{"gene":"VPS9D1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2023,"finding":"Vps9d1 is a guanine-nucleotide-exchange factor (GEF) for Rab22A that specifically activates Rab22A to promote tubular endosome formation. Unlike other reported Rab22A-GEFs, Vps9d1 does not activate Rab5A. Depletion of Vps9d1 in HeLa cells severely impairs tubular endosome formation and alters the distribution and recycling of clathrin-independent endocytosed cargos. Expression of constitutively active Rab22A rescues the tubular endosome defect in Vps9d1-depleted cells, but a GEF-activity-deficient Vps9d1 mutant does not, confirming the mechanism requires GEF activity.","method":"siRNA depletion, constitutively active Rab22A rescue, GEF-activity-deficient mutant rescue, cargo trafficking assays, live imaging/fractionation in HeLa cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (KD, active mutant rescue, catalytic mutant rescue, cargo trafficking) in a single rigorous study","pmids":["36762583"],"is_preprint":false},{"year":2022,"finding":"VPS9D1-AS1 lncRNA acts as a scaffolding lncRNA by binding ribosomal protein RPS3, thereby increasing the translation of TGF-β, TGFBR1, and SMAD1/5/9 in colorectal cancer cells. Additionally, VPS9D1-AS1 promotes expression of OAS1 (an ISG), which in turn maintains IFNAR1 levels in tumor cells. Knockout of VPS9D1-AS1 downregulates this cascade, and tumor cells overexpressing VPS9D1-AS1 resist CD8+ T cell killing.","method":"VPS9D1-AS1 knockout, lncRNA-RPS3 binding assays, ribosome association experiments, conditional overexpression mouse model, antisense oligonucleotide treatment, IFNAR1 functional readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, binding assay, in vivo model, ASO treatment) with mechanistic pathway placement in one study","pmids":["36458816"],"is_preprint":false},{"year":2019,"finding":"In prostate cancer, ZEB1 binds the VPS9D1-AS1 promoter and transcriptionally activates VPS9D1-AS1. VPS9D1-AS1 then acts as a competing endogenous RNA (ceRNA) sponging miR-4739, which de-represses MEF2D expression, promoting proliferation, migration, and invasion.","method":"Promoter binding assays, siRNA knockdown/overexpression, luciferase reporter assays, rescue experiments in prostate cancer cell lines","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 — single lab with promoter binding + ceRNA mechanistic follow-up but no in vitro reconstitution","pmids":["31918265"],"is_preprint":false},{"year":2020,"finding":"In acute lymphoblastic leukemia, VPS9D1-AS1 functions as a ceRNA that sponges miR-491-5p and miR-214-3p, thereby relieving their repression of GPX1 mRNA and increasing GPX1 protein expression to promote cell proliferation.","method":"siRNA knockdown, overexpression, luciferase reporter assays, functional proliferation/apoptosis assays in ALL cell lines","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, ceRNA mechanism supported by luciferase assay and functional rescue","pmids":["32808668"],"is_preprint":false},{"year":2020,"finding":"In AML cells, VPS9D1-AS1 knockdown inhibits the MEK/ERK signaling pathway, leading to impaired cell proliferation, cell cycle arrest, and enhanced sensitivity to the HDAC inhibitor Chidamide. VPS9D1-AS1 overexpression reverses Chidamide-mediated growth inhibition.","method":"siRNA knockdown, overexpression, transcriptome sequencing, western blotting for MEK/ERK, in vivo xenograft tumor formation assay","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with defined pathway (MEK/ERK) and in vivo data, single lab","pmids":["33192510"],"is_preprint":false},{"year":2020,"finding":"In non-small cell lung cancer, VPS9D1-AS1 directly interacts with miR-532-3p and acts as a ceRNA, increasing HMGA2 expression. VPS9D1-AS1 knockdown decreases HMGA2 and suppresses malignant phenotype; this is reversed by miR-532-3p inhibition or HMGA2 restoration.","method":"siRNA knockdown, luciferase reporter assay, RNA immunoprecipitation, in vivo xenograft assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, ceRNA mechanism validated by RIP and luciferase assays","pmids":["31902794"],"is_preprint":false},{"year":2021,"finding":"In hepatocellular carcinoma, VPS9D1-AS1 binds the HuR RNA-binding protein and through this interaction stabilizes CDK4 mRNA, increasing