{"gene":"TYMS","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2019,"finding":"FOXM1 transcription factor directly regulates TYMS expression in colorectal cancer cells; ChIP and ChIP-seq confirmed FOXM1 binding to the TYMS promoter, and FOXM1 knockdown decreased TYMS expression, while FOXM1 overexpression increased it, contributing to 5-FU resistance.","method":"ChIP, ChIP-seq, siRNA knockdown, overexpression studies in colon cancer cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP and functional knockdown/overexpression in single lab with two orthogonal methods","pmids":["30728402"],"is_preprint":false},{"year":2018,"finding":"FOXM1 binds the TYMS promoter and regulates TYMS expression upon 5-FU treatment in 5-FU-sensitive cholangiocarcinoma cells (KKU-D131), but not in highly resistant HuCCA cells, demonstrating that uncoupling of the FOXM1-TYMS regulatory axis underlies severe 5-FU resistance.","method":"ChIP, siRNA knockdown, RT-qPCR, Western blot, clonogenicity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional siRNA knockdown, single lab, multiple orthogonal methods","pmids":["30538221"],"is_preprint":false},{"year":2013,"finding":"miR-433 post-transcriptionally represses TYMS expression by binding the 3'-UTR of TYMS mRNA, reducing TYMS protein levels and increasing 5-FU sensitivity in HeLa cells.","method":"Dual-luciferase reporter assay, RT-PCR, Western blot, WST-8 cell proliferation assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus Western blot and proliferation assay, single lab, multiple orthogonal methods","pmids":["23915286"],"is_preprint":false},{"year":2019,"finding":"MYC transcriptionally upregulates TYMS expression in gastrointestinal cancer cells; MYC-driven TYMS upregulation predetermines sensitivity to the TYMS inhibitor raltitrexed. NIPBL inactivation decreases RTX therapeutic responses by blocking MYC-driven TYMS transcription.","method":"Genome-scale CRISPR-Cas9 knockout screening, cell-based functional assays, in vivo xenograft experiments","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screening plus in vitro and in vivo validation, single lab","pmids":["31648989"],"is_preprint":false},{"year":2021,"finding":"miR-140-3p directly targets the TYMS 3'-UTR (confirmed by dual-luciferase reporter assay) and suppresses TYMS expression; miR-140-3p upregulation inhibited proliferation, migration, invasion, and angiogenesis of lung adenocarcinoma cells, effects reversed by TYMS silencing.","method":"Dual-luciferase reporter assay, qRT-PCR, Western blot, colony formation, Scratch, Transwell, tube formation assays","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation plus multiple functional assays, single lab","pmids":["34818974"],"is_preprint":false},{"year":2006,"finding":"Genetic engineering of loss of heterozygosity (LOH) at the TYMS locus (deletion of the short 2-repeat allele) in a diploid colorectal cancer cell line reduced TS protein expression and caused hypersensitivity to 5-FU and 5-fluoro-2'-deoxyuridine; re-introduction of exogenous TYMS cDNA restored resistance, directly linking TYMS copy number and expression level to 5-FU sensitivity.","method":"Genetic engineering (allele deletion), exogenous cDNA complementation, in vitro drug sensitivity assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic reconstitution with deletion and cDNA complementation establishing direct causal link between TYMS copy number/expression and drug sensitivity","pmids":["17018589"],"is_preprint":false},{"year":2023,"finding":"TYMS overexpression in an Ink4a/Arf-null mouse model cooperates with Ink4a/Arf loss to accelerate tumorigenesis and metastasis; TYMS-expressing tumors exhibited genomic instability (double-strand DNA damage, aneuploidy, loss of G1/S checkpoint). TYMS shRNA knockdown in vivo reduced tumor incidence, delayed progression, and prolonged survival.","method":"Genetically engineered mouse model, shRNA in vivo knockdown, flow cytometry, DNA damage assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo genetic mouse model with shRNA rescue, multiple orthogonal phenotypic readouts","pmids":["37106126"],"is_preprint":false},{"year":2019,"finding":"TYMS and DHFR are positive regulators of glioma cell growth; inhibition of DHFR/TYMS by pemetrexed combined with temozolomide (TMZ) produced synergistic anti-glioma activity in vitro and in U251 xenografts via activation of AMPK and subsequent suppression of the mTOR signaling pathway.","method":"Cell proliferation assays, xenograft in vivo model, Western blot for AMPK/mTOR pathway","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with