{"gene":"GNG7","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2023,"finding":"FOXO3A directly binds to the promoter of GNG7 and preserves its expression; GNG7 protein in turn interacts with mTOR and restricts phosphorylated (activated) mTOR. Loss of FOXO3A reduces GNG7 expression, thereby releasing mTOR suppression and causing adaptive resistance in AML cells.","method":"Chromatin immunoprecipitation (FOXO3A binding to GNG7 promoter), co-immunoprecipitation (GNG7–mTOR interaction), loss-of-function/rescue experiments, mouse AML model, patient-derived xenograft model","journal":"Genes & diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing GNG7–mTOR interaction, ChIP establishing direct FOXO3A→GNG7 transcriptional regulation, functional epistasis in cell lines and two in vivo models in a single rigorous study","pmids":["37588187"],"is_preprint":false},{"year":2024,"finding":"GNG7 is a transmembrane binding partner of RSPO3; Co-IP and LC-MS/MS confirmed direct physical interaction. RSPO3 increases phosphorylation of Akt and GSK-3β and stabilises β-catenin to promote gastric cancer stem-cell properties, and this effect is blocked by GNG7 knockdown, placing GNG7 upstream of the Akt/GSK-3β/β-catenin axis in this pathway.","method":"Co-immunoprecipitation + LC-MS/MS (RSPO3–GNG7 interaction), siRNA knockdown of GNG7 with rescue of β-catenin/Akt/GSK-3β phosphorylation, spheroid-formation and in vivo peritoneal-seeding assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus MS identification of GNG7 as RSPO3 interactor, functional epistasis with knockdown and in vivo model, single lab","pmids":["38581123"],"is_preprint":false},{"year":2026,"finding":"H3K18 lactylation suppresses GNG7 transcription: ChIP-qPCR showed elevated H3K18la enrichment at the GNG7 promoter in bladder cancer cells, correlating with reduced GNG7 expression. Overexpression of GNG7 inhibited PI3K-AKT pathway activation and reduced glycolysis and tumor growth.","method":"ChIP-qPCR (H3K18la at GNG7 promoter), GNG7 overexpression with Western blot for PI3K-AKT, glycolysis assays (glucose uptake, lactate production, ECAR), xenograft mouse model","journal":"World journal of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly linking epigenetic mark to GNG7 promoter, functional overexpression with pathway readout, single lab","pmids":["42163331"],"is_preprint":false},{"year":2021,"finding":"GNG7 overexpression in lung adenocarcinoma cells inhibits activation of Hedgehog signaling and suppresses proliferation and invasion in vitro and tumor formation in vivo. miR-19b-3p directly targets GNG7 (verified by reporter assay), and GNG7 re-introduction rescues miR-19b-3p-driven aggressive phenotypes.","method":"GNG7 gain-of-function (overexpression), Hedgehog pathway reporter/western blot, dual-luciferase miRNA target validation, xenograft assay","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase reporter confirms miR-19b-3p→GNG7 targeting, functional epistasis linking GNG7 to Hedgehog pathway, in vitro and in vivo, single lab","pmids":["34635014"],"is_preprint":false},{"year":2019,"finding":"GNG7 silencing in placental cytotrophoblasts activates the mTOR signaling pathway (increased phosphorylation of mTOR, p70S6K, 4E-BP1), enhances cell proliferation and differentiation, and inhibits apoptosis. Conversely, mTOR inhibition (rapamycin) blocks the pro-proliferative effects of GNG7 knockdown, establishing GNG7 as a negative regulator of mTOR in trophoblasts.","method":"siRNA knockdown of GNG7, mTOR pathway activator (HIV-1 Tat) and inhibitor (rapamycin) treatments, proliferation/apoptosis assays, Western blot for mTOR/p70S6K/4E-BP1, ELISA for sFlt-1/sEng","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with pharmacological epistasis (rapamycin rescue) confirming pathway placement, single lab","pmids":["30864685"],"is_preprint":false},{"year":2025,"finding":"CAF-derived extracellular vesicles transfer miR-6765-3p to colorectal cancer cells; miR-6765-3p directly targets the 3'-UTR of GNG7 (dual-luciferase assay), reducing GNG7 expression, which releases mTOR pathway inhibition and promotes aerobic glycolysis. GNG7 overexpression rescues mTOR phosphorylation suppression and reduces CRC progression.","method":"Dual-luciferase 3'-UTR reporter assay, GNG7 overexpression rescue, mTOR pathway Western blot, glycolysis assays, cellular and xenograft experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct 3'-UTR luciferase validation plus