{"gene":"GNG7","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2008,"finding":"GNG7 expression is suppressed in esophageal cancer through loss of heterozygosity (LOH) and promoter hypermethylation, and miR-328 was identified as a potential regulator of GNG7 expression in esophageal cancer cell lines.","method":"TaqMan qRT-PCR, LOH analysis, promoter methylation assay, microRNA correlation analysis","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple methods but correlative; no direct functional rescue of methylation/LOH on GNG7 expression","pmids":["18219292"],"is_preprint":false},{"year":2019,"finding":"GNG7 silencing activates the mTOR signaling pathway (evidenced by increased phosphorylation of 4E-BP1, p70S6K, and mTOR), enhancing proliferation and differentiation while inhibiting apoptosis of placental cytotrophoblasts in a rat preeclampsia model, indicating GNG7 acts as a negative regulator of mTOR.","method":"siRNA knockdown, cell proliferation/apoptosis assays, western blot for mTOR pathway components, pharmacological activation (HIV-1 Tat) and inhibition (rapamycin) of mTOR","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple orthogonal methods (KD, pharmacological rescue, pathway readouts)","pmids":["30864685"],"is_preprint":false},{"year":2020,"finding":"FOXP1 directly restrains GNG7 expression and promotes the mTOR pathway; miR-183 suppresses FOXP1, leading to elevated GNG7 and impaired trophoblast migration, invasion, and angiogenesis in preeclampsia.","method":"Gain- and loss-of-function experiments, luciferase reporter assay (implied), RT-qPCR, western blot, functional cell assays (migration, invasion, angiogenesis), in vivo PE model","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with functional gain/loss-of-function and pathway readouts; FOXP1→GNG7 axis established by rescue experiments","pmids":["33139493"],"is_preprint":false},{"year":2021,"finding":"GNG7 overexpression inhibits proliferation and invasion of lung adenocarcinoma cells and tumor formation in vivo by suppressing Hedgehog signaling activation; miR-19b-3p directly targets GNG7 mRNA to promote LUAD progression.","method":"RT-qPCR, western blot, IHC, cell proliferation/invasion assays, mouse xenograft, bioinformatics, rescue experiments with GNG7 re-introduction","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 — KD/OE with defined phenotype and pathway placement (Hedgehog signaling), rescue experiments","pmids":["34635014"],"is_preprint":false},{"year":2021,"finding":"miR-146a indirectly downregulates GNG7 in sebocytes; GNG7 inhibition increases lipid content and decreases proliferation of SZ95 sebocytes, placing GNG7 downstream of miR-146a in the regulation of sebocyte lipid production and proliferation.","method":"miR-146a mimic/inhibitor treatment, gene expression profiling, in situ hybridization, GNG7 siRNA knockdown, lipid content assay, proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple orthogonal methods (ISH, KD, lipid/proliferation phenotypic readouts)","pmids":["34728702"],"is_preprint":false},{"year":2021,"finding":"CDR1as functions as a sponge for miR-876-5p, thereby upregulating GNG7 expression and suppressing gastric cancer cell migration, invasion, and EMT (evidenced by changes in EMT-associated proteins, MMP2, and MMP9).","method":"Dual-luciferase reporter assay, western blot, RT-qPCR, migration/invasion assays, functional rescue experiments, in vivo xenograft","journal":"Gastroenterology research and practice","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase validation of miR-876-5p/GNG7 interaction, rescue experiments establishing pathway","pmids":["34221006"],"is_preprint":false},{"year":2022,"finding":"LINC01526 interacts with TARBP2 protein to induce GNG7 mRNA decay, thereby promoting gastric cancer cell proliferation and migration; downregulation of GNG7 partially rescues the anti-proliferative effect of LINC01526 silencing.","method":"RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, rescue assay, cell proliferation/migration assays, in vivo xenograft","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — RIP demonstrated LINC01526-TARBP2 interaction; mRNA stability and rescue experiments link to GNG7","pmids":["36230863"],"is_preprint":false},{"year":2023,"finding":"FOXO3A directly binds to the promoter of GNG7 to maintain its expression; GNG7 protein interacts with mTOR and restricts phosphorylated (activated) mTOR; FOXO3A