pathway mechanistic readout, single lab","pmids":["31542479"],"is_preprint":false},{"year":2024,"finding":"TYMS knockdown in triple-negative breast cancer cells suppressed proliferation and promoted ferroptosis, associated with increased ROS and Fe2+ accumulation, upregulation of ACSL4, and downregulation of GPX4; mechanistically linked to inhibition of PI3K/Akt/mTOR signaling pathway.","method":"siRNA knockdown, Western blot, flow cytometry (ROS/apoptosis), xenograft tumor model, IHC","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro knockdown with in vivo xenograft, pathway-level mechanistic readout, single lab","pmids":["38961034"],"is_preprint":false},{"year":2022,"finding":"TYMS knockdown in hepatocellular carcinoma cells inhibited growth and invasion, decreased DNA synthesis, and reduced extracellular matrix (ECM) degradation, implicating TYMS in HCC metastasis via these mechanisms.","method":"siRNA knockdown, cell invasion assay, DNA synthesis assay","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method class (knockdown with phenotypic readout), limited mechanistic depth from abstract","pmids":["34858842"],"is_preprint":false},{"year":2022,"finding":"TYMS knockdown in colorectal cancer cells inhibited proliferation, migration, and invasion, and reduced spheroid formation. TYMS promotes CRC progression by regulating EMT-related proteins (E-cadherin, Vimentin, MMP-9) and stem cell biomarkers (CD133, CD44) via a TYMS-TM4SF4 axis; TM4SF4 was identified as a downstream target of TYMS.","method":"siRNA knockdown, cell functional assays (CCK-8, migration, invasion, spheroid), RNA sequencing, Western blot","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus RNA-seq plus downstream target identification, single lab, multiple methods","pmids":["35411242"],"is_preprint":false},{"year":2017,"finding":"The rs7911488 C-allele in pre-miR-1307 leads to downregulation of miR-1307-3p, which directly targets TYMS; reduced miR-1307-3p results in elevated TYMS expression, conferring resistance to capecitabine/5-FU in colon cancer cells in vitro and in vivo.","method":"Patient genotyping, in vitro 5-FU resistance assays, in vivo xenograft, miRNA-target functional analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional validation of miRNA-TYMS axis, single lab","pmids":["29088787"],"is_preprint":false},{"year":2005,"finding":"The TYMS 3'UTR insertion/deletion polymorphism (ins/del) is significantly associated with red blood cell folate and homocysteine concentrations in non-smokers; del/del homozygotes had substantially higher RBC folate and lower homocysteine compared to ins/ins or ins/del individuals, indicating a functional role of this polymorphism in folate metabolism.","method":"Population genetic association study with biochemical measurements (RBC folate, homocysteine)","journal":"Human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — population association without direct functional/enzymatic experiment on the protein mechanism","pmids":["15682292"],"is_preprint":false},{"year":2004,"finding":"TYMS-derived HLA-A2-binding peptides were recognized by cytotoxic T lymphocytes (CTLs) from colon cancer patients, demonstrating that TYMS protein is presented as a tumor-associated antigen on HLA-A2+ colon cancer cells and can elicit tumor-reactive CTL responses.","method":"Gene expression cloning, HLA-A2 peptide binding assay, CTL cytotoxicity assay with tumor-infiltrating lymphocytes","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct CTL functional assay with peptide identification, single lab, multiple orthogonal methods","pmids":["15355913"],"is_preprint":false}],"current_model":"TYMS encodes thymidylate synthase, a folate-dependent enzyme essential for de novo dTMP synthesis and DNA replication; its expression is transcriptionally upregulated by FOXM1 (via direct promoter binding) and MYC, post-transcriptionally repressed by miR-433 and miR-140-3p (via 3'-UTR binding), and its copy number directly determines 5-FU sensitivity; elevated TYMS promotes tumor cell proliferation, EMT, and genomic instability, while TYMS knockdown triggers ferroptosis via PI3K/Akt/mTOR inhibition and increases sensitivity to fluoropyrimidine and antifolate chemotherapy."