{"gene":"TWF1","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2010,"finding":"Twinfilin-1 (TWF1) is a direct target of microRNA-1 (miR-1) in cardiomyocytes. miR-1 suppresses TWF1 expression by binding the 3' UTR of twinfilin-1 mRNA (luciferase reporter and endogenous protein suppression confirmed). miR-1 is downregulated in hypertrophic rat left ventricles and phenylephrine-treated cardiomyocytes, leading to upregulation of twinfilin-1 protein. Overexpression of twinfilin-1 promotes cardiomyocyte hypertrophy, and silencing miR-1 phenocopies this effect, establishing that miR-1 attenuation derepresses TWF1 to drive cytoskeletal remodeling and cardiac hypertrophy.","method":"Luciferase 3' UTR reporter assay, Western blot of endogenous protein, microRNA microarray, cardiomyocyte overexpression/knockdown with cell-size and hypertrophic-marker readouts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (reporter assay, endogenous protein measurement, gain- and loss-of-function phenotypic readouts) in a single study with strong mechanistic conclusion","pmids":["20571053"],"is_preprint":false},{"year":2013,"finding":"TWF1 (twinfilin-1) is a direct target of microRNA-30c in human breast cancer cells. miR-30c suppresses TWF1 expression, and TWF1 promotes epithelial-to-mesenchymal transition (EMT). Reduced miR-30c leads to TWF1 upregulation, which in turn induces EMT and contributes to chemotherapy resistance. Interleukin-11 (IL-11) was identified as a secondary downstream target of twinfilin-1 in this pathway, and miR-30c is transcriptionally regulated by GATA3.","method":"Direct miRNA targeting validated by reporter assay; TWF1 knockdown/overexpression with EMT marker readouts; IL-11 identified as downstream effector; GATA3 transcriptional regulation of miR-30c established","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including direct miRNA target validation, loss-of-function rescue, and pathway epistasis in a well-controlled study","pmids":["23340433"],"is_preprint":false},{"year":2019,"finding":"LncRNA SBF2-AS1 acts as a competing endogenous RNA (ceRNA) that sponges miR-142-3p, thereby relieving miR-142-3p-mediated suppression of TWF1 expression. In gemcitabine-resistant pancreatic cancer cells, elevated SBF2-AS1 increases TWF1 protein levels. Knockdown of TWF1 inhibited proliferation, EMT, and drug resistance while promoting apoptosis. The binding of miR-142-3p to the TWF1 3' UTR was confirmed, placing TWF1 as a functional downstream effector in the SBF2-AS1/miR-142-3p/TWF1 axis driving gemcitabine resistance.","method":"Luciferase reporter assay (miR-142-3p binding to TWF1 3' UTR and SBF2-AS1), siRNA knockdown of TWF1 and SBF2-AS1, cell viability/apoptosis/EMT assays in drug-resistant pancreatic cancer cell lines","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple validated interactions (reporter assay, knockdown phenotypes) but single laboratory study with functional but indirect pathway placement","pmids":["31619579"],"is_preprint":false},{"year":2021,"finding":"LncRNA FGD5-AS1 promotes cisplatin (DDP) resistance in hepatocellular carcinoma by sponging miR-153-3p, which directly targets TWF1. miR-153-3p binding to TWF1 was confirmed by luciferase reporter and RIP assays. Knockdown of TWF1 inhibited DDP resistance, reduced invasion, and promoted apoptosis in HCC cells; this effect was reversed by miR-153-3p deletion. FGD5-AS1 silencing decreased TWF1 expression, which was rescued by miR-153-3p inhibition, establishing FGD5-AS1/miR-153-3p/TWF1 as a functional axis in cisplatin resistance.","method":"Luciferase reporter assay, RIP assay, RT-qPCR, siRNA knockdown, CCK-8/colony formation/Transwell/TUNEL assays","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct miRNA-TWF1 interaction validated by two independent methods (luciferase + RIP), functional rescue experiments, single laboratory","pmids":["34519634"],"is_preprint":false},{"year":2022,"finding":"MiR-30a-5p and miR-30c-5p directly target TWF1 in clear cell renal cell carcinoma (ccRCC). Both miRs are epigenetically silenced by promoter methylation in ccRCC. Re-expression of miR-30a/c-5p decreased TWF1 protein levels and reduced cell aggressiveness, decreased expression of EMT-promoting markers, and upregulated epithelial markers (Claudin-1, ZO-1). TWF1 was confirmed as a direct