deficiency reduces GNG7 levels, relieving mTOR inhibition and causing adaptive mTOR reactivation in AML cells.","method":"ChIP (FOXO3A binding to GNG7 promoter), Co-immunoprecipitation (GNG7-mTOR interaction), western blot for phospho-mTOR, shRNA/siRNA knockdown, in vivo AML mouse model and PDX model","journal":"Genes & diseases","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP establishes direct transcriptional regulation, Co-IP establishes GNG7-mTOR physical interaction, multiple functional readouts in vitro and in vivo","pmids":["37588187"],"is_preprint":false},{"year":2024,"finding":"GNG7 physically interacts with RSPO3 (identified by Co-IP and LC-MS/MS); RSPO3 signals through GNG7 to phosphorylate Akt and GSK-3β and upregulate β-catenin, promoting gastric cancer stem cell properties; GNG7 knockdown blocks RSPO3-induced β-catenin activation and stemness.","method":"Co-immunoprecipitation, LC-MS/MS, western blot for p-Akt, p-GSK-3β, β-catenin, siRNA knockdown of GNG7, spheroid formation assay, in vivo peritoneal seeding model, IHC","journal":"Cancer medicine","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP/MS identifies GNG7 as RSPO3 binding partner; mechanistic epistasis shown by GNG7 KD blocking RSPO3 signaling; multiple orthogonal methods","pmids":["38581123"],"is_preprint":false},{"year":2025,"finding":"GNG7 suppresses mTOR pathway phosphorylation and thereby inhibits aerobic glycolysis in colorectal cancer cells; CAF-derived extracellular vesicles deliver miR-6765-3p that directly targets the 3'-UTR of GNG7 mRNA, reducing GNG7 expression and activating the mTOR pathway to promote aerobic glycolysis and cancer progression.","method":"Luciferase 3'-UTR reporter assay, GNG7 overexpression rescue, western blot for mTOR phosphorylation, aerobic glycolysis assays, in vivo tumor model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — 3'-UTR validation of miR-6765-3p/GNG7 interaction, GNG7 OE rescue, pathway (mTOR/glycolysis) mechanistic readouts","pmids":["41352746"],"is_preprint":false}],"current_model":"GNG7 encodes a G protein gamma 7 subunit that functions as a tumor suppressor by physically interacting with mTOR to restrict its phosphorylated activation, is transcriptionally maintained by FOXO3A, can interact with transmembrane proteins such as RSPO3 to modulate downstream β-catenin signaling, and is post-transcriptionally silenced in multiple cancers through miRNA-mediated mechanisms (miR-19b-3p, miR-876-5p, miR-146a, miR-6765-3p) and lncRNA/circRNA sponge axes, with its loss consistently leading to mTOR pathway hyperactivation, enhanced Hedgehog signaling, and increased aerobic glycolysis that promote tumor cell proliferation, invasion, and stemness."},"narrative":{"teleology":[{"year":2008,"claim":"The first evidence that GNG7 is epigenetically silenced in cancer was established by demonstrating LOH and promoter hypermethylation in esophageal carcinoma, raising the question of whether GNG7 loss has functional consequences.","evidence":"LOH analysis, promoter methylation assay, and qRT-PCR in esophageal cancer cell lines and tissues","pmids":["18219292"],"confidence":"Medium","gaps":["No functional rescue to show methylation reversal restores GNG7 activity","miR-328 regulation correlative only","Mechanism by which GNG7 loss promotes cancer not addressed"]},{"year":2019,"claim":"GNG7 was placed mechanistically as a negative regulator of the mTOR pathway, answering the question of which signaling axis it controls: siRNA-mediated GNG7 silencing increased phosphorylation of mTOR, 4E-BP1, and p70S6K, and this was reversed by rapamycin.","evidence":"siRNA knockdown, western blot for mTOR pathway components, rapamycin rescue in rat trophoblast model","pmids":["30864685"],"confidence":"Medium","gaps":["Physical interaction between GNG7 and mTOR not yet demonstrated","Rat trophoblast context may not generalize to cancer","Upstream transcriptional control of GNG7 unknown"]},{"year":2020,"claim":"Upstream transcriptional control of GNG7 was partially resolved: FOXP1 represses GNG7 expression, and the miR-183/FOXP1 axis modulates GNG7 levels and mTOR-dependent trophoblast functions in preeclampsia.","evidence":"Gain/loss-of-function experiments, rescue experiments, functional cell assays in trophoblast model","pmids":["33139493"],"confidence":"Medium","gaps":["Direct FOXP1 binding to GNG7 promoter not shown by ChIP","Relevance to cancer suppressor function of