functional rescue, single lab","pmids":["41352746"],"is_preprint":false},{"year":2022,"finding":"LINC01526 interacts with TARBP2 and this complex decreases GNG7 mRNA stability, leading to GNG7 mRNA decay and enhanced gastric cancer proliferation and migration. Rescue experiments showed that GNG7 downregulation partially reversed the anti-proliferative effect of LINC01526 or TARBP2 silencing.","method":"RNA immunoprecipitation (LINC01526–TARBP2 interaction), mRNA stability assay, siRNA knockdown, functional rescue experiments in vitro and xenograft","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP confirming lncRNA–protein interaction with mRNA stability readout and epistasis rescue, single lab","pmids":["36230863"],"is_preprint":false},{"year":2021,"finding":"In sebocytes, miR-146a inversely regulates GNG7 expression (miR-146a inhibitor induces GNG7; miR-146a mimic suppresses GNG7). GNG7 inhibition in SZ95 sebocytes increases lipid content and decreases proliferation, indicating GNG7 restrains lipid production and promotes proliferation downstream of TLR1/2 and TLR4 signaling.","method":"miR-146a inhibitor/mimic treatment with gene expression profiling, GNG7 siRNA knockdown with lipid content and proliferation assays, in situ hybridization in acne tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotypes (lipid/proliferation), validated in tissue by ISH, single lab","pmids":["34728702"],"is_preprint":false},{"year":2008,"finding":"GNG7 overexpression in oesophageal cancer cells reduced tumour invasion in vitro and in vivo. GNG7 suppression in patient tumours was associated with promoter hypermethylation or loss of heterozygosity, establishing epigenetic silencing as a mechanism of GNG7 downregulation.","method":"GNG7 transfection/overexpression with invasion assays, LOH analysis, bisulfite sequencing/methylation-specific PCR for promoter hypermethylation","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function invasion assay with direct epigenetic mechanism (methylation/LOH) demonstrated, single lab","pmids":["18219292"],"is_preprint":false}],"current_model":"GNG7 encodes the gamma-7 subunit of heterotrimeric G proteins and functions as a tumor-suppressive signaling node: its expression is transcriptionally activated by FOXO3A and epigenetically silenced by H3K18 lactylation or promoter hypermethylation/LOH; GNG7 protein directly interacts with mTOR to restrict its phosphorylation, interacts with RSPO3 to suppress Akt/GSK-3β/β-catenin activation, and inhibits Hedgehog signaling, while in non-cancer cells it restrains lipid production and modulates proliferation downstream of TLR signaling."},"narrative":{"mechanistic_narrative":"GNG7 functions as a tumor-suppressive signaling node whose loss releases growth-promoting pathways across multiple epithelial and hematopoietic tissues [PMID:37588187, PMID:18219292]. The protein physically restrains mTOR: it co-immunoprecipitates with mTOR and limits its activating phosphorylation, so that GNG7 depletion increases phospho-mTOR, p70S6K and 4E-BP1 signaling, drives proliferation, and promotes aerobic glycolysis [PMID:37588187, PMID:30864685, PMID:41352746]. GNG7 additionally acts upstream of the Akt/GSK-3β/β-catenin axis through a direct interaction with RSPO3, where GNG7 knockdown is required for RSPO3-driven β-catenin stabilization and cancer stem-cell properties [PMID:38581123], and it suppresses Hedgehog pathway activation [PMID:34635014]. GNG7 expression is governed by a layered set of controls: transcriptional activation by FOXO3A [PMID:37588187], epigenetic silencing via H3K18 lactylation and promoter hypermethylation/loss of heterozygosity [PMID:42163331, PMID:18219292], and post-transcriptional repression by multiple microRNAs (miR-19b-3p, miR-6765-3p, miR-146a) and the LINC01526–TARBP2 complex that destabilizes GNG7 mRNA [PMID:34635014, PMID:41352746, PMID:36230863, PMID:34728702]. Outside cancer, GNG7 negatively regulates mTOR in placental trophoblasts and restrains lipid production while modulating proliferation downstream of TLR signaling in sebocytes [PMID:30864685, PMID:34728702]. The biochemical role of GNG7 as a canonical heterotrimeric G-protein gamma subunit is not characterized in the available corpus, which instead documents its non-canonical scaffolding interactions with mTOR and RSPO3.","teleology":[{"year":2008,"claim":"Established that GNG7 acts as a tumor suppressor and is silenced by a defined epigenetic mechanism, framing its