CDK4 protein expression and driving HCC cell cycle progression and proliferation.","method":"siRNA knockdown, RNA immunoprecipitation (VPS9D1-AS1–HuR binding), western blotting for CDK4/HuR, in vivo xenograft model","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP demonstrates VPS9D1-AS1/HuR binding with mechanistic link to CDK4 mRNA stability, single lab","pmids":["34558987"],"is_preprint":false},{"year":2021,"finding":"In hepatocellular carcinoma, EGR1 is a transcriptional activator of both VPS9D1-AS1 and SEC61A1; VPS9D1-AS1 sponges miR-491-5p to upregulate SEC61A1, promoting HCC cell proliferation, migration, and stemness.","method":"siRNA knockdown, luciferase reporter assay, bioinformatics, functional cell assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single pulldown/luciferase method, limited mechanistic follow-up","pmids":["33627127"],"is_preprint":false},{"year":2021,"finding":"In esophageal squamous cell carcinoma, VPS9D1-AS1 knockdown downregulates the Wnt/β-catenin signaling pathway, decreasing key pathway proteins β-catenin and c-Myc; activation of the pathway with the agonist CT99021 reverses the growth inhibitory effects of VPS9D1-AS1 silencing.","method":"siRNA knockdown, western blotting, pathway agonist rescue experiment, in vivo and in vitro functional assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement supported by pharmacological rescue, single lab","pmids":["34659577"],"is_preprint":false},{"year":2025,"finding":"VPS9D1-AS1 promotes angiogenesis in colorectal cancer by upregulating VEGFA and activating the downstream PI3K/AKT pathway. The transcription factor CEBPB directly binds to the VPS9D1-AS1 promoter at the -698 to -794 bp site to enhance its transcription, as validated by ChIP and dual-luciferase assays.","method":"ChIP assay, dual-luciferase reporter assay, HUVEC functional assays (tube formation, CAM assay), western blotting, siRNA knockdown","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and luciferase validate CEBPB binding; VEGFA/PI3K-AKT linkage established by functional assays; single lab","pmids":["40371141"],"is_preprint":false},{"year":2025,"finding":"In LUAD, exosomal transfer of VPS9D1-AS1 from tumor cells to macrophages induces M2 polarization, promoting erlotinib resistance. Mechanistically, exosomal VPS9D1-AS1 recruits NCYM to promote GSK-3β ubiquitination and degradation, thereby activating the Wnt/β-catenin pathway; VPS9D1-AS1 also sequesters miR-532-3p to upregulate CTNNB1.","method":"Exosome transfer experiments, siRNA knockdown, co-immunoprecipitation for NCYM/GSK-3β interaction, miRNA sponge assays, macrophage polarization functional assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 — multiple functional assays and mechanistic targets (NCYM/GSK-3β/miR-532-3p) explored, single lab","pmids":["41207568"],"is_preprint":false},{"year":2025,"finding":"Targeting VPS9D1-AS1 with antisense oligonucleotides delivered via lipid nanoparticles activates MLKL-induced immunogenic cell death (ICD) in colorectal cancer cells, promotes antigen exposure, and inhibits HLA-G to sensitize tumor cells to CD8+ T cell killing. VPS9D1-AS1 blockade also modulates the AXL/GAS6 pathway to alter dendritic cell crosstalk.","method":"ASO-LNP knockdown in tumor cells and PDX models, MLKL functional assays, HLA-G expression analysis, in vivo combination immunotherapy experiments, AXL/GAS6 pathway analysis","journal":"Journal of controlled release","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic pathway placement (MLKL/ICD, HLA-G, AXL/GAS6) supported by in vivo PDX and mouse model data, single lab","pmids":["40412657"],"is_preprint":false}],"current_model":"VPS9D1 (the protein) functions as a VPS9-domain-containing guanine-nucleotide exchange factor (GEF) that specifically activates the small GTPase Rab22A at tubular endosomes to promote clathrin-independent endocytic cargo recycling, without activating Rab5A; the antisense lncRNA from the same locus (VPS9D1-AS1/MYU) operates through distinct mechanisms including ribosome-associated scaffolding with RPS3 to amplify TGF-β/ISG translation, ceRNA sponging of multiple miRNAs, interaction with HuR to stabilize CDK4 mRNA, and activation of Wnt/β-catenin and MEK/ERK signaling in various cancers."