, 21601192, 12180238\n- Many papers are about: Comprehensive Geriatric Assessment (CGA acronym), chromogranin A (CHGA gene - different gene), CGA codon (arginine codon), chlorogenic acid (CGA acronym), Chinese medicine formula CGA, etc.\n\nKey papers about the glycoprotein hormone alpha subunit (CGA gene):\n- PMID 17596563: ADCYAP1 signaling via cAMP/PKA and MAPK3/1 regulates Cga promoter activity\n- PMID 25869399: T3 regulates CGA synthesis/secretion\n- PMID 22446105: POU5F1 represses CGA via squelching ETS2; DLX3+ETS2 synergistically activate CGA\n- PMID 35289315: CGA binds EGFR, N-glycosylation required; GATA2/CGA/EGFR feedback circuit\n- PMID 38960034: miR-107 targets CGA and GATA2; CGA activates EGFR/ERK/AKT\n- PMID 21601192: SNP in miR-1302 binding site in CGA 3'UTR affects miR-1302 binding and CGA expression\n- PMID 52184: Not in list\n- PMID 12180238: CGA overexpression in ERα-positive prostate tumors (expression study)\n- PMID 11245479: CGA as ERα-responsive gene in breast cancer (expression study)\n- PMID 60521536: L3MBTL2 represses CGA via H2AK119ub1; glycosylated CGA-T1 inhibits autophagy via PI3K/Akt/mTOR\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ADCYAP1 (PACAP) stimulates Cga promoter activity in gonadotroph LβT2 cells via two parallel pathways: cAMP/PKA (acting through a CRE element) and MAPK3/1 (ERK1/2, acting through an SRE element). Both pathways are required for full Cga induction, as shown by inhibition with H89 (PKA inhibitor) and U0126 (MEK inhibitor) separately and in combination, with additive but not complete inhibition when combined.\",\n      \"method\": \"Luciferase reporter assay with Cga promoter constructs, pharmacological inhibition of PKA (H89, PKI) and MEK (U0126), constitutively active PKA transfection, measurement of cAMP accumulation and MAPK3/1 activation in gonadotroph LβT2 cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, pharmacological inhibitors, activated kinase constructs) in a single lab\",\n      \"pmids\": [\"17596563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Thyroid hormone T3 negatively regulates CGA at multiple steps: it down-regulates Cga mRNA expression, inhibits association of Cga mRNA with ribosomes, and inhibits CGA secretion from pituitary thyrotrophs and gonadotrophs. Hypothyroidism increased Cga mRNA and its ribosomal association but paradoxically decreased intracellular CGA protein content; all were reversed by acute or chronic T3 treatment.\",\n      \"method\": \"Rat hypothyroidism model with acute and chronic T3 treatment; qRT-PCR for Cga mRNA; polysome fractionation to assess mRNA-ribosome association; measurement of intracellular CGA content and secretion by RIA/ELISA\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (mRNA quantification, polysome fractionation, secretion assay) in a single lab using in vivo model\",\n      \"pmids\": [\"25869399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"POU5F1 (OCT4) silences the CGA promoter by squelching ETS2: POU5F1 forms a complex with ETS2 that prevents ETS2 from binding the CGA promoter. DLX3 and ETS2 synergistically activate the CGA promoter ~100-fold when both bind the promoter simultaneously. POU5F1 disrupts the DLX3/ETS2 synergy. In human embryonic stem cells, ETS2 is sequestered in a soluble complex with POU5F1 away from the CGA promoter; upon BMP4-induced differentiation, POU5F1 levels fall and ETS2 occupies the CGA promoter.\",\n      \"method\": \"Luciferase reporter assays with CGA promoter mutations; co-immunoprecipitation of POU5F1-ETS2 complex; chromatin immunoprecipitation (ChIP) of ETS2 binding to CGA promoter in ES cells before and after BMP4 differentiation; co-transfection of DLX3, ETS2, and POU5F1 expression constructs\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, reporter mutagenesis, and functional complementation across multiple cell systems in one study\",\n      \"pmids\": [\"22446105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Secreted CGA protein directly binds EGFR and activates EGFR downstream signaling, conferring chemoresistance in gastric cancer cells. N-glycosylation of CGA at Asn52 and Asn78 is required for CGA stability, secretion, and interaction with EGFR. GATA2 transcriptionally activates CGA, and CGA in turn induces GATA2 expression and phosphorylation in an EGFR-dependent manner, forming a positive feedback circuit. Anti-EGFR therapy or CGA knockdown (via miR-708-3p and miR-761) restored chemotherapy sensitivity.\",\n      \"method\": \"Co-immunoprecipitation of CGA with EGFR; site-directed mutagenesis of N-glycosylation sites (Asn52 and Asn78); conditioned media experiments; EGFR phosphorylation assays; ChIP for GATA2 on CGA promoter; luciferase reporter assays; miRNA overexpression; xenograft mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, mutagenesis of glycosylation sites, ChIP, reporter assays, and in vivo validation across multiple orthogonal methods in one study\",\n      \"pmids\": [\"35289315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"L3MBTL2 (a component of ncPRC1.6) transcriptionally represses CGA through an H2AK119ub1-dependent mechanism. The MGA/MAX heterodimer binds an E-box on the CGA promoter and is required for selective L3MBTL2-mediated repression of CGA. Glycosylated CGA-T1 (the major CGA transcript product) inhibits pancreatic ductal adenocarcinoma (PDAC) progression partly by suppressing autophagy through the PI3K/Akt/mTOR and TP53INP2 pathways; this tumor-suppressive function depends on CGA glycosylation.