downregulation as a driver of cancer aggressiveness.","evidence":"GNG7 overexpression with invasion assays plus LOH analysis and methylation-specific PCR in oesophageal cancer","pmids":["18219292"],"confidence":"Medium","gaps":["No molecular partner or signaling pathway identified","Mechanism by which GNG7 suppresses invasion not defined"]},{"year":2019,"claim":"Placed GNG7 mechanistically as a negative regulator of the mTOR pathway, moving beyond correlation to pathway epistasis.","evidence":"siRNA knockdown with rapamycin rescue and Western blot for mTOR/p70S6K/4E-BP1 in placental cytotrophoblasts","pmids":["30864685"],"confidence":"Medium","gaps":["Did not establish direct physical GNG7–mTOR contact","Single lab, non-cancer context"]},{"year":2021,"claim":"Connected GNG7 to Hedgehog signaling and to microRNA control, showing miR-19b-3p directly targets GNG7 to drive lung adenocarcinoma aggressiveness.","evidence":"GNG7 overexpression with Hedgehog reporter/Western blot, dual-luciferase miR-19b-3p target validation, xenograft","pmids":["34635014"],"confidence":"Medium","gaps":["Mechanism linking GNG7 to Hedgehog pathway components unresolved","Single lab"]},{"year":2021,"claim":"Extended GNG7 function to non-cancer sebocyte biology, defining a role in restraining lipid production downstream of TLR signaling.","evidence":"miR-146a mimic/inhibitor with expression profiling, GNG7 siRNA with lipid and proliferation assays, ISH in acne tissue","pmids":["34728702"],"confidence":"Medium","gaps":["Direct link between TLR signaling and GNG7 not biochemically defined","Effector mechanism for lipid regulation unknown"]},{"year":2022,"claim":"Identified a post-transcriptional silencing route, showing the LINC01526–TARBP2 complex decreases GNG7 mRNA stability to promote gastric cancer.","evidence":"RNA immunoprecipitation, mRNA stability assay, knockdown with rescue and xenograft","pmids":["36230863"],"confidence":"Medium","gaps":["Downstream GNG7 effector pathway in gastric cancer not delineated here","Single lab"]},{"year":2023,"claim":"Defined the upstream transcriptional control (FOXO3A) and the direct GNG7–mTOR physical interaction, unifying GNG7 as a regulated brake on mTOR whose loss confers therapy resistance.","evidence":"ChIP for FOXO3A binding, reciprocal Co-IP for GNG7–mTOR, loss-of-function/rescue in AML cells, mouse and PDX models","pmids":["37588187"],"confidence":"High","gaps":["Structural basis of the GNG7–mTOR contact unknown","Whether GNG7 acts on mTORC1 vs mTORC2 not resolved"]},{"year":2024,"claim":"Revealed a second direct partner, RSPO3, placing GNG7 upstream of the Akt/GSK-3β/β-catenin axis controlling cancer stem-cell properties.","evidence":"Co-IP + LC-MS/MS for RSPO3–GNG7, GNG7 knockdown with phospho-rescue, spheroid and in vivo peritoneal-seeding assays","pmids":["38581123"],"confidence":"Medium","gaps":["How the RSPO3–GNG7 interaction modulates the Akt axis mechanistically unclear","Single lab"]},{"year":2026,"claim":"Added H3K18 lactylation as an epigenetic silencer of GNG7 and tied GNG7 loss to PI3K-AKT activation and glycolytic reprogramming.","evidence":"ChIP-qPCR for H3K18la at GNG7 promoter, GNG7 overexpression with PI3K-AKT Western blot, glycolysis assays, xenograft","pmids":["42163331"],"confidence":"Medium","gaps":["Enzymes writing/erasing the GNG7-promoter lactylation mark not identified","Single lab"]},{"year":null,"claim":"Whether GNG7 functions through its canonical heterotrimeric G-protein gamma-subunit role or solely as a non-canonical scaffold for mTOR/RSPO3 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No Gβ partner or G-protein complex characterized in the corpus","No structural model of GNG7 interaction interfaces","Tissue-specific selection among mTOR, Hedgehog, and β-catenin outputs unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,5]}],"complexes":[],"partners":["MTOR","RSPO3"],"other_free_text":[]}},"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":14,"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":12,"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":"42163331","id":"PMC_42163331","title":"H3K18 lactylation promotes glycolysis in bladder cancer via inhibiting GNG7 through regulating PI3K-AKT signaling pathway.","date":"2026","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42163331","citation_count":0,"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":9439,"output_tokens":2579,"usd":0.033501,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9828,"output_tokens":2877,"usd":0.060533,"stage2_stop_reason":"end_turn"},"total_usd":0.094034,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXO3A directly binds to the promoter of GNG7 and preserves its expression; GNG7 protein in turn interacts with mTOR and restricts phosphorylated (activated) mTOR. Loss of FOXO3A reduces GNG7 expression, thereby releasing mTOR suppression and causing adaptive resistance in AML cells.