},"narrative":{"teleology":[{"year":2019,"claim":"Establishing VPS9D1-AS1 as a transcriptionally regulated ceRNA: ZEB1-driven expression of VPS9D1-AS1 and its sponging of miR-4739 to de-repress MEF2D provided the first mechanistic framework for this lncRNA's oncogenic activity.","evidence":"Promoter binding assays, luciferase reporters, and knockdown/overexpression rescue in prostate cancer cell lines","pmids":["31918265"],"confidence":"Medium","gaps":["No biochemical reconstitution of ceRNA stoichiometry","Only one cancer type tested","No in vivo validation"]},{"year":2020,"claim":"The ceRNA paradigm was extended to additional miRNA–target axes (miR-491-5p/GPX1 in ALL; miR-532-3p/HMGA2 in NSCLC) and a distinct signaling mode (MEK/ERK activation in AML), demonstrating that VPS9D1-AS1 engages different downstream effectors in different malignancies.","evidence":"Luciferase reporters, RNA immunoprecipitation, siRNA knockdown/overexpression, xenograft models across three cancer types","pmids":["32808668","31902794","33192510"],"confidence":"Medium","gaps":["ceRNA mechanisms rely on single-lab luciferase/RIP validation","No quantitative assessment of miRNA:lncRNA stoichiometry","MEK/ERK link lacks a defined intermediate target"]},{"year":2021,"claim":"Beyond miRNA sponging, VPS9D1-AS1 was shown to operate through protein–RNA scaffolding—binding HuR to stabilize CDK4 mRNA—and to activate Wnt/β-catenin signaling, revealing mechanistic diversity beyond the ceRNA model.","evidence":"RNA immunoprecipitation (VPS9D1-AS1–HuR), CDK4 protein/mRNA stability assays, Wnt pathway agonist rescue experiments in HCC and ESCC cell lines","pmids":["34558987","34659577"],"confidence":"Medium","gaps":["HuR–CDK4 mRNA stabilization from single lab without domain mapping","Wnt pathway link lacks identification of a direct molecular intermediate","Relationship between HuR scaffolding and ceRNA functions unresolved"]},{"year":2022,"claim":"A ribosome-associated scaffolding mechanism was established: VPS9D1-AS1 binds RPS3 to enhance translation of TGF-β, TGFBR1, and SMAD1/5/9, linking the lncRNA to immune evasion through OAS1-mediated IFNAR1 maintenance and resistance to CD8+ T cell killing.","evidence":"VPS9D1-AS1 knockout, lncRNA–RPS3 binding assays, ribosome association experiments, conditional overexpression mouse model, ASO treatment","pmids":["36458816"],"confidence":"High","gaps":["Structural basis of RPS3 interaction undefined","Whether translational enhancement is specific to TGF-β targets or broader is unclear","Contribution relative to ceRNA activity not quantified"]},{"year":2023,"claim":"The VPS9D1 protein itself was functionally characterized as a Rab22A-specific GEF that drives tubular endosome biogenesis and clathrin-independent cargo recycling, distinguishing the protein from its antisense lncRNA.","evidence":"siRNA depletion, constitutively active Rab22A rescue, GEF-dead mutant failure to rescue, cargo trafficking assays and live imaging in HeLa cells","pmids":["36762583"],"confidence":"High","gaps":["In vitro GEF kinetic parameters not reported","Structural basis for Rab22A specificity over Rab5A unknown","Physiological cargos in non-HeLa cell types not defined"]},{"year":2025,"claim":"Therapeutic targeting of VPS9D1-AS1 was demonstrated: ASO-loaded lipid nanoparticles trigger MLKL-dependent immunogenic cell death, suppress HLA-G, and modulate AXL/GAS6 to sensitize tumors to immunotherapy; exosomal transfer of VPS9D1-AS1 to macrophages induces M2 polarization and drug resistance via GSK-3β ubiquitination and Wnt activation.","evidence":"ASO-LNP knockdown in PDX models, MLKL/ICD assays, exosome transfer and co-IP for NCYM/GSK-3β, macrophage polarization assays, in vivo combination immunotherapy","pmids":["40412657","41207568"],"confidence":"Medium","gaps":["MLKL activation mechanism downstream of VPS9D1-AS1 loss not fully resolved","Exosomal transfer and NCYM recruitment from single lab","In vivo pharmacokinetics and off-target effects of ASO-LNP not characterized"]},{"year":null,"claim":"A unified model integrating VPS9D1 protein GEF activity and VPS9D1-AS1 lncRNA functions is lacking; whether the two gene products are co-regulated or functionally interdependent remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study has examined cross-regulation between