target of both miRs by luciferase assay and functional siRNA knockdown of TWF1 recapitulated the anti-aggressiveness phenotype. Higher TWF1 protein expression (by IHC) correlated with metastatic disease in primary ccRCC tissues.","method":"Luciferase 3' UTR reporter assay, Western blot, siRNA knockdown of TWF1, functional assays (migration/invasion/EMT markers), immunohistochemistry on ccRCC patient tissues, decitabine treatment to restore miR expression","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct target validation by reporter assay plus functional loss-of-function with defined EMT phenotype, single laboratory","pmids":["35697274"],"is_preprint":false}],"current_model":"TWF1 (twinfilin-1) is an actin cytoskeleton regulatory protein whose expression is post-transcriptionally repressed by multiple microRNAs (miR-1, miR-30c, miR-30a/c-5p, miR-142-3p, miR-153-3p); derepression of TWF1 through miRNA downregulation or lncRNA-mediated ceRNA sponging promotes epithelial-to-mesenchymal transition, cardiomyocyte hypertrophy, and chemotherapy resistance, with TWF1 acting downstream of these regulatory axes to remodel the actin cytoskeleton and drive cell aggressiveness."},"narrative":{"teleology":[{"year":2010,"claim":"Identifying TWF1 as a miR-1 target answered how hypertrophic stimuli remodel the cardiomyocyte cytoskeleton: miR-1 downregulation during cardiac hypertrophy derepresses twinfilin-1, whose overexpression is sufficient to enlarge cardiomyocytes.","evidence":"Luciferase 3ʹ-UTR reporter, endogenous protein Western blot, gain- and loss-of-function in rat cardiomyocytes with hypertrophic-marker and cell-size readouts","pmids":["20571053"],"confidence":"High","gaps":["Mechanism by which elevated twinfilin-1 protein reorganizes actin to enlarge cardiomyocytes was not resolved","In vivo cardiac phenotype of TWF1 overexpression or deletion not tested","Whether other ADF-H domain proteins compensate for TWF1 loss in cardiomyocytes is unknown"]},{"year":2013,"claim":"Establishing the GATA3→miR-30c⊣TWF1→IL-11 axis in breast cancer revealed that twinfilin-1 is not only a cytoskeletal regulator but also an EMT inducer and chemoresistance factor, broadening its functional significance beyond cardiomyocytes.","evidence":"miR-30c target validation by reporter assay, TWF1 knockdown/overexpression with EMT marker analysis, IL-11 identified as downstream mediator, in breast cancer cell lines","pmids":["23340433"],"confidence":"High","gaps":["How twinfilin-1 activates IL-11 expression is mechanistically undefined","Direct actin-remodeling activity of TWF1 was not measured in this cancer context","In vivo tumor model validation was limited"]},{"year":2019,"claim":"Demonstrating that lncRNA SBF2-AS1 sponges miR-142-3p to derepress TWF1 in gemcitabine-resistant pancreatic cancer established ceRNA-mediated regulation as a recurrent mechanism controlling TWF1 levels in drug resistance.","evidence":"Luciferase reporter confirming miR-142-3p binding to TWF1 3ʹ-UTR, siRNA knockdown of TWF1, proliferation/apoptosis/EMT assays in drug-resistant pancreatic cancer lines","pmids":["31619579"],"confidence":"Medium","gaps":["Single-laboratory study; independent replication in additional pancreatic cancer models lacking","Contribution of TWF1 versus other miR-142-3p targets to the resistance phenotype not deconvolved","No in vivo xenograft validation"]},{"year":2021,"claim":"A parallel ceRNA axis—FGD5-AS1/miR-153-3p/TWF1—was shown to drive cisplatin resistance in hepatocellular carcinoma, reinforcing the generality of miRNA-mediated TWF1 derepression as a chemoresistance mechanism across cancer types.","evidence":"Luciferase reporter plus RIP assay confirming miR-153-3p–TWF1 interaction, functional rescue with miR-153-3p inhibition, CCK-8/colony/Transwell/TUNEL assays in HCC cells","pmids":["34519634"],"confidence":"Medium","gaps":["Single-laboratory study without in vivo validation","Downstream signaling connecting TWF1 to apoptosis resistance not identified","Overlap or redundancy with twinfilin-2 not assessed"]},{"year":2022,"claim":"Showing that epigenetic silencing of miR-30a-5p/miR-30c-5p elevates TWF1 in clear cell renal cell carcinoma, and that higher TWF1 protein correlates with metastasis in patient tissues, provided the first clinical-pathological link between