{"gene":"TWF1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2013,"finding":"TWF1 (twinfilin 1), an actin-binding protein, is a direct target of microRNA-30c in breast cancer cells; miR-30c suppression of TWF1 promotes epithelial-to-mesenchymal transition and chemotherapy resistance, and IL-11 was identified as a secondary downstream target of this pathway.","method":"Direct targeting validated by miRNA overexpression/knockdown, functional assays for EMT and chemoresistance, with miR-30c shown to be transcriptionally regulated by GATA3","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct miRNA-target relationship established with functional readouts (EMT, chemoresistance) in a single study, but mechanistic detail on how TWF1 protein itself promotes EMT is not biochemically resolved","pmids":["23340433"],"is_preprint":false},{"year":2022,"finding":"TWF1 (twinfilin actin binding protein 1) is a direct target of miR-30a/c-5p in clear cell renal cell carcinoma (ccRCC); both miRs directly bind TWF1 3'UTR (confirmed by luciferase assay), and TWF1 knockdown reduced cell aggressiveness and EMT markers while upregulating epithelial markers Claudin-1 and ZO-1, implicating TWF1 in EMT regulation.","method":"Luciferase reporter assay confirming direct miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown of TWF1 with functional assays (migration, invasion, EMT marker expression); immunohistochemistry in patient tissues","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional siRNA knockdown with defined EMT phenotype, single lab with orthogonal methods","pmids":["35697274"],"is_preprint":false},{"year":2019,"finding":"TWF1 expression is regulated by the lncRNA SBF2-AS1/miR-142-3p axis in gemcitabine-resistant pancreatic cancer: SBF2-AS1 acts as a ceRNA to sponge miR-142-3p, thereby relieving miR-142-3p-mediated repression of TWF1 and promoting drug resistance and EMT.","method":"Luciferase reporter and RNA immunoprecipitation (RIP) assays confirming SBF2-AS1 binding to miR-142-3p and miR-142-3p targeting of TWF1; knockdown/overexpression functional assays in gemcitabine-resistant cell lines","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ceRNA axis validated by reporter and RIP in single lab; TWF1 protein mechanism itself not directly studied","pmids":["31619579"],"is_preprint":false},{"year":2021,"finding":"TWF1 expression is regulated by the lncRNA FGD5-AS1/miR-153-3p axis in cisplatin-resistant hepatocellular carcinoma: FGD5-AS1 sponges miR-153-3p to upregulate TWF1, and TWF1 knockdown reduced drug resistance, invasion, and promoted apoptosis in HCC cells.","method":"Luciferase reporter and RIP assays confirming FGD5-AS1/miR-153-3p and miR-153-3p/TWF1 interactions; siRNA knockdown of TWF1 with CCK-8, colony formation, Transwell, and TUNEL functional assays","journal":"Bioengineered","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ceRNA axis and functional knockdown in single lab; mechanistic role of TWF1 protein itself not resolved beyond drug resistance phenotype","pmids":["34519634"],"is_preprint":false}],"current_model":"TWF1 (twinfilin 1) is an actin-binding protein whose expression is post-transcriptionally suppressed by miR-30c (in breast cancer) and miR-30a/c-5p (in renal cancer), and is upregulated via ceRNA sponging by lncRNAs SBF2-AS1 and FGD5-AS1; elevated TWF1 promotes epithelial-to-mesenchymal transition and chemotherapy resistance, though the precise biochemical mechanism by which TWF1 drives these phenotypes remains uncharacterized in the available literature."},"narrative":{"mechanistic_narrative":"TWF1 (twinfilin 1) is an actin-binding protein that functions as a downstream effector promoting epithelial-to-mesenchymal transition (EMT) and chemotherapy resistance across multiple carcinoma contexts [PMID:23340433, PMID:35697274]. Its expression is held in check post-transcriptionally by microRNAs that bind its 3'UTR: miR-30c in breast cancer [PMID:23340433] and miR-30a/c-5p in clear cell renal cell carcinoma, where direct binding was confirmed by luciferase reporter assay [PMID:35697274]. When this repression is relieved, elevated TWF1 drives a mesenchymal program—knockdown of TWF1 reduces migration, invasion, and EMT-marker expression while restoring epithelial markers Claudin-1 and ZO-1 [PMID:35697274]. In breast cancer, miR-30c is itself transcriptionally controlled by GATA3, and IL-11 acts as a secondary downstream target of the miR-30c–TWF1 axis [PMID:23340433]. The biochemical mechanism by which the TWF1 protein itself executes EMT and chemoresistance has not been characterized in the available corpus; the evidence establishes TWF1 as a regulated node in these phenotypes rather than defining its molecular