GNG7 not tested","FOXO3A as an activator not yet identified"]},{"year":2021,"claim":"GNG7 was linked to Hedgehog pathway suppression in lung adenocarcinoma, broadening its downstream effector repertoire beyond mTOR, and miR-19b-3p was validated as a direct negative regulator of GNG7 mRNA.","evidence":"GNG7 overexpression/knockdown, Hedgehog pathway readouts, xenograft, rescue with GNG7 re-introduction","pmids":["34635014"],"confidence":"Medium","gaps":["Physical interaction between GNG7 and Hedgehog pathway components not shown","Whether mTOR and Hedgehog suppression are independent functions unclear"]},{"year":2021,"claim":"Two additional post-transcriptional silencing mechanisms were identified: miR-876-5p directly targets GNG7 in gastric cancer (sponged by CDR1as), and miR-146a indirectly reduces GNG7 in sebocytes, establishing that GNG7 is a convergent target of multiple miRNAs across tissues.","evidence":"Dual-luciferase reporter assays, miRNA mimic/inhibitor treatment, functional rescue, xenograft (gastric cancer); siRNA knockdown and lipid assays (sebocytes)","pmids":["34221006","34728702"],"confidence":"Medium","gaps":["miR-146a effect on GNG7 is indirect — intermediate unknown","Whether GNG7 loss in sebocytes operates through mTOR not tested"]},{"year":2022,"claim":"A non-miRNA post-transcriptional mechanism was identified: lncRNA LINC01526 recruits TARBP2 to GNG7 mRNA to accelerate its decay, providing the first evidence of RNA-binding-protein-mediated GNG7 silencing in gastric cancer.","evidence":"RNA immunoprecipitation for LINC01526-TARBP2 interaction, mRNA stability assay, rescue experiments, xenograft","pmids":["36230863"],"confidence":"Medium","gaps":["Structural basis of TARBP2 recognition of GNG7 mRNA unknown","Whether TARBP2 acts endonucleolytically or recruits decay machinery not resolved"]},{"year":2023,"claim":"Two key mechanistic questions were resolved: FOXO3A directly binds the GNG7 promoter (by ChIP), establishing the principal transcriptional activator, and GNG7 protein physically interacts with mTOR (by Co-IP), explaining how GNG7 restricts mTOR phosphorylation in AML.","evidence":"ChIP for FOXO3A at GNG7 promoter, Co-IP of GNG7-mTOR, phospho-mTOR western blot, shRNA knockdown, in vivo AML and PDX models","pmids":["37588187"],"confidence":"High","gaps":["Binding domain on mTOR not mapped","Whether GNG7 competes with Raptor/Rictor for mTOR binding unknown","Structural basis of GNG7-mTOR complex not resolved"]},{"year":2024,"claim":"GNG7 was found to physically interact with RSPO3 and relay Akt/GSK-3β/β-catenin signaling, revealing a second direct protein partner and a Wnt-related pro-stemness function, which paradoxically contrasts with its tumor-suppressive role via mTOR inhibition.","evidence":"Co-IP and LC-MS/MS identification of GNG7-RSPO3 interaction, epistasis by GNG7 knockdown blocking RSPO3-induced β-catenin, spheroid and in vivo peritoneal seeding models","pmids":["38581123"],"confidence":"High","gaps":["How the same protein simultaneously suppresses mTOR and promotes β-catenin is unreconciled","Whether Gβγ complex formation is required for RSPO3 interaction unknown","Context-dependent tumor-suppressive vs. oncogenic roles not resolved"]},{"year":2025,"claim":"The metabolic consequence of GNG7 loss was defined: GNG7 suppresses mTOR-driven aerobic glycolysis in colorectal cancer, and cancer-associated fibroblast-derived extracellular vesicles deliver miR-6765-3p to silence GNG7 in trans, linking tumor microenvironment communication to metabolic reprogramming.","evidence":"3′-UTR luciferase reporter for miR-6765-3p/GNG7, GNG7 overexpression rescue of glycolysis, in vivo tumor model","pmids":["41352746"],"confidence":"Medium","gaps":["Whether GNG7 affects glycolytic enzymes directly or solely via mTOR unknown","Single-study finding of EV-mediated miR-6765-3p delivery not independently replicated"]},{"year":null,"claim":"The structural basis of GNG7 interaction with mTOR and RSPO3, the requirement for Gβ dimerization in these interactions, and how GNG7 simultaneously suppresses mTOR while facilitating β-catenin activation remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for GNG7-mTOR or GNG7-RSPO3 complexes","Role of canonical Gβγ heterodimerization in tumor-suppressive function not tested","Context-dependent pro- vs. anti-tumorigenic activities