TWF1 expression and tumor progression.","evidence":"Luciferase 3ʹ-UTR reporter, siRNA knockdown of TWF1, EMT marker analysis, IHC on primary ccRCC tissues, decitabine-mediated miR re-expression","pmids":["35697274"],"confidence":"Medium","gaps":["Correlation between TWF1 IHC and metastasis is associative; causal role in vivo not tested","Whether methylation-dependent miR silencing is a driver or passenger in ccRCC unknown","Structural basis for TWF1-driven EMT remains uncharacterized"]},{"year":null,"claim":"The direct actin-remodeling mechanism by which elevated twinfilin-1 induces EMT and hypertrophy—including identification of specific actin structures affected and whether its barbed-end capping or monomer-sequestering activity is required—remains unresolved across all disease contexts studied.","evidence":"","pmids":[],"confidence":"High","gaps":["No mutagenesis separating ADF-H domain actin-binding activities from EMT/hypertrophy phenotypes","No structural or biophysical characterization of TWF1 in the EMT or cardiac contexts","In vivo genetic models (knockout/knock-in) for TWF1 in cancer or cardiac hypertrophy are absent from the literature captured here"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,3,4]}],"complexes":[],"partners":["IL11"],"other_free_text":[]},"mechanistic_narrative":"Twinfilin-1 (TWF1) is an actin-binding protein that, when upregulated, drives actin cytoskeletal remodeling to promote epithelial-to-mesenchymal transition (EMT), cardiomyocyte hypertrophy, and chemotherapy resistance. TWF1 expression is post-transcriptionally repressed by multiple microRNAs—miR-1 in cardiomyocytes [PMID:20571053], miR-30c and miR-30a/c-5p in breast and renal carcinoma cells [PMID:23340433, PMID:35697274], and miR-142-3p and miR-153-3p in pancreatic and hepatocellular carcinoma cells [PMID:31619579, PMID:34519634]—such that loss of these miRNAs or their sequestration by competing endogenous lncRNAs derepresses TWF1 and activates downstream EMT and pro-survival programs. Silencing of TWF1 consistently suppresses invasion, restores epithelial marker expression, promotes apoptosis, and sensitizes cancer cells to gemcitabine and cisplatin, establishing TWF1 as a functional effector downstream of these regulatory axes [PMID:31619579, PMID:34519634, PMID:35697274]."},"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":"10435578","id":"PMC_10435578","title":"Four 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FASN.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30425250","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27872092","id":"PMC_27872092","title":"Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27872092","citation_count":121,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27545878","id":"PMC_27545878","title":"SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27545878","citation_count":115,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34591612","id":"PMC_34591612","title":"A protein interaction landscape of breast cancer.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/34591612","citation_count":111,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29478914","id":"PMC_29478914","title":"Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/29478914","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35013218","id":"PMC_35013218","title":"EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013218","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52094,"output_tokens":1616,"usd":0.090261},"stage2":{"model":"claude-opus-4-6","input_tokens":4526,"output_tokens":1624,"usd":0.094845},"total_usd":0.414267,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":64114,"output_tokens":2482,"usd":0.114786},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5385,"output_tokens":1973,"usd":0.114375}},"stage1_raw":"Looking at the corpus, I need to identify papers about TWF1 (Twinfilin 1, also known as twinfilin actin binding protein 1). Most papers in this corpus are about other genes/proteins that share \"A6\" in their names (Annexin A6, Coxsackievirus A6, HIV subtype A6, etc.) or are completely unrelated. I need to find papers specifically about TWF1/twinfilin-1.