action.","teleology":[{"year":2013,"claim":"Established TWF1 as a functionally relevant, microRNA-regulated driver of cancer phenotype by showing it is a direct miR-30c target whose suppression promotes EMT and chemoresistance.","evidence":"miR-30c overexpression/knockdown with EMT and chemoresistance functional assays in breast cancer cells; GATA3 shown to regulate miR-30c and IL-11 identified as a downstream target","pmids":["23340433"],"confidence":"Medium","gaps":["How the TWF1 protein biochemically promotes EMT was not resolved","Direct 3'UTR binding not demonstrated by reporter assay in this study","Link between TWF1 actin-binding activity and the EMT phenotype unestablished"]},{"year":2019,"claim":"Extended TWF1 regulation to a ceRNA framework in drug-resistant pancreatic cancer, positioning lncRNA SBF2-AS1 as an upstream de-repressor of TWF1 via miR-142-3p sponging.","evidence":"Luciferase reporter and RIP assays for SBF2-AS1/miR-142-3p and miR-142-3p/TWF1; knockdown/overexpression in gemcitabine-resistant cell lines","pmids":["31619579"],"confidence":"Low","gaps":["Single-lab ceRNA axis; TWF1 protein mechanism not directly studied","Whether TWF1 alone is sufficient to confer gemcitabine resistance not isolated"]},{"year":2021,"claim":"Generalized the lncRNA-sponging mode of TWF1 upregulation to cisplatin-resistant hepatocellular carcinoma, linking TWF1 levels to drug resistance, invasion, and apoptosis suppression.","evidence":"Luciferase reporter and RIP for FGD5-AS1/miR-153-3p and miR-153-3p/TWF1; siRNA knockdown with CCK-8, colony formation, Transwell, and TUNEL assays","pmids":["34519634"],"confidence":"Low","gaps":["Single-lab ceRNA axis; biochemical role of TWF1 protein not resolved","Mechanism connecting TWF1 to apoptosis regulation unknown"]},{"year":2022,"claim":"Confirmed direct 3'UTR targeting of TWF1 by miR-30a/c-5p and demonstrated that loss of TWF1 reverses the mesenchymal program in renal cancer, solidifying TWF1 as an EMT effector.","evidence":"Luciferase reporter assay for miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown with migration/invasion and EMT-marker assays plus patient-tissue immunohistochemistry in ccRCC","pmids":["35697274"],"confidence":"Medium","gaps":["Molecular mechanism by which TWF1 modulates Claudin-1/ZO-1 and EMT not defined","Connection between TWF1 actin-binding function and EMT signaling unestablished"]},{"year":null,"claim":"The biochemical mechanism by which TWF1 protein executes EMT and chemoresistance—its actin-related activity, binding partners, and the signaling steps linking it to epithelial-marker loss—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or enzymatic characterization of TWF1 in the corpus","No identified protein partners or actin-regulatory mechanism tied to the EMT phenotype","Whether TWF1's actin-binding activity is required for chemoresistance is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12792","full_name":"Twinfilin-1","aliases":["Protein A6","Protein tyrosine kinase 9"],"length_aa":350,"mass_kda":40.3,"function":"Actin-binding protein involved in motile and morphological processes. Inhibits actin polymerization, likely by sequestering G-actin. By capping the barbed ends of filaments, it also regulates motility. Seems to play an important role in clathrin-mediated endocytosis and distribution of endocytic organelles (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q12792/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TWF1","classification":"Common Essential","n_dependent_lines":494,"n_total_lines":1208,"dependency_fraction":0.40894039735099336},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTG1","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TWF1","total_profiled":1310},"omim":[{"mim_id":"610932","title":"TWINFILIN ACTIN-BINDING PROTEIN 1; TWF1","url":"https://www.omim.org/entry/610932"},{"mim_id":"607971","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER), MEMBER 15; SLC6A15","url":"https://www.omim.org/entry/607971"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TWF1"},"hgnc":{"alias_symbol":["A6"],"prev_symbol":["PTK9"]},"alphafold":{"accession":"Q12792","domains":[{"cath_id":"3.40.20.10","chopping":"12-143","consensus_level":"high","plddt":94.7273,"start":12,"end":143},{"cath_id":"3.40.20.10","chopping":"185-313","consensus_level":"high","plddt":90.8502,"start":185,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12792","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12792-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12792-F1-predicted_aligned_error_v6.png","plddt_mean":85.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TWF1","jax_strain_url":"https://www.jax.org/strain/search?query=TWF1"},"sequence":{"accession":"Q12792","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12792.