VPS9D1 protein and VPS9D1-AS1","Structural basis for VPS9D1 Rab22A specificity unresolved","Relative contribution of ceRNA, HuR scaffolding, and RPS3-mediated translation to oncogenesis not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,11]}],"complexes":[],"partners":["RAB22A","RPS3","HUR","NCYM"],"other_free_text":[]},"mechanistic_narrative":"The VPS9D1 locus encodes both a VPS9-domain-containing guanine-nucleotide exchange factor (GEF) protein and an antisense long noncoding RNA (VPS9D1-AS1) with distinct biological functions. The VPS9D1 protein specifically activates Rab22A—but not Rab5A—to drive tubular endosome formation and clathrin-independent endocytic cargo recycling, as demonstrated by rescue with constitutively active Rab22A but not a GEF-dead mutant [PMID:36762583]. VPS9D1-AS1 functions as an oncogenic lncRNA that operates through multiple mechanisms: it scaffolds ribosomal protein RPS3 to enhance translation of TGF-β pathway components and ISGs in colorectal cancer [PMID:36458816], stabilizes CDK4 mRNA via HuR binding in hepatocellular carcinoma [PMID:34558987], sponges miRNAs (miR-4739, miR-491-5p, miR-532-3p) to de-repress targets such as MEF2D, GPX1, and HMGA2 [PMID:31918265, PMID:32808668, PMID:31902794], and activates Wnt/β-catenin and MEK/ERK signaling across multiple cancer types [PMID:34659577, PMID:33192510]. Antisense oligonucleotide-mediated knockdown of VPS9D1-AS1 triggers MLKL-dependent immunogenic cell death and restores CD8+ T cell-mediated tumor killing, establishing VPS9D1-AS1 as a potential immunotherapy target [PMID:40412657]."},"prefetch_data":{"uniprot":{"accession":"Q9Y2B5","full_name":"VPS9 domain-containing protein 1","aliases":["Protein ATP-BL"],"length_aa":631,"mass_kda":69.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y2B5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS9D1","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IST1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS9D1","total_profiled":1310},"omim":[{"mim_id":"619292","title":"VPS9 DOMAIN-CONTAINING PROTEIN 1; VPS9D1","url":"https://www.omim.org/entry/619292"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS9D1"},"hgnc":{"alias_symbol":["ATP-BL"],"prev_symbol":["C16orf7"]},"alphafold":{"accession":"Q9Y2B5","domains":[{"cath_id":"1.20.58.80","chopping":"13-57_67-91","consensus_level":"high","plddt":89.1237,"start":13,"end":91},{"cath_id":"-","chopping":"231-308_405-467","consensus_level":"medium","plddt":88.4765,"start":231,"end":467},{"cath_id":"1.20.1050.80","chopping":"482-549_565-624","consensus_level":"high","plddt":89.1794,"start":482,"end":624},{"cath_id":"1.10.287","chopping":"148-222","consensus_level":"medium","plddt":90.2653,"start":148,"end":222}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2B5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2B5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2B5-F1-predicted_aligned_error_v6.png","plddt_mean":75.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS9D1","jax_strain_url":"https://www.jax.org/strain/search?query=VPS9D1"},"sequence":{"accession":"Q9Y2B5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2B5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2B5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2B5"}},"corpus_meta":[{"pmid":"29036784","id":"PMC_29036784","title":"Decreased expression of lncRNA VPS9D1-AS1 in gastric cancer and its clinical significance.","date":"2017","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/29036784","citation_count":48,"is_preprint":false},{"pmid":"31918265","id":"PMC_31918265","title":"ZEB1 activated-VPS9D1-AS1 promotes the tumorigenesis and progression of prostate cancer by sponging miR-4739 to upregulate MEF2D.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31918265","citation_count":40,"is_preprint":false},{"pmid":"36458816","id":"PMC_36458816","title":"VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36458816","citation_count":26,"is_preprint":false},{"pmid":"32808668","id":"PMC_32808668","title":"LncRNA VPS9D1-AS1 promotes cell proliferation in acute lymphoblastic leukemia through modulating GPX1 expression by miR-491-5p and miR-214-3p evasion.