\n\nRelevant papers for TWF1:\n- PMID:23340433 (miR-30c targets twinfilin 1, promotes EMT, chemoresistance)\n- PMID:31619579 (SBF2-AS1/miR-142-3p/TWF1 axis in gemcitabine resistance)\n- PMID:35697274 (miR-30a/c-5p directly target TWF1, EMT in ccRCC)\n- PMID:34519634 (FGD5-AS1/miR-153-3p/TWF1 in cisplatin resistance in HCC)\n- PMID:34898626 (TWF1 mentioned as target but no mechanistic detail)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"MicroRNA-30c directly targets twinfilin 1 (TWF1), an actin-binding protein, to promote epithelial-to-mesenchymal transition (EMT) and chemotherapy resistance in breast cancer; TWF1 knockdown phenocopied miR-30c overexpression, and IL-11 was identified as a secondary downstream target of TWF1 in this pathway. GATA3 was found to transcriptionally regulate miR-30c upstream of this cascade.\",\n      \"method\": \"Direct miR-30c targeting of TWF1 confirmed by luciferase reporter assay and functional rescue experiments; TWF1 knockdown/overexpression with EMT and chemoresistance phenotypic readouts; IL-11 identified as downstream effector\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, KD/OE, functional phenotype) in a single rigorous study with strong mechanistic follow-through\",\n      \"pmids\": [\"23340433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LncRNA SBF2-AS1 acts as a competing endogenous RNA (ceRNA) to sponge miR-142-3p, thereby relieving miR-142-3p-mediated suppression of TWF1, which promotes gemcitabine resistance and epithelial-to-mesenchymal transition in pancreatic cancer cells.\",\n      \"method\": \"Luciferase reporter assay and RNA immunoprecipitation (RIP) confirming SBF2-AS1/miR-142-3p and miR-142-3p/TWF1 binding; TWF1 knockdown reversing gemcitabine resistance; cell proliferation, apoptosis, and EMT phenotypic assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — binding confirmed by luciferase and RIP, functional KD with defined phenotype, but single lab\",\n      \"pmids\": [\"31619579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MiR-30a/c-5p directly target TWF1 in clear cell renal cell carcinoma (ccRCC); miR-30a/c-5p overexpression decreased TWF1 protein levels and reduced cell aggressiveness (migration, invasion) and EMT, while TWF1 siRNA knockdown phenocopied these effects, implicating TWF1 in EMT-driven ccRCC progression. miR-30c-5p promoter is aberrantly methylated in ccRCC, epigenetically silencing the miRNA and allowing TWF1 upregulation.\",\n      \"method\": \"Luciferase reporter assay confirming direct miR-30a/c-5p targeting of TWF1 3'UTR; Western blot for TWF1 protein; siRNA knockdown with functional assays (invasion, migration, EMT marker expression); decitabine treatment restoring miR expression; IHC in patient tissues\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct target validation by luciferase plus functional KD, single lab with multiple methods\",\n      \"pmids\": [\"35697274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA FGD5-AS1 acts as a ceRNA to sponge miR-153-3p, thereby upregulating TWF1 expression and promoting cisplatin resistance in hepatocellular carcinoma; TWF1 knockdown inhibited DDP resistance, invasion, and promoted apoptosis, whereas miR-153-3p inhibition reversed these effects.\",\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 apoptosis assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct binding validated by luciferase and RIP, functional KD with defined phenotype, single lab\",\n      \"pmids\": [\"34519634\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TWF1 (twinfilin 1) is an actin-binding protein that is directly targeted and suppressed by microRNAs of the miR-30 family (miR-30c, miR-30a/c-5p) and miR-142-3p/miR-153-3p; when these miRNAs are themselves suppressed (by lncRNA ceRNA sponging or epigenetic silencing), TWF1 upregulation promotes epithelial-to-mesenchymal transition and chemotherapy/targeted therapy resistance across multiple cancer types including breast, pancreatic, renal, and hepatocellular carcinoma.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nFrom the retrieved 100 papers, I need to identify papers about TWF1 (Twinfilin-1, the actin-binding protein). Most papers are about \"A6\" designations that refer to completely different entities (Coxsackievirus A6, Annexin A6, EphA6, HIV subtype A6, A6 kidney cell line, etc.).