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12792/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12792"}},"corpus_meta":[{"pmid":"23340433","id":"PMC_23340433","title":"MicroRNA-30c 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Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/32752001","citation_count":30,"is_preprint":false},{"pmid":"2529773","id":"PMC_2529773","title":"Aldosterone receptors in A6 cells: physicochemical characterization and autoradiographic study.","date":"1989","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2529773","citation_count":30,"is_preprint":false},{"pmid":"22399299","id":"PMC_22399299","title":"Intracellular modulation of signaling pathways by annexin A6 regulates terminal differentiation of chondrocytes.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22399299","citation_count":29,"is_preprint":false},{"pmid":"11083899","id":"PMC_11083899","title":"Activation of A(3) adenosine receptor induces calcium entry and chloride secretion in A(6) 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15671346","citation_count":27,"is_preprint":false},{"pmid":"34898626","id":"PMC_34898626","title":"Origin and evolution of HIV-1 subtype A6.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34898626","citation_count":26,"is_preprint":false},{"pmid":"27334756","id":"PMC_27334756","title":"Annexin A6 protein is downregulated in human hepatocellular carcinoma.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27334756","citation_count":24,"is_preprint":false},{"pmid":"32298680","id":"PMC_32298680","title":"Binding specificity of ostreolysin A6 towards Sf9 insect cell lipids.","date":"2020","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/32298680","citation_count":24,"is_preprint":false},{"pmid":"35737740","id":"PMC_35737740","title":"Anti-inflammatory effect of Bifidobacterium animalis subsp. lactis A6 on DSS-induced colitis in mice.","date":"2022","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35737740","citation_count":23,"is_preprint":false},{"pmid":"27702590","id":"PMC_27702590","title":"Annexin A6 regulates adipocyte lipid storage and adiponectin release.","date":"2016","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27702590","citation_count":22,"is_preprint":false},{"pmid":"34978890","id":"PMC_34978890","title":"Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine.","date":"2022","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/34978890","citation_count":22,"is_preprint":false},{"pmid":"22814500","id":"PMC_22814500","title":"Functional expression of amylosucrase, a glucan-synthesizing enzyme, from Arthrobacter chlorophenolicus A6.","date":"2012","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22814500","citation_count":22,"is_preprint":false},{"pmid":"9357761","id":"PMC_9357761","title":"Cloning and functional expression of a ClC Cl- channel from the renal cell line A6.","date":"1997","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9357761","citation_count":22,"is_preprint":false},{"pmid":"34490141","id":"PMC_34490141","title":"Characterization of Coxsackievirus A6 Strains Isolated From Children With Hand, Foot, and Mouth Disease.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34490141","citation_count":22,"is_preprint":false},{"pmid":"33739899","id":"PMC_33739899","title":"Efficacy of a coxsackievirus A6 vaccine candidate in an actively immunized mouse model.","date":"2021","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/33739899","citation_count":21,"is_preprint":false},{"pmid":"21272378","id":"PMC_21272378","title":"Interaction of annexin A6 with alpha actinin in cardiomyocytes.","date":"2011","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21272378","citation_count":21,"is_preprint":false},{"pmid":"8943313","id":"PMC_8943313","title":"Rapamycin inhibits protein kinase C activity and stimulates Na+ transport in A6 cells.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8943313","citation_count":21,"is_preprint":false},{"pmid":"35866481","id":"PMC_35866481","title":"A conserved annexin A6-mediated membrane repair mechanism in muscle, heart, and nerve.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35866481","citation_count":20,"is_preprint":false},{"pmid":"28771766","id":"PMC_28771766","title":"Impact of Coxsackievirus A6 emergence on hand, foot, and mouth disease epidemic in Osaka City, Japan.","date":"2017","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/28771766","citation_count":20,"is_preprint":false},{"pmid":"37218507","id":"PMC_37218507","title":"Annexin A1, A2, A5, and A6 involvement in human pathologies.","date":"2023","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/37218507","citation_count":19,"is_preprint":false},{"pmid":"20885977","id":"PMC_20885977","title":"Carboxypeptidase A6 in zebrafish development and implications for VIth cranial nerve pathfinding.