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32808668","citation_count":26,"is_preprint":false},{"pmid":"33192510","id":"PMC_33192510","title":"Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33192510","citation_count":25,"is_preprint":false},{"pmid":"31902794","id":"PMC_31902794","title":"Long noncoding RNA VPS9D1-AS1 augments the malignant phenotype of non-small cell lung cancer by sponging microRNA-532-3p and thereby enhancing HMGA2 expression.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31902794","citation_count":24,"is_preprint":false},{"pmid":"33627127","id":"PMC_33627127","title":"Long non-coding RNA VPS9D1-AS1 facilitates cell 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Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/41460448","citation_count":1,"is_preprint":false},{"pmid":"40908689","id":"PMC_40908689","title":"Long Non-Coding RNA VPS9D1-AS1 in Human Cancer: Functions, Mechanisms, and Clinical Utility.","date":"2025","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40908689","citation_count":0,"is_preprint":false},{"pmid":"37469373","id":"PMC_37469373","title":"Long Noncoding RNA VPS9D1-AS1 Sequesters microRNA-525-5p to Promote the Oncogenicity of Colorectal Cancer Cells by Upregulating HMGA1 [Retraction].","date":"2023","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/37469373","citation_count":0,"is_preprint":false},{"pmid":"41207568","id":"PMC_41207568","title":"Exosomal transfer of VPS9D1-AS1 induces M2 polarization to promote erlotinib resistance of LUAD cells via activation of the Wnt/β-catenin signaling pathway.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41207568","citation_count":0,"is_preprint":false},{"pmid":"41527363","id":"PMC_41527363","title":"Emergence and Tandem Repeat-Mediated Elongation of a Translated De Novo Open Reading Frame in Human Oncogenic RNA Gene VPS9D1-AS1 (MYU).","date":"2026","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/41527363","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16538,"output_tokens":3210,"usd":0.048882},"stage2":{"model":"claude-opus-4-6","input_tokens":6595,"output_tokens":2253,"usd":0.13395},"total_usd":0.182832,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"Vps9d1 is a guanine-nucleotide-exchange factor (GEF) for Rab22A that specifically activates Rab22A to promote tubular endosome formation. Unlike other reported Rab22A-GEFs, Vps9d1 does not activate Rab5A. Depletion of Vps9d1 in HeLa cells severely impairs tubular endosome formation and alters the distribution and recycling of clathrin-independent endocytosed cargos. Expression of constitutively active Rab22A rescues the tubular endosome defect in Vps9d1-depleted cells, but a GEF-activity-deficient Vps9d1 mutant does not, confirming the mechanism requires GEF activity.\",\n      \"method\": \"siRNA depletion, constitutively active Rab22A rescue, GEF-activity-deficient mutant rescue, cargo trafficking assays, live imaging/fractionation in HeLa cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (KD, active mutant rescue, catalytic mutant rescue, cargo trafficking) in a single rigorous study\",\n      \"pmids\": [\"36762583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS9D1-AS1 lncRNA acts as a scaffolding lncRNA by binding ribosomal protein RPS3, thereby increasing the translation of TGF-β, TGFBR1, and SMAD1/5/9 in colorectal cancer cells. Additionally, VPS9D1-AS1 promotes expression of OAS1 (an ISG), which in turn maintains IFNAR1 levels in tumor cells. Knockout of VPS9D1-AS1 downregulates this cascade, and tumor cells overexpressing VPS9D1-AS1 resist CD8+ T cell killing.\",\n      \"method\": \"VPS9D1-AS1 knockout, lncRNA-RPS3 binding assays, ribosome association experiments, conditional overexpression mouse model, antisense oligonucleotide treatment, IFNAR1 functional readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, binding assay, in vivo model, ASO treatment) with mechanistic pathway placement in one study\",\n      \"pmids\": [\"36458816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In prostate cancer, ZEB1 binds the VPS9D1-AS1 promoter and transcriptionally activates VPS9D1-AS1. VPS9D1-AS1 then acts as a competing endogenous RNA (ceRNA) sponging miR-4739, which de-represses MEF2D expression, promoting proliferation, migration, and invasion.