\",\n      \"method\": \"Chromatin immunoprecipitation (FOXO3A binding to GNG7 promoter), co-immunoprecipitation (GNG7–mTOR interaction), loss-of-function/rescue experiments, mouse AML model, patient-derived xenograft model\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing GNG7–mTOR interaction, ChIP establishing direct FOXO3A→GNG7 transcriptional regulation, functional epistasis in cell lines and two in vivo models in a single rigorous study\",\n      \"pmids\": [\"37588187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GNG7 is a transmembrane binding partner of RSPO3; Co-IP and LC-MS/MS confirmed direct physical interaction. RSPO3 increases phosphorylation of Akt and GSK-3β and stabilises β-catenin to promote gastric cancer stem-cell properties, and this effect is blocked by GNG7 knockdown, placing GNG7 upstream of the Akt/GSK-3β/β-catenin axis in this pathway.\",\n      \"method\": \"Co-immunoprecipitation + LC-MS/MS (RSPO3–GNG7 interaction), siRNA knockdown of GNG7 with rescue of β-catenin/Akt/GSK-3β phosphorylation, spheroid-formation and in vivo peritoneal-seeding assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus MS identification of GNG7 as RSPO3 interactor, functional epistasis with knockdown and in vivo model, single lab\",\n      \"pmids\": [\"38581123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"H3K18 lactylation suppresses GNG7 transcription: ChIP-qPCR showed elevated H3K18la enrichment at the GNG7 promoter in bladder cancer cells, correlating with reduced GNG7 expression. Overexpression of GNG7 inhibited PI3K-AKT pathway activation and reduced glycolysis and tumor growth.\",\n      \"method\": \"ChIP-qPCR (H3K18la at GNG7 promoter), GNG7 overexpression with Western blot for PI3K-AKT, glycolysis assays (glucose uptake, lactate production, ECAR), xenograft mouse model\",\n      \"journal\": \"World journal of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly linking epigenetic mark to GNG7 promoter, functional overexpression with pathway readout, single lab\",\n      \"pmids\": [\"42163331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNG7 overexpression in lung adenocarcinoma cells inhibits activation of Hedgehog signaling and suppresses proliferation and invasion in vitro and tumor formation in vivo. miR-19b-3p directly targets GNG7 (verified by reporter assay), and GNG7 re-introduction rescues miR-19b-3p-driven aggressive phenotypes.\",\n      \"method\": \"GNG7 gain-of-function (overexpression), Hedgehog pathway reporter/western blot, dual-luciferase miRNA target validation, xenograft assay\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase reporter confirms miR-19b-3p→GNG7 targeting, functional epistasis linking GNG7 to Hedgehog pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"34635014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GNG7 silencing in placental cytotrophoblasts activates the mTOR signaling pathway (increased phosphorylation of mTOR, p70S6K, 4E-BP1), enhances cell proliferation and differentiation, and inhibits apoptosis. Conversely, mTOR inhibition (rapamycin) blocks the pro-proliferative effects of GNG7 knockdown, establishing GNG7 as a negative regulator of mTOR in trophoblasts.\",\n      \"method\": \"siRNA knockdown of GNG7, mTOR pathway activator (HIV-1 Tat) and inhibitor (rapamycin) treatments, proliferation/apoptosis assays, Western blot for mTOR/p70S6K/4E-BP1, ELISA for sFlt-1/sEng\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with pharmacological epistasis (rapamycin rescue) confirming pathway placement, single lab\",\n      \"pmids\": [\"30864685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-derived extracellular vesicles transfer miR-6765-3p to colorectal cancer cells; miR-6765-3p directly targets the 3'-UTR of GNG7 (dual-luciferase assay), reducing GNG7 expression, which releases mTOR pathway inhibition and promotes aerobic glycolysis. GNG7 overexpression rescues mTOR phosphorylation suppression and reduces CRC progression.