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20885977","citation_count":19,"is_preprint":false},{"pmid":"15950771","id":"PMC_15950771","title":"Identification and distribution of mouse carboxypeptidase A-6.","date":"2005","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15950771","citation_count":19,"is_preprint":false},{"pmid":"11549852","id":"PMC_11549852","title":"Naloxone inhibits A6 cell Na(+)/H(+) exchange by activating protein kinase C via the mobilization of intracellular calcium.","date":"2001","source":"Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/11549852","citation_count":18,"is_preprint":false},{"pmid":"38846357","id":"PMC_38846357","title":"Evolutionary Diversity of Coxsackievirus A6 Causing Severe Hand, Foot, and Mouth Disease - China, 2012-2023.","date":"2024","source":"China CDC weekly","url":"https://pubmed.ncbi.nlm.nih.gov/38846357","citation_count":18,"is_preprint":false},{"pmid":"34519634","id":"PMC_34519634","title":"Long non-coding RNA FGD5-AS1 contributes to cisplatin resistance in hepatocellular carcinoma via sponging microRNA-153-3p by upregulating Twinfilin Actin Binding Protein 1 (TWF1).","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34519634","citation_count":17,"is_preprint":false},{"pmid":"31869496","id":"PMC_31869496","title":"Annexin A6 improves anti-migratory and anti-invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells.","date":"2020","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/31869496","citation_count":17,"is_preprint":false},{"pmid":"23105115","id":"PMC_23105115","title":"Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23105115","citation_count":17,"is_preprint":false},{"pmid":"35022465","id":"PMC_35022465","title":"Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35022465","citation_count":16,"is_preprint":false},{"pmid":"38749308","id":"PMC_38749308","title":"Evolution, recombination and geographic spreading of global Coxsackievirus A6.","date":"2024","source":"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology","url":"https://pubmed.ncbi.nlm.nih.gov/38749308","citation_count":16,"is_preprint":false},{"pmid":"29921656","id":"PMC_29921656","title":"Inhibition of somatosensory mechanotransduction by annexin A6.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29921656","citation_count":16,"is_preprint":false},{"pmid":"1556737","id":"PMC_1556737","title":"Na+ transport and impedance properties of cultured renal (A6 and 2F3) epithelia.","date":"1992","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/1556737","citation_count":16,"is_preprint":false},{"pmid":"25875328","id":"PMC_25875328","title":"Novel carboxypeptidase A6 (CPA6) mutations identified in patients with juvenile myoclonic and generalized epilepsy.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25875328","citation_count":16,"is_preprint":false},{"pmid":"29981169","id":"PMC_29981169","title":"Molecular epidemiology of coxsackievirus A6 derived from hand, foot, and mouth disease in Fukuoka between 2013 and 2017.","date":"2018","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/29981169","citation_count":16,"is_preprint":false},{"pmid":"31502682","id":"PMC_31502682","title":"Hand-foot-and-mouth disease in uruguay: Coxsackievirus A6 identified as causative of an outbreak in a rural childcare center.","date":"2019","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/31502682","citation_count":15,"is_preprint":false},{"pmid":"12190814","id":"PMC_12190814","title":"The increase in the frequency of MICA gene A6 allele in oral squamous cell carcinoma.","date":"2002","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12190814","citation_count":15,"is_preprint":false},{"pmid":"7522974","id":"PMC_7522974","title":"A monoclonal antibody (A6) recognizing a unique epitope restricted to CD45RO and RB isoforms of the leukocyte common antigen family identifies functional T cell subsets.","date":"1994","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7522974","citation_count":15,"is_preprint":false},{"pmid":"35697274","id":"PMC_35697274","title":"Epigenetically-regulated miR-30a/c-5p directly target TWF1 and hamper ccRCC cell aggressiveness.","date":"2022","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35697274","citation_count":14,"is_preprint":false},{"pmid":"31483918","id":"PMC_31483918","title":"Tyrosine kinase Eph receptor A6 sensitizes glioma-initiating cells towards bone morphogenetic protein-induced apoptosis.