\",\n      \"method\": \"Promoter binding assays, siRNA knockdown/overexpression, luciferase reporter assays, rescue experiments in prostate cancer cell lines\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with promoter binding + ceRNA mechanistic follow-up but no in vitro reconstitution\",\n      \"pmids\": [\"31918265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In acute lymphoblastic leukemia, VPS9D1-AS1 functions as a ceRNA that sponges miR-491-5p and miR-214-3p, thereby relieving their repression of GPX1 mRNA and increasing GPX1 protein expression to promote cell proliferation.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter assays, functional proliferation/apoptosis assays in ALL cell lines\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ceRNA mechanism supported by luciferase assay and functional rescue\",\n      \"pmids\": [\"32808668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In AML cells, VPS9D1-AS1 knockdown inhibits the MEK/ERK signaling pathway, leading to impaired cell proliferation, cell cycle arrest, and enhanced sensitivity to the HDAC inhibitor Chidamide. VPS9D1-AS1 overexpression reverses Chidamide-mediated growth inhibition.\",\n      \"method\": \"siRNA knockdown, overexpression, transcriptome sequencing, western blotting for MEK/ERK, in vivo xenograft tumor formation assay\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with defined pathway (MEK/ERK) and in vivo data, single lab\",\n      \"pmids\": [\"33192510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In non-small cell lung cancer, VPS9D1-AS1 directly interacts with miR-532-3p and acts as a ceRNA, increasing HMGA2 expression. VPS9D1-AS1 knockdown decreases HMGA2 and suppresses malignant phenotype; this is reversed by miR-532-3p inhibition or HMGA2 restoration.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, RNA immunoprecipitation, in vivo xenograft assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ceRNA mechanism validated by RIP and luciferase assays\",\n      \"pmids\": [\"31902794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In hepatocellular carcinoma, VPS9D1-AS1 binds the HuR RNA-binding protein and through this interaction stabilizes CDK4 mRNA, increasing CDK4 protein expression and driving HCC cell cycle progression and proliferation.\",\n      \"method\": \"siRNA knockdown, RNA immunoprecipitation (VPS9D1-AS1–HuR binding), western blotting for CDK4/HuR, in vivo xenograft model\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP demonstrates VPS9D1-AS1/HuR binding with mechanistic link to CDK4 mRNA stability, single lab\",\n      \"pmids\": [\"34558987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In hepatocellular carcinoma, EGR1 is a transcriptional activator of both VPS9D1-AS1 and SEC61A1; VPS9D1-AS1 sponges miR-491-5p to upregulate SEC61A1, promoting HCC cell proliferation, migration, and stemness.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, bioinformatics, functional cell assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single pulldown/luciferase method, limited mechanistic follow-up\",\n      \"pmids\": [\"33627127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In esophageal squamous cell carcinoma, VPS9D1-AS1 knockdown downregulates the Wnt/β-catenin signaling pathway, decreasing key pathway proteins β-catenin and c-Myc; activation of the pathway with the agonist CT99021 reverses the growth inhibitory effects of VPS9D1-AS1 silencing.\",\n      \"method\": \"siRNA knockdown, western blotting, pathway agonist rescue experiment, in vivo and in vitro functional assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement supported by pharmacological rescue, single lab\",\n      \"pmids\": [\"34659577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS9D1-AS1 promotes angiogenesis in colorectal cancer by upregulating VEGFA and activating the downstream PI3K/AKT pathway. The transcription factor CEBPB directly binds to the VPS9D1-AS1 promoter at the -698 to -794 bp site to enhance its transcription, as validated by ChIP and dual-luciferase assays.