\",\n      \"method\": \"Dual-luciferase 3'-UTR reporter assay, GNG7 overexpression rescue, mTOR pathway Western blot, glycolysis assays, cellular and xenograft experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct 3'-UTR luciferase validation plus functional rescue, single lab\",\n      \"pmids\": [\"41352746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC01526 interacts with TARBP2 and this complex decreases GNG7 mRNA stability, leading to GNG7 mRNA decay and enhanced gastric cancer proliferation and migration. Rescue experiments showed that GNG7 downregulation partially reversed the anti-proliferative effect of LINC01526 or TARBP2 silencing.\",\n      \"method\": \"RNA immunoprecipitation (LINC01526–TARBP2 interaction), mRNA stability assay, siRNA knockdown, functional rescue experiments in vitro and xenograft\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP confirming lncRNA–protein interaction with mRNA stability readout and epistasis rescue, single lab\",\n      \"pmids\": [\"36230863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In sebocytes, miR-146a inversely regulates GNG7 expression (miR-146a inhibitor induces GNG7; miR-146a mimic suppresses GNG7). GNG7 inhibition in SZ95 sebocytes increases lipid content and decreases proliferation, indicating GNG7 restrains lipid production and promotes proliferation downstream of TLR1/2 and TLR4 signaling.\",\n      \"method\": \"miR-146a inhibitor/mimic treatment with gene expression profiling, GNG7 siRNA knockdown with lipid content and proliferation assays, in situ hybridization in acne tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotypes (lipid/proliferation), validated in tissue by ISH, single lab\",\n      \"pmids\": [\"34728702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GNG7 overexpression in oesophageal cancer cells reduced tumour invasion in vitro and in vivo. GNG7 suppression in patient tumours was associated with promoter hypermethylation or loss of heterozygosity, establishing epigenetic silencing as a mechanism of GNG7 downregulation.\",\n      \"method\": \"GNG7 transfection/overexpression with invasion assays, LOH analysis, bisulfite sequencing/methylation-specific PCR for promoter hypermethylation\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function invasion assay with direct epigenetic mechanism (methylation/LOH) demonstrated, single lab\",\n      \"pmids\": [\"18219292\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNG7 encodes the gamma-7 subunit of heterotrimeric G proteins and functions as a tumor-suppressive signaling node: its expression is transcriptionally activated by FOXO3A and epigenetically silenced by H3K18 lactylation or promoter hypermethylation/LOH; GNG7 protein directly interacts with mTOR to restrict its phosphorylation, interacts with RSPO3 to suppress Akt/GSK-3β/β-catenin activation, and inhibits Hedgehog signaling, while in non-cancer cells it restrains lipid production and modulates proliferation downstream of TLR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNG7 functions as a tumor-suppressive signaling node whose loss releases growth-promoting pathways across multiple epithelial and hematopoietic tissues [#0, #8]. The protein physically restrains mTOR: it co-immunoprecipitates with mTOR and limits its activating phosphorylation, so that GNG7 depletion increases phospho-mTOR, p70S6K and 4E-BP1 signaling, drives proliferation, and promotes aerobic glycolysis [#0, #4, #5]. GNG7 additionally acts upstream of the Akt/GSK-3\\u03b2/\\u03b2-catenin axis through a direct interaction with RSPO3, where GNG7 knockdown is required for RSPO3-driven \\u03b2-catenin stabilization and cancer stem-cell properties [#1], and it suppresses Hedgehog pathway activation [#3]. GNG7 expression is governed by a layered set of controls: transcriptional activation by FOXO3A [#0], epigenetic silencing via H3K18 lactylation and promoter hypermethylation/loss of heterozygosity [#2, #8], and post-transcriptional repression by multiple microRNAs (miR-19b-3p, miR-6765-3p, miR-146a) and the LINC01526\\u2013TARBP2 complex that destabilizes GNG7 mRNA [#3, #5, #6, #7]. Outside cancer, GNG7 negatively regulates mTOR in placental trophoblasts and restrains lipid production while modulating proliferation downstream of TLR signaling in sebocytes [#4, #7]. The biochemical role of GNG7 as a canonical heterotrimeric G-protein gamma subunit is not characterized in the available corpus, which instead documents its non-canonical scaffolding interactions with mTOR and RSPO3.