\",\n      \"method\": \"ChIP for L3MBTL2 and H2AK119ub1 at the CGA promoter; L3MBTL2 knockdown/overexpression with CGA expression readout; MGA/MAX complex co-IP; CGA glycosylation mutants; autophagy flux assays; PI3K/Akt/mTOR pathway western blotting; PDAC cell proliferation and tumor growth assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, glycosylation mutagenesis, and pathway assays in a single lab\",\n      \"pmids\": [\"35521536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A SNP (rs6631, T-to-A substitution) in the miR-1302 binding site within the 3' UTR of CGA reduces the binding affinity of miR-1302 and results in overexpression of CGA in vitro, as demonstrated by dual luciferase reporter assay. This SNP is associated with idiopathic male infertility (azoospermia/severe oligozoospermia).\",\n      \"method\": \"Dual luciferase reporter assay with wild-type and mutant CGA 3'UTR; case-control association study; computational miRNA binding site prediction\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase reporter assay directly validating miR-1302 binding, single lab, single functional method\",\n      \"pmids\": [\"21601192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-107 directly targets both CGA and GATA2 mRNAs, as validated by luciferase reporter assays. Overexpression of miR-107 in multidrug-resistant GC cells reduces CGA and GATA2 protein levels, inhibits EGFR downstream signaling (reduced ERK and AKT phosphorylation), and restores chemotherapy sensitivity in vitro and in vivo. This confirms CGA functions as an EGFR ligand upstream of ERK/AKT in the resistance circuit.\",\n      \"method\": \"Luciferase reporter assays with CGA and GATA2 3'UTR constructs; western blot for CGA, GATA2, p-ERK, p-AKT; cell viability assays with chemotherapeutic agents; intratumoral miR-107 injection in xenograft models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of miR-107 targeting, western blots, in vivo xenograft confirmation; single lab replicating and extending prior CGA/EGFR finding\",\n      \"pmids\": [\"38960034\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CGA (glycoprotein hormone alpha subunit) is transcriptionally regulated by ERα, T3 (which represses Cga mRNA, its ribosomal loading, and its secretion), ADCYAP1/cAMP/PKA and MAPK3/1 signaling, and a POU5F1-squelching mechanism that sequesters the ETS2/DLX3 transcriptional activators; L3MBTL2 represses CGA via H2AK119ub1 in a MGA/MAX E-box-dependent manner. Beyond its classical role as a glycoprotein hormone subunit, secreted CGA acts as a direct ligand for EGFR (requiring N-glycosylation at Asn52/Asn78 for stability and interaction), activating EGFR/ERK/AKT signaling and forming a GATA2/CGA/EGFR positive feedback circuit that drives chemoresistance in gastric cancer; glycosylated CGA also suppresses autophagy via PI3K/Akt/mTOR and TP53INP2 pathways to inhibit pancreatic cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CGA encodes the glycoprotein hormone alpha subunit, whose expression is integrated by multiple signaling and transcriptional inputs in pituitary gonadotrophs and thyrotrophs and is repurposed as a secreted signaling ligand in cancer [#0, #3]. In gonadotrophs, ADCYAP1 (PACAP) drives Cga promoter activity through two parallel and additive routes, cAMP/PKA acting via a CRE and MAPK3/1 (ERK1/2) acting via an SRE [#0], while thyroid hormone T3 imposes negative control at several steps by lowering Cga mRNA, reducing its ribosomal loading, and suppressing CGA secretion [#1]. Transcriptional activation requires DLX3 and ETS2 acting synergistically at the CGA promoter, an output that POU5F1 (OCT4) gates by sequestering ETS2 in a soluble complex away from the promoter until differentiation lowers POU5F1 and frees ETS2 to bind [#2]; an opposing repressive arm operates through L3MBTL2 of ncPRC1.6, which deposits H2AK119ub1 at the CGA promoter in a manner dependent on MGA/MAX binding an E-box [#4]. Beyond its classical hormone-subunit role, secreted CGA functions as a direct EGFR ligand: N-glycosylation at Asn52 and Asn78 is required for its stability, secretion, and EGFR binding, and CGA–EGFR engagement activates ERK and AKT signaling within a GATA2/CGA/EGFR positive-feedback circuit that drives chemoresistance in gastric cancer [#3, #6]. In pancreatic ductal adenocarcinoma, glycosylated CGA instead suppresses autophagy through PI3K/Akt/mTOR and TP53INP2 to restrain tumor progression, a function dependent on CGA glycosylation [#4]. CGA expression is further tuned post-transcriptionally by miRNAs targeting its 3' UTR, including miR-107 (which co-targets GATA2), miR-708-3p/miR-761, and miR-1302, whose binding is reduced by the rs6631 polymorphism associated with idiopathic male infertility [#3, #5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established how an upstream neuropeptide signal is transduced into CGA gene activation, defining two convergent kinase pathways rather than a single route.