},"narrative":{"mechanistic_narrative":"TYMS encodes thymidylate synthase, an enzyme whose expression level directly determines tumor cell sensitivity to fluoropyrimidine chemotherapy: genetic deletion of a TYMS allele in colorectal cancer cells lowers protein expression and confers hypersensitivity to 5-FU and 5-fluoro-2'-deoxyuridine, with resistance restored by re-introduction of exogenous TYMS cDNA [PMID:17018589]. TYMS expression is controlled at multiple levels — transcriptionally activated by FOXM1, which binds the TYMS promoter to drive expression and 5-FU resistance [PMID:30728402, PMID:30538221], and by MYC, whose activation predetermines sensitivity to the TYMS inhibitor raltitrexed [PMID:31648989] — and post-transcriptionally repressed through 3'-UTR targeting by miR-433 [PMID:23915286], miR-140-3p [PMID:34818974], and miR-1307-3p, the last of which is itself modulated by a pre-miRNA polymorphism that elevates TYMS and confers capecitabine/5-FU resistance [PMID:29088787]. Beyond its canonical role in nucleotide synthesis, elevated TYMS acts oncogenically: in an Ink4a/Arf-null mouse model TYMS overexpression accelerates tumorigenesis and metastasis and produces genomic instability, double-strand DNA damage, aneuploidy, and loss of the G1/S checkpoint, while in vivo shRNA knockdown reduces tumor incidence and prolongs survival [PMID:37106126]. TYMS promotes proliferation, migration, invasion, and EMT in colorectal cancer through a TYMS-TM4SF4 axis [PMID:35411242], and its knockdown suppresses proliferation while promoting ferroptosis via inhibition of PI3K/Akt/mTOR signaling with ACSL4 upregulation and GPX4 downregulation [PMID:38961034]. TYMS-derived peptides are presented on HLA-A2 and recognized by tumor-reactive cytotoxic T lymphocytes, marking the protein as a tumor-associated antigen [PMID:15355913].","teleology":[{"year":2004,"claim":"Established that TYMS protein is not only an enzyme but can serve as a tumor-associated antigen, opening an immunological dimension to its role in cancer.","evidence":"Gene expression cloning, HLA-A2 peptide binding and CTL cytotoxicity assays with patient tumor-infiltrating lymphocytes","pmids":["15355913"],"confidence":"Medium","gaps":["Does not address enzymatic or proliferative function","Clinical relevance of CTL recognition for tumor control untested"]},{"year":2005,"claim":"Demonstrated that a TYMS 3'-UTR insertion/deletion polymorphism has functional consequences for systemic folate metabolism, linking germline TYMS variation to a measurable biochemical phenotype.","evidence":"Population genetic association study with RBC folate and homocysteine measurements","pmids":["15682292"],"confidence":"Low","gaps":["Association without direct enzymatic experiment on the protein","Mechanism connecting 3'-UTR variant to expression not demonstrated here"]},{"year":2006,"claim":"Resolved whether TYMS copy number/expression is causally rather than correlatively linked to fluoropyrimidine sensitivity, by directly manipulating the locus and rescuing the phenotype.","evidence":"Engineered LOH (allele deletion) plus exogenous cDNA complementation with in vitro drug sensitivity assays in a diploid colorectal cancer line","pmids":["17018589"],"confidence":"High","gaps":["Single cell-line context","Does not address transcriptional/post-transcriptional regulators that set expression in tumors"]},{"year":2013,"claim":"Identified the first post-transcriptional brake on TYMS, showing that miRNA-mediated 3'-UTR repression lowers TYMS protein and sensitizes cells to 5-FU.","evidence":"Dual-luciferase reporter, Western blot, and proliferation assays in HeLa cells (miR-433)","pmids":["23915286"],"confidence":"Medium","gaps":["Single cell line","Endogenous regulation of miR-433 in tumors not addressed"]},{"year":2019,"claim":"Defined the transcriptional inputs that drive TYMS, establishing FOXM1 as a direct promoter-binding activator and MYC as an activator whose status predetermines antifolate response.","evidence":"ChIP/ChIP-seq with siRNA knockdown and overexpression (FOXM1, colorectal and cholangiocarcinoma); genome-scale CRISPR screen with xenograft validation (MYC/NIPBL/raltitrexed)","pmids":["30728402","30538221","31648989"],"confidence":"Medium","gaps":["Quantitative contribution of FOXM1 vs MYC to TYMS levels unresolved","How regulatory uncoupling arises in highly resistant cells not mechanistically defined"]},{"year":2019,"claim":"Connected TYMS (with DHFR) to growth signaling, showing combined antifolate inhibition acts through AMPK activation and mTOR suppression.","evidence":"Proliferation assays, U251 xenografts, and AMPK/mTOR Western blot (pemetrexed + temozolomide in glioma)","pmids":["31542479"],"confidence":"Medium","gaps":["Whether AMPK/mTOR effects are direct TYMS consequences or secondary to drug combination unclear","Single tumor type"]},{"year":2022,"claim":"Extended TYMS function beyond nucleotide