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, HUVEC functional assays (tube formation, CAM assay), western blotting, siRNA knockdown\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and luciferase validate CEBPB binding; VEGFA/PI3K-AKT linkage established by functional assays; single lab\",\n      \"pmids\": [\"40371141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In LUAD, exosomal transfer of VPS9D1-AS1 from tumor cells to macrophages induces M2 polarization, promoting erlotinib resistance. Mechanistically, exosomal VPS9D1-AS1 recruits NCYM to promote GSK-3β ubiquitination and degradation, thereby activating the Wnt/β-catenin pathway; VPS9D1-AS1 also sequesters miR-532-3p to upregulate CTNNB1.\",\n      \"method\": \"Exosome transfer experiments, siRNA knockdown, co-immunoprecipitation for NCYM/GSK-3β interaction, miRNA sponge assays, macrophage polarization functional assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple functional assays and mechanistic targets (NCYM/GSK-3β/miR-532-3p) explored, single lab\",\n      \"pmids\": [\"41207568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Targeting VPS9D1-AS1 with antisense oligonucleotides delivered via lipid nanoparticles activates MLKL-induced immunogenic cell death (ICD) in colorectal cancer cells, promotes antigen exposure, and inhibits HLA-G to sensitize tumor cells to CD8+ T cell killing. VPS9D1-AS1 blockade also modulates the AXL/GAS6 pathway to alter dendritic cell crosstalk.\",\n      \"method\": \"ASO-LNP knockdown in tumor cells and PDX models, MLKL functional assays, HLA-G expression analysis, in vivo combination immunotherapy experiments, AXL/GAS6 pathway analysis\",\n      \"journal\": \"Journal of controlled release\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway placement (MLKL/ICD, HLA-G, AXL/GAS6) supported by in vivo PDX and mouse model data, single lab\",\n      \"pmids\": [\"40412657\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS9D1 (the protein) functions as a VPS9-domain-containing guanine-nucleotide exchange factor (GEF) that specifically activates the small GTPase Rab22A at tubular endosomes to promote clathrin-independent endocytic cargo recycling, without activating Rab5A; the antisense lncRNA from the same locus (VPS9D1-AS1/MYU) operates through distinct mechanisms including ribosome-associated scaffolding with RPS3 to amplify TGF-β/ISG translation, ceRNA sponging of multiple miRNAs, interaction with HuR to stabilize CDK4 mRNA, and activation of Wnt/β-catenin and MEK/ERK signaling in various cancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"The VPS9D1 locus encodes both a VPS9-domain-containing guanine-nucleotide exchange factor (GEF) protein and an antisense long noncoding RNA (VPS9D1-AS1) with distinct biological functions. The VPS9D1 protein specifically activates Rab22A—but not Rab5A—to drive tubular endosome formation and clathrin-independent endocytic cargo recycling, as demonstrated by rescue with constitutively active Rab22A but not a GEF-dead mutant [PMID:36762583]. VPS9D1-AS1 functions as an oncogenic lncRNA that operates through multiple mechanisms: it scaffolds ribosomal protein RPS3 to enhance translation of TGF-β pathway components and ISGs in colorectal cancer [PMID:36458816], stabilizes CDK4 mRNA via HuR binding in hepatocellular carcinoma [PMID:34558987], sponges miRNAs (miR-4739, miR-491-5p, miR-532-3p) to de-repress targets such as MEF2D, GPX1, and HMGA2 [PMID:31918265, PMID:32808668, PMID:31902794], and activates Wnt/β-catenin and MEK/ERK signaling across multiple cancer types [PMID:34659577, PMID:33192510]. Antisense oligonucleotide-mediated knockdown of VPS9D1-AS1 triggers MLKL-dependent immunogenic cell death and restores CD8+ T cell-mediated tumor killing, establishing VPS9D1-AS1 as a potential immunotherapy target [PMID:40412657].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing VPS9D1-AS1 as a transcriptionally regulated ceRNA: ZEB1-driven expression of VPS9D1-AS1 and its sponging of miR-4739 to de-repress MEF2D provided the first mechanistic framework for this lncRNA's oncogenic activity.\",\n      \"evidence\": \"Promoter binding assays, luciferase reporters, and knockdown/overexpression rescue in prostate cancer cell lines\",\n      \"pmids\": [\"31918265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical reconstitution of ceRNA stoichiometry\", \"Only one cancer type tested\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The ceRNA paradigm was extended to additional miRNA–target axes (miR-491-5p/GPX1 in ALL; miR-532-3p/HMGA2 in NSCLC) and a distinct signaling mode (MEK/ERK activation in AML), demonstrating that VPS9D1-AS1 engages different downstream effectors in different malignancies.