\n\n- PMID 23340433 (miR-30c targets TWF1/twinfilin-1): KEEP\n- PMID 31619579 (SBF2-AS1/miR-142-3p/TWF1): KEEP  \n- PMID 34519634 (FGD5-AS1/miR-153-3p/TWF1): KEEP\n- PMID 35697274 (miR-30a/c-5p target TWF1): KEEP\n- PMID 20571053 (miR-1 targets twinfilin-1 in cardiac hypertrophy): KEEP\n\nFrom gene2pubmed papers:\n- PMID 21423176 (focal adhesion proteome, mentions TWF1 in proteomics context): borderline — it's a proteomics dataset paper, not mechanistic for TWF1 specifically → EXCLUDE\n- PMID 12477932, 14702039, 28514442, 26496610, 32296183, 33961781, 22939629, 21873635, 18976975, 26344197, 25796446, 34079125, 22863883, 28524877, 32807901, 25468996, 30833792, 18461144, 31871319, 21832049, 30425250, 27872092, 27545878, 18029348, 34591612, 29478914, 35013218: These are large-scale proteomics/interactome/screen papers where TWF1 may appear as a data point but no specific mechanistic finding about TWF1 is described → EXCLUDE\n\nAll other retrieved papers (Annexin A6, CVA6, EphA6, A6 cell line, HIV A6, etc.) are EXCLUDE (alias collision).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Twinfilin-1 (TWF1) is a direct target of microRNA-1 (miR-1) in cardiomyocytes. miR-1 suppresses TWF1 expression by binding the 3' UTR of twinfilin-1 mRNA (luciferase reporter and endogenous protein suppression confirmed). miR-1 is downregulated in hypertrophic rat left ventricles and phenylephrine-treated cardiomyocytes, leading to upregulation of twinfilin-1 protein. Overexpression of twinfilin-1 promotes cardiomyocyte hypertrophy, and silencing miR-1 phenocopies this effect, establishing that miR-1 attenuation derepresses TWF1 to drive cytoskeletal remodeling and cardiac hypertrophy.\",\n      \"method\": \"Luciferase 3' UTR reporter assay, Western blot of endogenous protein, microRNA microarray, cardiomyocyte overexpression/knockdown with cell-size and hypertrophic-marker readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (reporter assay, endogenous protein measurement, gain- and loss-of-function phenotypic readouts) in a single study with strong mechanistic conclusion\",\n      \"pmids\": [\"20571053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWF1 (twinfilin-1) is a direct target of microRNA-30c in human breast cancer cells. miR-30c suppresses TWF1 expression, and TWF1 promotes epithelial-to-mesenchymal transition (EMT). Reduced miR-30c leads to TWF1 upregulation, which in turn induces EMT and contributes to chemotherapy resistance. Interleukin-11 (IL-11) was identified as a secondary downstream target of twinfilin-1 in this pathway, and miR-30c is transcriptionally regulated by GATA3.\",\n      \"method\": \"Direct miRNA targeting validated by reporter assay; TWF1 knockdown/overexpression with EMT marker readouts; IL-11 identified as downstream effector; GATA3 transcriptional regulation of miR-30c established\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including direct miRNA target validation, loss-of-function rescue, and pathway epistasis in a well-controlled study\",\n      \"pmids\": [\"23340433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LncRNA SBF2-AS1 acts as a competing endogenous RNA (ceRNA) that sponges miR-142-3p, thereby relieving miR-142-3p-mediated suppression of TWF1 expression. In gemcitabine-resistant pancreatic cancer cells, elevated SBF2-AS1 increases TWF1 protein levels. Knockdown of TWF1 inhibited proliferation, EMT, and drug resistance while promoting apoptosis. The binding of miR-142-3p to the TWF1 3' UTR was confirmed, placing TWF1 as a functional downstream effector in the SBF2-AS1/miR-142-3p/TWF1 axis driving gemcitabine resistance.\",\n      \"method\": \"Luciferase reporter assay (miR-142-3p binding to TWF1 3' UTR and SBF2-AS1), siRNA knockdown of TWF1 and SBF2-AS1, cell viability/apoptosis/EMT assays in drug-resistant pancreatic cancer cell lines\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple validated interactions (reporter assay, knockdown phenotypes) but single laboratory study with functional but indirect pathway placement\",\n      \"pmids\": [\"31619579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA FGD5-AS1 promotes cisplatin (DDP) resistance in hepatocellular carcinoma by sponging miR-153-3p, which directly targets TWF1. miR-153-3p binding to TWF1 was confirmed by luciferase reporter and RIP assays. Knockdown of TWF1 inhibited DDP resistance, reduced invasion, and promoted apoptosis in HCC cells; this effect was reversed by miR-153-3p deletion. FGD5-AS1 silencing decreased TWF1 expression, which was rescued by miR-153-3p inhibition, establishing FGD5-AS1/miR-153-3p/TWF1 as a functional axis in cisplatin resistance.