not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,9]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,7,8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,5,6,8,9]}],"complexes":[],"partners":["MTOR","RSPO3","TARBP2","FOXO3A","FOXP1"],"other_free_text":[]},"mechanistic_narrative":"GNG7 encodes the gamma-7 subunit of heterotrimeric G proteins and functions as a broadly acting tumor suppressor whose loss drives oncogenic signaling through multiple pathways. GNG7 physically interacts with mTOR to restrict its phosphorylation-dependent activation; FOXO3A directly binds the GNG7 promoter to maintain its expression, and loss of this axis causes adaptive mTOR reactivation that promotes aerobic glycolysis, proliferation, and survival in leukemia and colorectal cancer [PMID:37588187, PMID:41352746]. GNG7 also interacts with RSPO3 to relay Akt/GSK-3β/β-catenin signaling that sustains gastric cancer stemness, and its overexpression suppresses Hedgehog pathway activation in lung adenocarcinoma [PMID:38581123, PMID:34635014]. GNG7 is recurrently silenced in cancers through promoter hypermethylation, LOH, and post-transcriptional mechanisms including direct targeting by miR-19b-3p, miR-876-5p, and miR-6765-3p, as well as lncRNA/TARBP2-mediated mRNA decay [PMID:18219292, PMID:34635014, PMID:34221006, PMID:36230863, PMID:41352746]."},"prefetch_data":{"uniprot":{"accession":"O60262","full_name":"Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7","aliases":[],"length_aa":68,"mass_kda":7.5,"function":"Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Plays a role in the regulation of adenylyl cyclase signaling in certain regions of the brain. Plays a role in the formation or stabilization of a G protein heterotrimer (G(olf) subunit alpha-beta-gamma-7) that is required for adenylyl cyclase activity in the striatum (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60262/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GNG7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GNB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GNG7","total_profiled":1310},"omim":[{"mim_id":"615405","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, GAMMA-12; GNG12","url":"https://www.omim.org/entry/615405"},{"mim_id":"604430","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, GAMMA-7; GNG7","url":"https://www.omim.org/entry/604430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":421.2}],"url":"https://www.proteinatlas.org/search/GNG7"},"hgnc":{"alias_symbol":["FLJ00058"],"prev_symbol":[]},"alphafold":{"accession":"O60262","domains":[{"cath_id":"4.10.260.10","chopping":"1-46","consensus_level":"medium","plddt":94.2813,"start":1,"end":46}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60262","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60262-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60262-F1-predicted_aligned_error_v6.png","plddt_mean":90.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNG7","jax_strain_url":"https://www.jax.org/strain/search?query=GNG7"},"sequence":{"accession":"O60262","fasta_url":"https://rest.uniprot.org/uniprotkb/O60262.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60262/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60262"}},"corpus_meta":[{"pmid":"18219292","id":"PMC_18219292","title":"Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer.","date":"2008","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18219292","citation_count":59,"is_preprint":false},{"pmid":"30864685","id":"PMC_30864685","title":"GNG7 silencing promotes the proliferation and differentiation of placental cytotrophoblasts in preeclampsia rats through activation of the mTOR signaling pathway.","date":"2019","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30864685","citation_count":23,"is_preprint":false},{"pmid":"33139493","id":"PMC_33139493","title":"Elevated MicroRNA 183 Impairs Trophoblast Migration and Invasiveness by Downregulating FOXP1 Expression and Elevating GNG7 Expression during Preeclampsia.","date":"2020","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33139493","citation_count":22,"is_preprint":false},{"pmid":"33727922","id":"PMC_33727922","title":"Osthole Inhibits Breast Cancer Progression through Upregulating Tumor Suppressor GNG7.","date":"2021","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33727922","citation_count":21,"is_preprint":false},{"pmid":"34221006","id":"PMC_34221006","title":"Circular RNA CDR1as Inhibits the Metastasis of Gastric Cancer through Targeting miR-876-5p/GNG7 Axis.","date":"2021","source":"Gastroenterology research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/34221006","citation_count":20,"is_preprint":false},{"pmid":"34728702","id":"PMC_34728702","title":"miR-146a modulates TLR1/2 and 4 induced inflammation and links it with proliferation and lipid production via the indirect regulation of GNG7 in human SZ95 sebocytes.