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/31483918","citation_count":14,"is_preprint":false},{"pmid":"32298357","id":"PMC_32298357","title":"Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32298357","citation_count":14,"is_preprint":false},{"pmid":"38658084","id":"PMC_38658084","title":"Defluorination of PFAS by Acidimicrobium sp. strain A6 and potential applications for remediation.","date":"2024","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/38658084","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53613,"output_tokens":1621,"usd":0.092577,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7866,"output_tokens":2002,"usd":0.04469,"stage2_stop_reason":"end_turn"},"total_usd":0.137267,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about TWF1 (twinfilin 1, also known as PTK9 or A6 in its protein alias context - not to be confused with the many other \"A6\" genes/organisms in this corpus).\n\nThe key papers about TWF1 (twinfilin 1) as the actin-binding protein are:\n- PMID:23340433 - microRNA-30c targets twinfilin 1 (TWF1) in breast cancer\n- PMID:31619579 - lncRNA SBF2-AS1/miR-142-3p/TWF1 axis in pancreatic cancer\n- PMID:34519634 - lncRNA FGD5-AS1/miR-153-3p/TWF1 axis in HCC\n- PMID:35697274 - miR-30a/c-5p directly target TWF1 in ccRCC\n\nAll other papers are about different \"A6\" entities (Annexin A6/ANXA6, Coxsackievirus A6, noradrenergic A6 neurons, HIV subtype A6, renal A6 cell line, EphA6, CPA6, etc.) - none of these are TWF1/twinfilin 1.\n\nThe TWF1-relevant papers provide limited mechanistic detail - mostly ceRNA/miRNA regulatory axes and EMT associations, without direct biochemical characterization of TWF1 protein mechanism.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TWF1 (twinfilin 1), an actin-binding protein, is a direct target of microRNA-30c in breast cancer cells; miR-30c suppression of TWF1 promotes epithelial-to-mesenchymal transition and chemotherapy resistance, and IL-11 was identified as a secondary downstream target of this pathway.\",\n      \"method\": \"Direct targeting validated by miRNA overexpression/knockdown, functional assays for EMT and chemoresistance, with miR-30c shown to be transcriptionally regulated by GATA3\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct miRNA-target relationship established with functional readouts (EMT, chemoresistance) in a single study, but mechanistic detail on how TWF1 protein itself promotes EMT is not biochemically resolved\",\n      \"pmids\": [\"23340433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TWF1 (twinfilin actin binding protein 1) is a direct target of miR-30a/c-5p in clear cell renal cell carcinoma (ccRCC); both miRs directly bind TWF1 3'UTR (confirmed by luciferase assay), and TWF1 knockdown reduced cell aggressiveness and EMT markers while upregulating epithelial markers Claudin-1 and ZO-1, implicating TWF1 in EMT regulation.\",\n      \"method\": \"Luciferase reporter assay confirming direct miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown of TWF1 with functional assays (migration, invasion, EMT marker expression); immunohistochemistry in patient tissues\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional siRNA knockdown with defined EMT phenotype, single lab with orthogonal methods\",\n      \"pmids\": [\"35697274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TWF1 expression is regulated by the lncRNA SBF2-AS1/miR-142-3p axis in gemcitabine-resistant pancreatic cancer: SBF2-AS1 acts as a ceRNA to sponge miR-142-3p, thereby relieving miR-142-3p-mediated repression of TWF1 and promoting drug resistance and EMT.\",\n      \"method\": \"Luciferase reporter and RNA immunoprecipitation (RIP) assays confirming SBF2-AS1 binding to miR-142-3p and miR-142-3p targeting of TWF1; knockdown/overexpression functional assays in gemcitabine-resistant cell lines\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ceRNA axis validated by reporter and RIP in single lab; TWF1 protein mechanism itself not directly studied\",\n      \"pmids\": [\"31619579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TWF1 expression is regulated by the lncRNA FGD5-AS1/miR-153-3p axis in cisplatin-resistant hepatocellular carcinoma: FGD5-AS1 sponges miR-153-3p to upregulate TWF1, and TWF1 knockdown reduced drug resistance, invasion, and promoted apoptosis in HCC cells.