\",\n      \"evidence\": \"Luciferase reporter assays with Cga promoter constructs, PKA/MEK pharmacological inhibition, and activated kinase constructs in gonadotroph LβT2 cells\",\n      \"pmids\": [\"17596563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transcription factors binding the CRE and SRE in vivo\", \"Restricted to a single gonadotroph cell line\", \"Endogenous Cga transcription not assayed beyond reporter constructs\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that CGA is under post-transcriptional miRNA control, with a 3' UTR variant altering miRNA binding and linking CGA dysregulation to a reproductive phenotype.\",\n      \"evidence\": \"Dual luciferase reporter assay of wild-type/mutant CGA 3'UTR plus case-control association in idiopathic male infertility\",\n      \"pmids\": [\"21601192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"miR-1302 regulation of endogenous CGA not demonstrated\", \"Causal link between the SNP and infertility is associative\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the activating transcription-factor logic of the CGA promoter and how a stem-cell factor gates it, explaining why CGA is silent in pluripotency and induced on differentiation.\",\n      \"evidence\": \"Reciprocal Co-IP of POU5F1-ETS2, ChIP of ETS2 at the CGA promoter before/after BMP4 differentiation, and reporter mutagenesis with DLX3/ETS2/POU5F1 across cell systems\",\n      \"pmids\": [\"22446105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not connect the DLX3/ETS2 axis to the CRE/SRE signaling inputs\", \"Squelching mechanism studied in ES-cell context only\", \"Stoichiometry of the POU5F1-ETS2 complex not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that CGA is negatively regulated by thyroid hormone at transcriptional, translational, and secretory levels, revealing multi-step control rather than simple transcriptional repression.\",\n      \"evidence\": \"Rat hypothyroidism model with T3 treatment, qRT-PCR, polysome fractionation, and CGA secretion/content assays\",\n      \"pmids\": [\"25869399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediators of T3 repression at each step not identified\", \"Paradoxical drop in intracellular CGA in hypothyroidism unexplained mechanistically\", \"Findings in rat pituitary not validated in human cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed secreted CGA as a direct EGFR ligand and uncovered a self-reinforcing transcriptional circuit driving chemoresistance, a function distinct from its classical hormone-subunit role.\",\n      \"evidence\": \"CGA-EGFR Co-IP, N-glycosylation site mutagenesis (Asn52/Asn78), conditioned media, GATA2 ChIP/reporter assays, miRNA knockdown, and xenografts in gastric cancer\",\n      \"pmids\": [\"35289315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CGA-EGFR binding not resolved\", \"Whether CGA acts as a monomer or with a beta partner in this context unaddressed\", \"Generality across EGFR-driven cancers not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an epigenetic repressor of CGA and showed a context-dependent tumor-suppressive function, contrasting with the oncogenic gastric-cancer circuit.\",\n      \"evidence\": \"ChIP for L3MBTL2/H2AK119ub1 at the CGA promoter, MGA/MAX Co-IP, CGA glycosylation mutants, and autophagy/PI3K-Akt-mTOR assays in PDAC cells\",\n      \"pmids\": [\"35521536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why CGA is tumor-suppressive in PDAC yet oncogenic in gastric cancer not reconciled\", \"Direct receptor for CGA in the autophagy-suppressing role not identified\", \"Single-lab pathway evidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed CGA's position upstream of ERK/AKT in the resistance circuit by identifying a single miRNA that co-targets CGA and GATA2 to dismantle the feedback loop.\",\n      \"evidence\": \"Luciferase validation of miR-107 targeting CGA and GATA2 3'UTRs, western blots for p-ERK/p-AKT, viability assays, and intratumoral miR-107 xenograft injection\",\n      \"pmids\": [\"38960034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish endogenous miR-107 regulation under physiological conditions\", \"Clinical translatability of miR-107 delivery not demonstrated\", \"Relative contribution of CGA vs GATA2 targeting not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the divergent CGA functions—classical glycoprotein hormone subunit versus secreted EGFR ligand versus autophagy-modulating tumor suppressor—are partitioned across tissues and what determines this context dependence remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking transcriptional inputs to functional output\", \"Structural determinants of CGA-EGFR engagement uncharacterized\", \"Tissue-specific glycosylation requirements not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EGFR\", \"GATA2\", \"ETS2\", \"DLX3\", \"POU5F1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}