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34728702","citation_count":13,"is_preprint":false},{"pmid":"37588187","id":"PMC_37588187","title":"Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin.","date":"2023","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37588187","citation_count":11,"is_preprint":false},{"pmid":"34635014","id":"PMC_34635014","title":"MicroRNA miR-19b-3p mediated G protein γ subunit 7 (GNG7) loss contributes lung adenocarcinoma progression through activating Hedgehog signaling.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34635014","citation_count":8,"is_preprint":false},{"pmid":"36230863","id":"PMC_36230863","title":"LINC01526 Promotes Proliferation and Metastasis of Gastric Cancer by Interacting with TARBP2 to Induce GNG7 mRNA Decay.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36230863","citation_count":8,"is_preprint":false},{"pmid":"35240924","id":"PMC_35240924","title":"Long non-coding RNA LINC00472 inhibits oral squamous cell carcinoma via miR-4311/GNG7 axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35240924","citation_count":6,"is_preprint":false},{"pmid":"36092318","id":"PMC_36092318","title":"Circ_0007099 upregulates GNG7 to function as a tumor inhibitor in gastric carcinoma by interacting with miR-425-3p.","date":"2022","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36092318","citation_count":5,"is_preprint":false},{"pmid":"38581123","id":"PMC_38581123","title":"RSPO3 induced by Helicobacter pylori extracts promotes gastric cancer stem cell properties through the GNG7/β-catenin signaling pathway.","date":"2024","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38581123","citation_count":4,"is_preprint":false},{"pmid":"41352746","id":"PMC_41352746","title":"CAFs-EVs-miR-6765-3p promotes malignant progression of colorectal cancer by regulating aerobic glycolysis mediated by the GNG7/mTOR pathway.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41352746","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8117,"output_tokens":2549,"usd":0.031293},"stage2":{"model":"claude-opus-4-6","input_tokens":5882,"output_tokens":2601,"usd":0.141652},"total_usd":0.172945,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"GNG7 expression is suppressed in esophageal cancer through loss of heterozygosity (LOH) and promoter hypermethylation, and miR-328 was identified as a potential regulator of GNG7 expression in esophageal cancer cell lines.\",\n      \"method\": \"TaqMan qRT-PCR, LOH analysis, promoter methylation assay, microRNA correlation analysis\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple methods but correlative; no direct functional rescue of methylation/LOH on GNG7 expression\",\n      \"pmids\": [\"18219292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GNG7 silencing activates the mTOR signaling pathway (evidenced by increased phosphorylation of 4E-BP1, p70S6K, and mTOR), enhancing proliferation and differentiation while inhibiting apoptosis of placental cytotrophoblasts in a rat preeclampsia model, indicating GNG7 acts as a negative regulator of mTOR.\",\n      \"method\": \"siRNA knockdown, cell proliferation/apoptosis assays, western blot for mTOR pathway components, pharmacological activation (HIV-1 Tat) and inhibition (rapamycin) of mTOR\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple orthogonal methods (KD, pharmacological rescue, pathway readouts)\",\n      \"pmids\": [\"30864685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXP1 directly restrains GNG7 expression and promotes the mTOR pathway; miR-183 suppresses FOXP1, leading to elevated GNG7 and impaired trophoblast migration, invasion, and angiogenesis in preeclampsia.\",\n      \"method\": \"Gain- and loss-of-function experiments, luciferase reporter assay (implied), RT-qPCR, western blot, functional cell assays (migration, invasion, angiogenesis), in vivo PE model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with functional gain/loss-of-function and pathway readouts; FOXP1→GNG7 axis established by rescue experiments\",\n      \"pmids\": [\"33139493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNG7 overexpression inhibits proliferation and invasion of lung adenocarcinoma cells and tumor formation in vivo by suppressing Hedgehog signaling activation; miR-19b-3p directly targets GNG7 mRNA to promote LUAD progression.