\",\n      \"method\": \"Luciferase reporter and RIP assays confirming FGD5-AS1/miR-153-3p and miR-153-3p/TWF1 interactions; siRNA knockdown of TWF1 with CCK-8, colony formation, Transwell, and TUNEL functional assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ceRNA axis and functional knockdown in single lab; mechanistic role of TWF1 protein itself not resolved beyond drug resistance phenotype\",\n      \"pmids\": [\"34519634\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TWF1 (twinfilin 1) is an actin-binding protein whose expression is post-transcriptionally suppressed by miR-30c (in breast cancer) and miR-30a/c-5p (in renal cancer), and is upregulated via ceRNA sponging by lncRNAs SBF2-AS1 and FGD5-AS1; elevated TWF1 promotes epithelial-to-mesenchymal transition and chemotherapy resistance, though the precise biochemical mechanism by which TWF1 drives these phenotypes remains uncharacterized in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TWF1 (twinfilin 1) is an actin-binding protein that functions as a downstream effector promoting epithelial-to-mesenchymal transition (EMT) and chemotherapy resistance across multiple carcinoma contexts [#0, #1]. Its expression is held in check post-transcriptionally by microRNAs that bind its 3'UTR: miR-30c in breast cancer [#0] and miR-30a/c-5p in clear cell renal cell carcinoma, where direct binding was confirmed by luciferase reporter assay [#1]. When this repression is relieved, elevated TWF1 drives a mesenchymal program—knockdown of TWF1 reduces migration, invasion, and EMT-marker expression while restoring epithelial markers Claudin-1 and ZO-1 [#1]. In breast cancer, miR-30c is itself transcriptionally controlled by GATA3, and IL-11 acts as a secondary downstream target of the miR-30c–TWF1 axis [#0]. The biochemical mechanism by which the TWF1 protein itself executes EMT and chemoresistance has not been characterized in the available corpus; the evidence establishes TWF1 as a regulated node in these phenotypes rather than defining its molecular action.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established TWF1 as a functionally relevant, microRNA-regulated driver of cancer phenotype by showing it is a direct miR-30c target whose suppression promotes EMT and chemoresistance.\",\n      \"evidence\": \"miR-30c overexpression/knockdown with EMT and chemoresistance functional assays in breast cancer cells; GATA3 shown to regulate miR-30c and IL-11 identified as a downstream target\",\n      \"pmids\": [\"23340433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How the TWF1 protein biochemically promotes EMT was not resolved\",\n        \"Direct 3'UTR binding not demonstrated by reporter assay in this study\",\n        \"Link between TWF1 actin-binding activity and the EMT phenotype unestablished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TWF1 regulation to a ceRNA framework in drug-resistant pancreatic cancer, positioning lncRNA SBF2-AS1 as an upstream de-repressor of TWF1 via miR-142-3p sponging.\",\n      \"evidence\": \"Luciferase reporter and RIP assays for SBF2-AS1/miR-142-3p and miR-142-3p/TWF1; knockdown/overexpression in gemcitabine-resistant cell lines\",\n      \"pmids\": [\"31619579\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-lab ceRNA axis; TWF1 protein mechanism not directly studied\",\n        \"Whether TWF1 alone is sufficient to confer gemcitabine resistance not isolated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the lncRNA-sponging mode of TWF1 upregulation to cisplatin-resistant hepatocellular carcinoma, linking TWF1 levels to drug resistance, invasion, and apoptosis suppression.\",\n      \"evidence\": \"Luciferase reporter and RIP for FGD5-AS1/miR-153-3p and miR-153-3p/TWF1; siRNA knockdown with CCK-8, colony formation, Transwell, and TUNEL assays\",\n      \"pmids\": [\"34519634\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-lab ceRNA axis; biochemical role of TWF1 protein not resolved\",\n        \"Mechanism connecting TWF1 to apoptosis regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed direct 3'UTR targeting of TWF1 by miR-30a/c-5p and demonstrated that loss of TWF1 reverses the mesenchymal program in renal cancer, solidifying TWF1 as an EMT effector.\",\n      \"evidence\": \"Luciferase reporter assay for miR-30a/c-5p binding to TWF1 3'UTR; siRNA knockdown with migration/invasion and EMT-marker assays plus patient-tissue immunohistochemistry in ccRCC\",\n      \"pmids\": [\"35697274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which TWF1 modulates Claudin-1/ZO-1 and EMT not defined\",\n        \"Connection between TWF1 actin-binding function and EMT signaling unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which TWF1 protein executes EMT and chemoresistance—its actin-related activity, binding partners, and the signaling steps linking it to epithelial-marker loss—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or enzymatic characterization of TWF1 in the corpus\",\n        \"No identified protein partners or actin-regulatory mechanism tied to the EMT phenotype\",\n        \"Whether TWF1's actin-binding activity is required for chemoresistance is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}