\",\n      \"evidence\": \"Luciferase reporters, RNA immunoprecipitation, siRNA knockdown/overexpression, xenograft models across three cancer types\",\n      \"pmids\": [\"32808668\", \"31902794\", \"33192510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ceRNA mechanisms rely on single-lab luciferase/RIP validation\", \"No quantitative assessment of miRNA:lncRNA stoichiometry\", \"MEK/ERK link lacks a defined intermediate target\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Beyond miRNA sponging, VPS9D1-AS1 was shown to operate through protein–RNA scaffolding—binding HuR to stabilize CDK4 mRNA—and to activate Wnt/β-catenin signaling, revealing mechanistic diversity beyond the ceRNA model.\",\n      \"evidence\": \"RNA immunoprecipitation (VPS9D1-AS1–HuR), CDK4 protein/mRNA stability assays, Wnt pathway agonist rescue experiments in HCC and ESCC cell lines\",\n      \"pmids\": [\"34558987\", \"34659577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HuR–CDK4 mRNA stabilization from single lab without domain mapping\", \"Wnt pathway link lacks identification of a direct molecular intermediate\", \"Relationship between HuR scaffolding and ceRNA functions unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A ribosome-associated scaffolding mechanism was established: VPS9D1-AS1 binds RPS3 to enhance translation of TGF-β, TGFBR1, and SMAD1/5/9, linking the lncRNA to immune evasion through OAS1-mediated IFNAR1 maintenance and resistance to CD8+ T cell killing.\",\n      \"evidence\": \"VPS9D1-AS1 knockout, lncRNA–RPS3 binding assays, ribosome association experiments, conditional overexpression mouse model, ASO treatment\",\n      \"pmids\": [\"36458816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RPS3 interaction undefined\", \"Whether translational enhancement is specific to TGF-β targets or broader is unclear\", \"Contribution relative to ceRNA activity not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The VPS9D1 protein itself was functionally characterized as a Rab22A-specific GEF that drives tubular endosome biogenesis and clathrin-independent cargo recycling, distinguishing the protein from its antisense lncRNA.\",\n      \"evidence\": \"siRNA depletion, constitutively active Rab22A rescue, GEF-dead mutant failure to rescue, cargo trafficking assays and live imaging in HeLa cells\",\n      \"pmids\": [\"36762583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro GEF kinetic parameters not reported\", \"Structural basis for Rab22A specificity over Rab5A unknown\", \"Physiological cargos in non-HeLa cell types not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Therapeutic targeting of VPS9D1-AS1 was demonstrated: ASO-loaded lipid nanoparticles trigger MLKL-dependent immunogenic cell death, suppress HLA-G, and modulate AXL/GAS6 to sensitize tumors to immunotherapy; exosomal transfer of VPS9D1-AS1 to macrophages induces M2 polarization and drug resistance via GSK-3β ubiquitination and Wnt activation.\",\n      \"evidence\": \"ASO-LNP knockdown in PDX models, MLKL/ICD assays, exosome transfer and co-IP for NCYM/GSK-3β, macrophage polarization assays, in vivo combination immunotherapy\",\n      \"pmids\": [\"40412657\", \"41207568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MLKL activation mechanism downstream of VPS9D1-AS1 loss not fully resolved\", \"Exosomal transfer and NCYM recruitment from single lab\", \"In vivo pharmacokinetics and off-target effects of ASO-LNP not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model integrating VPS9D1 protein GEF activity and VPS9D1-AS1 lncRNA functions is lacking; whether the two gene products are co-regulated or functionally interdependent remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study has examined cross-regulation between VPS9D1 protein and VPS9D1-AS1\", \"Structural basis for VPS9D1 Rab22A specificity unresolved\", \"Relative contribution of ceRNA, HuR scaffolding, and RPS3-mediated translation to oncogenesis not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB22A\", \"RPS3\", \"HuR\", \"NCYM\"],\n    \"other_free_text\": []\n  }\n}\n```"}