\",\n      \"method\": \"RT-qPCR, western blot, IHC, cell proliferation/invasion assays, mouse xenograft, bioinformatics, rescue experiments with GNG7 re-introduction\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with defined phenotype and pathway placement (Hedgehog signaling), rescue experiments\",\n      \"pmids\": [\"34635014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-146a indirectly downregulates GNG7 in sebocytes; GNG7 inhibition increases lipid content and decreases proliferation of SZ95 sebocytes, placing GNG7 downstream of miR-146a in the regulation of sebocyte lipid production and proliferation.\",\n      \"method\": \"miR-146a mimic/inhibitor treatment, gene expression profiling, in situ hybridization, GNG7 siRNA knockdown, lipid content assay, proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple orthogonal methods (ISH, KD, lipid/proliferation phenotypic readouts)\",\n      \"pmids\": [\"34728702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDR1as functions as a sponge for miR-876-5p, thereby upregulating GNG7 expression and suppressing gastric cancer cell migration, invasion, and EMT (evidenced by changes in EMT-associated proteins, MMP2, and MMP9).\",\n      \"method\": \"Dual-luciferase reporter assay, western blot, RT-qPCR, migration/invasion assays, functional rescue experiments, in vivo xenograft\",\n      \"journal\": \"Gastroenterology research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase validation of miR-876-5p/GNG7 interaction, rescue experiments establishing pathway\",\n      \"pmids\": [\"34221006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC01526 interacts with TARBP2 protein to induce GNG7 mRNA decay, thereby promoting gastric cancer cell proliferation and migration; downregulation of GNG7 partially rescues the anti-proliferative effect of LINC01526 silencing.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, rescue assay, cell proliferation/migration assays, in vivo xenograft\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP demonstrated LINC01526-TARBP2 interaction; mRNA stability and rescue experiments link to GNG7\",\n      \"pmids\": [\"36230863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXO3A directly binds to the promoter of GNG7 to maintain its expression; GNG7 protein interacts with mTOR and restricts phosphorylated (activated) mTOR; FOXO3A deficiency reduces GNG7 levels, relieving mTOR inhibition and causing adaptive mTOR reactivation in AML cells.\",\n      \"method\": \"ChIP (FOXO3A binding to GNG7 promoter), Co-immunoprecipitation (GNG7-mTOR interaction), western blot for phospho-mTOR, shRNA/siRNA knockdown, in vivo AML mouse model and PDX model\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP establishes direct transcriptional regulation, Co-IP establishes GNG7-mTOR physical interaction, multiple functional readouts in vitro and in vivo\",\n      \"pmids\": [\"37588187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GNG7 physically interacts with RSPO3 (identified by Co-IP and LC-MS/MS); RSPO3 signals through GNG7 to phosphorylate Akt and GSK-3β and upregulate β-catenin, promoting gastric cancer stem cell properties; GNG7 knockdown blocks RSPO3-induced β-catenin activation and stemness.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, western blot for p-Akt, p-GSK-3β, β-catenin, siRNA knockdown of GNG7, spheroid formation assay, in vivo peritoneal seeding model, IHC\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP/MS identifies GNG7 as RSPO3 binding partner; mechanistic epistasis shown by GNG7 KD blocking RSPO3 signaling; multiple orthogonal methods\",\n      \"pmids\": [\"38581123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GNG7 suppresses mTOR pathway phosphorylation and thereby inhibits aerobic glycolysis in colorectal cancer cells; CAF-derived extracellular vesicles deliver miR-6765-3p that directly targets the 3'-UTR of GNG7 mRNA, reducing GNG7 expression and activating the mTOR pathway to promote aerobic glycolysis and cancer progression.