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that GNG7 acts as a tumor suppressor and is silenced by a defined epigenetic mechanism, framing its downregulation as a driver of cancer aggressiveness.\",\n      \"evidence\": \"GNG7 overexpression with invasion assays plus LOH analysis and methylation-specific PCR in oesophageal cancer\",\n      \"pmids\": [\"18219292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or signaling pathway identified\", \"Mechanism by which GNG7 suppresses invasion not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GNG7 mechanistically as a negative regulator of the mTOR pathway, moving beyond correlation to pathway epistasis.\",\n      \"evidence\": \"siRNA knockdown with rapamycin rescue and Western blot for mTOR/p70S6K/4E-BP1 in placental cytotrophoblasts\",\n      \"pmids\": [\"30864685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct physical GNG7\\u2013mTOR contact\", \"Single lab, non-cancer context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected GNG7 to Hedgehog signaling and to microRNA control, showing miR-19b-3p directly targets GNG7 to drive lung adenocarcinoma aggressiveness.\",\n      \"evidence\": \"GNG7 overexpression with Hedgehog reporter/Western blot, dual-luciferase miR-19b-3p target validation, xenograft\",\n      \"pmids\": [\"34635014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GNG7 to Hedgehog pathway components unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended GNG7 function to non-cancer sebocyte biology, defining a role in restraining lipid production downstream of TLR signaling.\",\n      \"evidence\": \"miR-146a mimic/inhibitor with expression profiling, GNG7 siRNA with lipid and proliferation assays, ISH in acne tissue\",\n      \"pmids\": [\"34728702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between TLR signaling and GNG7 not biochemically defined\", \"Effector mechanism for lipid regulation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a post-transcriptional silencing route, showing the LINC01526\\u2013TARBP2 complex decreases GNG7 mRNA stability to promote gastric cancer.\",\n      \"evidence\": \"RNA immunoprecipitation, mRNA stability assay, knockdown with rescue and xenograft\",\n      \"pmids\": [\"36230863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream GNG7 effector pathway in gastric cancer not delineated here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the upstream transcriptional control (FOXO3A) and the direct GNG7\\u2013mTOR physical interaction, unifying GNG7 as a regulated brake on mTOR whose loss confers therapy resistance.\",\n      \"evidence\": \"ChIP for FOXO3A binding, reciprocal Co-IP for GNG7\\u2013mTOR, loss-of-function/rescue in AML cells, mouse and PDX models\",\n      \"pmids\": [\"37588187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the GNG7\\u2013mTOR contact unknown\", \"Whether GNG7 acts on mTORC1 vs mTORC2 not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a second direct partner, RSPO3, placing GNG7 upstream of the Akt/GSK-3\\u03b2/\\u03b2-catenin axis controlling cancer stem-cell properties.\",\n      \"evidence\": \"Co-IP + LC-MS/MS for RSPO3\\u2013GNG7, GNG7 knockdown with phospho-rescue, spheroid and in vivo peritoneal-seeding assays\",\n      \"pmids\": [\"38581123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the RSPO3\\u2013GNG7 interaction modulates the Akt axis mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added H3K18 lactylation as an epigenetic silencer of GNG7 and tied GNG7 loss to PI3K-AKT activation and glycolytic reprogramming.\",\n      \"evidence\": \"ChIP-qPCR for H3K18la at GNG7 promoter, GNG7 overexpression with PI3K-AKT Western blot, glycolysis assays, xenograft\",\n      \"pmids\": [\"42163331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymes writing/erasing the GNG7-promoter lactylation mark not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether GNG7 functions through its canonical heterotrimeric G-protein gamma-subunit role or solely as a non-canonical scaffold for mTOR/RSPO3 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No G\\u03b2 partner or G-protein complex characterized in the corpus\", \"No structural model of GNG7 interaction interfaces\", \"Tissue-specific selection among mTOR, Hedgehog, and \\u03b2-catenin outputs unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTOR\", \"RSPO3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}