\",\n      \"method\": \"Luciferase reporter assay, RIP assay, RT-qPCR, siRNA knockdown, CCK-8/colony formation/Transwell/TUNEL assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct miRNA-TWF1 interaction validated by two independent methods (luciferase + RIP), functional rescue experiments, single laboratory\",\n      \"pmids\": [\"34519634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MiR-30a-5p and miR-30c-5p directly target TWF1 in clear cell renal cell carcinoma (ccRCC). Both miRs are epigenetically silenced by promoter methylation in ccRCC. Re-expression of miR-30a/c-5p decreased TWF1 protein levels and reduced cell aggressiveness, decreased expression of EMT-promoting markers, and upregulated epithelial markers (Claudin-1, ZO-1). TWF1 was confirmed as a direct target of both miRs by luciferase assay and functional siRNA knockdown of TWF1 recapitulated the anti-aggressiveness phenotype. Higher TWF1 protein expression (by IHC) correlated with metastatic disease in primary ccRCC tissues.\",\n      \"method\": \"Luciferase 3' UTR reporter assay, Western blot, siRNA knockdown of TWF1, functional assays (migration/invasion/EMT markers), immunohistochemistry on ccRCC patient tissues, decitabine treatment to restore miR expression\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct target validation by reporter assay plus functional loss-of-function with defined EMT phenotype, single laboratory\",\n      \"pmids\": [\"35697274\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TWF1 (twinfilin-1) is an actin cytoskeleton regulatory protein whose expression is post-transcriptionally repressed by multiple microRNAs (miR-1, miR-30c, miR-30a/c-5p, miR-142-3p, miR-153-3p); derepression of TWF1 through miRNA downregulation or lncRNA-mediated ceRNA sponging promotes epithelial-to-mesenchymal transition, cardiomyocyte hypertrophy, and chemotherapy resistance, with TWF1 acting downstream of these regulatory axes to remodel the actin cytoskeleton and drive cell aggressiveness.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TWF1 encodes twinfilin 1, an actin-binding protein whose upregulation promotes epithelial-to-mesenchymal transition (EMT) and chemotherapy resistance across multiple cancer types. TWF1 is a direct target of miR-30 family members (miR-30c, miR-30a/c-5p) and miR-142-3p/miR-153-3p, which suppress TWF1 expression; relief of this suppression—through epigenetic silencing of the miRNA promoter or lncRNA-mediated ceRNA sponging—leads to TWF1 upregulation, increased cell migration and invasion, and drug resistance in breast, pancreatic, renal, and hepatocellular carcinoma [PMID:23340433, PMID:31619579, PMID:35697274, PMID:34519634]. TWF1 knockdown phenocopies miRNA overexpression by reducing EMT markers and restoring chemosensitivity, and in breast cancer TWF1 signals through IL-11 as a downstream effector [PMID:23340433].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"The first mechanistic link between a miRNA and TWF1 was established, showing that miR-30c directly suppresses TWF1 to control EMT and chemoresistance in breast cancer, with IL-11 identified as a downstream mediator of TWF1 signaling.\",\n      \"evidence\": \"Luciferase reporter assay confirming miR-30c targeting of TWF1 3′UTR, TWF1 knockdown/overexpression with EMT and doxorubicin resistance readouts in breast cancer cell lines\",\n      \"pmids\": [\"23340433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular mechanism by which TWF1 protein induces IL-11 expression is unknown\",\n        \"Whether TWF1's actin-binding activity is required for its EMT-promoting function was not tested\",\n        \"In vivo validation in animal models was limited\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The ceRNA paradigm was extended to TWF1 regulation when lncRNA SBF2-AS1 was shown to sponge miR-142-3p, derepressing TWF1 and driving gemcitabine resistance and EMT in pancreatic cancer, establishing TWF1 as a convergent node across cancer types and miRNA axes.