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, GNG7 overexpression rescue, western blot for mTOR phosphorylation, aerobic glycolysis assays, in vivo tumor model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'-UTR validation of miR-6765-3p/GNG7 interaction, GNG7 OE rescue, pathway (mTOR/glycolysis) mechanistic readouts\",\n      \"pmids\": [\"41352746\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNG7 encodes a G protein gamma 7 subunit that functions as a tumor suppressor by physically interacting with mTOR to restrict its phosphorylated activation, is transcriptionally maintained by FOXO3A, can interact with transmembrane proteins such as RSPO3 to modulate downstream β-catenin signaling, and is post-transcriptionally silenced in multiple cancers through miRNA-mediated mechanisms (miR-19b-3p, miR-876-5p, miR-146a, miR-6765-3p) and lncRNA/circRNA sponge axes, with its loss consistently leading to mTOR pathway hyperactivation, enhanced Hedgehog signaling, and increased aerobic glycolysis that promote tumor cell proliferation, invasion, and stemness.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GNG7 encodes the gamma-7 subunit of heterotrimeric G proteins and functions as a broadly acting tumor suppressor whose loss drives oncogenic signaling through multiple pathways. GNG7 physically interacts with mTOR to restrict its phosphorylation-dependent activation; FOXO3A directly binds the GNG7 promoter to maintain its expression, and loss of this axis causes adaptive mTOR reactivation that promotes aerobic glycolysis, proliferation, and survival in leukemia and colorectal cancer [PMID:37588187, PMID:41352746]. GNG7 also interacts with RSPO3 to relay Akt/GSK-3β/β-catenin signaling that sustains gastric cancer stemness, and its overexpression suppresses Hedgehog pathway activation in lung adenocarcinoma [PMID:38581123, PMID:34635014]. GNG7 is recurrently silenced in cancers through promoter hypermethylation, LOH, and post-transcriptional mechanisms including direct targeting by miR-19b-3p, miR-876-5p, and miR-6765-3p, as well as lncRNA/TARBP2-mediated mRNA decay [PMID:18219292, PMID:34635014, PMID:34221006, PMID:36230863, PMID:41352746].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The first evidence that GNG7 is epigenetically silenced in cancer was established by demonstrating LOH and promoter hypermethylation in esophageal carcinoma, raising the question of whether GNG7 loss has functional consequences.\",\n      \"evidence\": \"LOH analysis, promoter methylation assay, and qRT-PCR in esophageal cancer cell lines and tissues\",\n      \"pmids\": [\"18219292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue to show methylation reversal restores GNG7 activity\", \"miR-328 regulation correlative only\", \"Mechanism by which GNG7 loss promotes cancer not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"GNG7 was placed mechanistically as a negative regulator of the mTOR pathway, answering the question of which signaling axis it controls: siRNA-mediated GNG7 silencing increased phosphorylation of mTOR, 4E-BP1, and p70S6K, and this was reversed by rapamycin.\",\n      \"evidence\": \"siRNA knockdown, western blot for mTOR pathway components, rapamycin rescue in rat trophoblast model\",\n      \"pmids\": [\"30864685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction between GNG7 and mTOR not yet demonstrated\", \"Rat trophoblast context may not generalize to cancer\", \"Upstream transcriptional control of GNG7 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Upstream transcriptional control of GNG7 was partially resolved: FOXP1 represses GNG7 expression, and the miR-183/FOXP1 axis modulates GNG7 levels and mTOR-dependent trophoblast functions in preeclampsia.\",\n      \"evidence\": \"Gain/loss-of-function experiments, rescue experiments, functional cell assays in trophoblast model\",\n      \"pmids\": [\"33139493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FOXP1 binding to GNG7 promoter not shown by ChIP\", \"Relevance to cancer suppressor function of GNG7 not tested\", \"FOXO3A as an activator not yet identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"GNG7 was linked to Hedgehog pathway suppression in lung adenocarcinoma, broadening its downstream effector repertoire beyond mTOR, and miR-19b-3p was validated as a direct negative regulator of GNG7 mRNA.\",\n      \"evidence\": \"GNG7 overexpression/knockdown, Hedgehog pathway readouts, xenograft, rescue with GNG7 re-introduction\",\n      \"pmids\": [\"34635014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction between GNG7 and Hedgehog pathway components not shown\", \"Whether mTOR and Hedgehog suppression are independent functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two additional post-transcriptional silencing mechanisms were identified: miR-876-5p directly targets GNG7 in gastric cancer (sponged by CDR1as), and miR-146a indirectly reduces GNG7 in sebocytes, establishing that GNG7 is a convergent target of multiple miRNAs across tissues.\",\n      \"evidence\": \"Dual-luciferase reporter assays, miRNA mimic/inhibitor treatment, functional rescue, xenograft (gastric cancer); siRNA knockdown and lipid assays (sebocytes)\",\n      \"pmids\": [\"34221006\", \"34728702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"miR-146a effect on GNG7 is indirect — intermediate unknown\", \"Whether GNG7 loss in sebocytes operates through mTOR not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-miRNA post-transcriptional mechanism was identified: lncRNA LINC01526 recruits TARBP2 to GNG7 mRNA to accelerate its decay, providing the first evidence of RNA-binding-protein-mediated GNG7 silencing in gastric cancer.\",\n      \"evidence\": \"RNA immunoprecipitation for LINC01526-TARBP2 interaction, mRNA stability assay, rescue experiments, xenograft\",\n      \"pmids\": [\"36230863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TARBP2 recognition of GNG7 mRNA unknown\", \"Whether TARBP2 acts endonucleolytically or recruits decay machinery not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two key mechanistic questions were resolved: FOXO3A directly binds the GNG7 promoter (by ChIP), establishing the principal transcriptional activator, and GNG7 protein physically interacts with mTOR (by Co-IP), explaining how GNG7 restricts mTOR phosphorylation in AML.\",\n      \"evidence\": \"ChIP for FOXO3A at GNG7 promoter, Co-IP of GNG7-mTOR, phospho-mTOR western blot, shRNA knockdown, in vivo AML and PDX models\",\n      \"pmids\": [\"37588187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domain on mTOR not mapped\", \"Whether GNG7 competes with Raptor/Rictor for mTOR binding unknown\", \"Structural basis of GNG7-mTOR complex not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"GNG7 was found to physically interact with RSPO3 and relay Akt/GSK-3β/β-catenin signaling, revealing a second direct protein partner and a Wnt-related pro-stemness function, which paradoxically contrasts with its tumor-suppressive role via mTOR inhibition.\",\n      \"evidence\": \"Co-IP and LC-MS/MS identification of GNG7-RSPO3 interaction, epistasis by GNG7 knockdown blocking RSPO3-induced β-catenin, spheroid and in vivo peritoneal seeding models\",\n      \"pmids\": [\"38581123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein simultaneously suppresses mTOR and promotes β-catenin is unreconciled\", \"Whether Gβγ complex formation is required for RSPO3 interaction unknown\", \"Context-dependent tumor-suppressive vs. oncogenic roles not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The metabolic consequence of GNG7 loss was defined: GNG7 suppresses mTOR-driven aerobic glycolysis in colorectal cancer, and cancer-associated fibroblast-derived extracellular vesicles deliver miR-6765-3p to silence GNG7 in trans, linking tumor microenvironment communication to metabolic reprogramming.\",\n      \"evidence\": \"3′-UTR luciferase reporter for miR-6765-3p/GNG7, GNG7 overexpression rescue of glycolysis, in vivo tumor model\",\n      \"pmids\": [\"41352746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GNG7 affects glycolytic enzymes directly or solely via mTOR unknown\", \"Single-study finding of EV-mediated miR-6765-3p delivery not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of GNG7 interaction with mTOR and RSPO3, the requirement for Gβ dimerization in these interactions, and how GNG7 simultaneously suppresses mTOR while facilitating β-catenin activation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for GNG7-mTOR or GNG7-RSPO3 complexes\", \"Role of canonical Gβγ heterodimerization in tumor-suppressive function not tested\", \"Context-dependent pro- vs. anti-tumorigenic activities not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 9]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 5, 6, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTOR\", \"RSPO3\", \"TARBP2\", \"FOXO3A\", \"FOXP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}