\",\n      \"evidence\": \"Luciferase reporter and RNA immunoprecipitation confirming SBF2-AS1/miR-142-3p and miR-142-3p/TWF1 interactions; TWF1 knockdown reversing resistance in pancreatic cancer cells\",\n      \"pmids\": [\"31619579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Whether TWF1 engages IL-11 or distinct downstream effectors in pancreatic cancer is unexplored\",\n        \"No in vivo xenograft validation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A second ceRNA axis—lncRNA FGD5-AS1 sponging miR-153-3p—was shown to upregulate TWF1 and confer cisplatin resistance in hepatocellular carcinoma, broadening the repertoire of miRNAs converging on TWF1.\",\n      \"evidence\": \"Luciferase reporter and RIP assays for FGD5-AS1/miR-153-3p/TWF1 axis; TWF1 siRNA knockdown with drug resistance and apoptosis assays in HCC cells\",\n      \"pmids\": [\"34519634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; awaits independent replication\",\n        \"Downstream signaling from TWF1 in HCC not characterized\",\n        \"No assessment of whether TWF1 actin-binding function contributes to cisplatin resistance\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epigenetic silencing of miR-30c-5p by promoter methylation was identified as a mechanism of TWF1 upregulation in clear cell renal cell carcinoma, demonstrating that TWF1 derepression can occur through DNA methylation-dependent miRNA loss in addition to ceRNA sponging.\",\n      \"evidence\": \"Luciferase reporter confirming miR-30a/c-5p targeting of TWF1 3′UTR; decitabine treatment restoring miR-30c-5p expression; TWF1 siRNA knockdown reducing migration, invasion, and EMT markers in ccRCC cells and patient tissue IHC\",\n      \"pmids\": [\"35697274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent validation\",\n        \"Whether methylation-driven TWF1 upregulation is sufficient to drive metastasis in vivo is untested\",\n        \"The direct actin-related biochemical mechanism linking TWF1 to EMT remains undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which TWF1 protein—through its actin-binding activity or other interactions—drives EMT and drug resistance remains uncharacterized; no study has dissected whether actin dynamics remodeling, IL-11 signaling, or additional effectors are the primary mediators.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure-function analysis of TWF1 domains in the context of EMT or chemoresistance\",\n        \"No unbiased identification of TWF1 protein interactors or downstream signaling pathways beyond IL-11\",\n        \"No in vivo genetic models addressing TWF1 contribution to tumor progression or metastasis\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0008092\",\n        \"supporting_discovery_ids\": [0, 2]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1643685\",\n        \"supporting_discovery_ids\": [0, 1, 2, 3]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Twinfilin-1 (TWF1) is an actin-binding protein that, when upregulated, drives actin cytoskeletal remodeling to promote epithelial-to-mesenchymal transition (EMT), cardiomyocyte hypertrophy, and chemotherapy resistance. TWF1 expression is post-transcriptionally repressed by multiple microRNAs—miR-1 in cardiomyocytes [PMID:20571053], miR-30c and miR-30a/c-5p in breast and renal carcinoma cells [PMID:23340433, PMID:35697274], and miR-142-3p and miR-153-3p in pancreatic and hepatocellular carcinoma cells [PMID:31619579, PMID:34519634]—such that loss of these miRNAs or their sequestration by competing endogenous lncRNAs derepresses TWF1 and activates downstream EMT and pro-survival programs. Silencing of TWF1 consistently suppresses invasion, restores epithelial marker expression, promotes apoptosis, and sensitizes cancer cells to gemcitabine and cisplatin, establishing TWF1 as a functional effector downstream of these regulatory axes [PMID:31619579, PMID:34519634, PMID:35697274].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying TWF1 as a miR-1 target answered how hypertrophic stimuli remodel the cardiomyocyte cytoskeleton: miR-1 downregulation during cardiac hypertrophy derepresses twinfilin-1, whose overexpression is sufficient to enlarge cardiomyocytes.\",\n      \"evidence\": \"Luciferase 3ʹ-UTR reporter, endogenous protein Western blot, gain- and loss-of-function in rat cardiomyocytes with hypertrophic-marker and cell-size readouts\",\n      \"pmids\": [\"20571053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which elevated twinfilin-1 protein reorganizes actin to enlarge cardiomyocytes was not resolved\",\n        \"In vivo cardiac phenotype of TWF1 overexpression or deletion not tested\",\n        \"Whether other ADF-H domain proteins compensate for TWF1 loss in cardiomyocytes is unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing the GATA3→miR-30c⊣TWF1→IL-11 axis in breast cancer revealed that twinfilin-1 is not only a cytoskeletal regulator but also an EMT inducer and chemoresistance factor, broadening its functional significance beyond cardiomyocytes.\",\n      \"evidence\": \"miR-30c target validation by reporter assay, TWF1 knockdown/overexpression with EMT marker analysis, IL-11 identified as downstream mediator, in breast cancer cell lines\",\n      \"pmids\": [\"23340433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How twinfilin-1 activates IL-11 expression is mechanistically undefined\",\n        \"Direct actin-remodeling activity of TWF1 was not measured in this cancer context\",\n        \"In vivo tumor model validation was limited\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that lncRNA SBF2-AS1 sponges miR-142-3p to derepress TWF1 in gemcitabine-resistant pancreatic cancer established ceRNA-mediated regulation as a recurrent mechanism controlling TWF1 levels in drug resistance.\",\n      \"evidence\": \"Luciferase reporter confirming miR-142-3p binding to TWF1 3ʹ-UTR, siRNA knockdown of TWF1, proliferation/apoptosis/EMT assays in drug-resistant pancreatic cancer lines\",\n      \"pmids\": [\"31619579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-laboratory study; independent replication in additional pancreatic cancer models lacking\",\n        \"Contribution of TWF1 versus other miR-142-3p targets to the resistance phenotype not deconvolved\",\n        \"No in vivo xenograft validation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A parallel ceRNA axis—FGD5-AS1/miR-153-3p/TWF1—was shown to drive cisplatin resistance in hepatocellular carcinoma, reinforcing the generality of miRNA-mediated TWF1 derepression as a chemoresistance mechanism across cancer types.\",\n      \"evidence\": \"Luciferase reporter plus RIP assay confirming miR-153-3p–TWF1 interaction, functional rescue with miR-153-3p inhibition, CCK-8/colony/Transwell/TUNEL assays in HCC cells\",\n      \"pmids\": [\"34519634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-laboratory study without in vivo validation\",\n        \"Downstream signaling connecting TWF1 to apoptosis resistance not identified\",\n        \"Overlap or redundancy with twinfilin-2 not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that epigenetic silencing of miR-30a-5p/miR-30c-5p elevates TWF1 in clear cell renal cell carcinoma, and that higher TWF1 protein correlates with metastasis in patient tissues, provided the first clinical-pathological link between TWF1 expression and tumor progression.\",\n      \"evidence\": \"Luciferase 3ʹ-UTR reporter, siRNA knockdown of TWF1, EMT marker analysis, IHC on primary ccRCC tissues, decitabine-mediated miR re-expression\",\n      \"pmids\": [\"35697274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlation between TWF1 IHC and metastasis is associative; causal role in vivo not tested\",\n        \"Whether methylation-dependent miR silencing is a driver or passenger in ccRCC unknown\",\n        \"Structural basis for TWF1-driven EMT remains uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct actin-remodeling mechanism by which elevated twinfilin-1 induces EMT and hypertrophy—including identification of specific actin structures affected and whether its barbed-end capping or monomer-sequestering activity is required—remains unresolved across all disease contexts studied.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No mutagenesis separating ADF-H domain actin-binding activities from EMT/hypertrophy phenotypes\",\n        \"No structural or biophysical characterization of TWF1 in the EMT or cardiac contexts\",\n        \"In vivo genetic models (knockout/knock-in) for TWF1 in cancer or cardiac hypertrophy are absent from the literature captured here\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}