supply to invasion and EMT, identifying a downstream TYMS-TM4SF4 axis controlling EMT and stemness markers.","evidence":"siRNA knockdown with functional assays, RNA-seq, and Western blot in colorectal cancer; additional knockdown/invasion/DNA-synthesis assays in HCC","pmids":["35411242","34858842"],"confidence":"Medium","gaps":["Mechanism by which TYMS regulates TM4SF4 not defined","HCC findings rest on a single method class"]},{"year":2023,"claim":"Provided in vivo genetic proof that TYMS overexpression is oncogenic and drives genomic instability, not merely a proliferation marker.","evidence":"Ink4a/Arf-null genetically engineered mouse model with in vivo shRNA knockdown, flow cytometry, and DNA damage assays","pmids":["37106126"],"confidence":"High","gaps":["Molecular basis of TYMS-induced double-strand breaks and checkpoint loss not defined","Cooperation specific to Ink4a/Arf loss context"]},{"year":2024,"claim":"Linked TYMS loss to a regulated cell death program, showing knockdown promotes ferroptosis through PI3K/Akt/mTOR inhibition with ACSL4/GPX4 remodeling.","evidence":"siRNA knockdown, ROS/Fe2+ and Western blot readouts, xenograft and IHC in triple-negative breast cancer","pmids":["38961034"],"confidence":"Medium","gaps":["Whether ferroptosis follows from nucleotide depletion or a distinct TYMS function unresolved","Direct link between TYMS and PI3K/Akt/mTOR not biochemically defined"]},{"year":null,"claim":"How TYMS enzymatic output and its non-canonical oncogenic and signaling roles are mechanistically coupled remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural/biochemical account in the corpus linking TYMS catalysis to genomic instability or EMT","Direct molecular connection of TYMS to PI3K/Akt/mTOR and AMPK/mTOR signaling unestablished","Mechanism of the TYMS-TM4SF4 axis undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04818","full_name":"Thymidylate synthase","aliases":[],"length_aa":313,"mass_kda":35.7,"function":"Catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to the mitochondrial and nuclear de novo thymidylate biosynthesis pathway","subcellular_location":"Nucleus; Cytoplasm; Mitochondrion; Mitochondrion matrix; Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P04818/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TYMS","classification":"Not Classified","n_dependent_lines":635,"n_total_lines":1208,"dependency_fraction":0.5256622516556292},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TYMS","total_profiled":1310},"omim":[{"mim_id":"620040","title":"DYSKERATOSIS CONGENITA, DIGENIC; DKCD","url":"https://www.omim.org/entry/620040"},{"mim_id":"611449","title":"EXPORTIN 4; XPO4","url":"https://www.omim.org/entry/611449"},{"mim_id":"610323","title":"METADHERIN; MTDH","url":"https://www.omim.org/entry/610323"},{"mim_id":"607427","title":"ENOLASE SUPERFAMILY MEMBER 1; ENOSF1","url":"https://www.omim.org/entry/607427"},{"mim_id":"300624","title":"FRAGILE X SYNDROME; FXS","url":"https://www.omim.org/entry/300624"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":83.5},{"tissue":"lymphoid tissue","ntpm":105.9}],"url":"https://www.proteinatlas.org/search/TYMS"},"hgnc":{"alias_symbol":["Tsase","TMS","HsT422"],"prev_symbol":["TS"]},"alphafold":{"accession":"P04818","domains":[{"cath_id":"3.30.572.10","chopping":"28-298","consensus_level":"high","plddt":97.6373,"start":28,"end":298}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04818","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04818-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04818-F1-predicted_aligned_error_v6.png","plddt_mean":93.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TYMS","jax_strain_url":"https://www.jax.org/strain/search?query=TYMS"},"sequence":{"accession":"P04818","fasta_url":"https://rest.uniprot.org/uniprotkb/P04818.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04818/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04818"}},"corpus_meta":[{"pmid":"27461082","id":"PMC_27461082","title":"Characterization of Glutamatergic and GABAA-Mediated Neurotransmission in Motor and Dorsolateral Prefrontal Cortex Using Paired-Pulse TMS-EEG.","date":"2016","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27461082","citation_count":128,"is_preprint":false},{"pmid":"30728402","id":"PMC_30728402","title":"FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30728402","citation_count":110,"is_preprint":false},{"pmid":"18259738","id":"PMC_18259738","title":"The effects of low- and high-frequency repetitive TMS on the input/output properties of the human corticospinal pathway.","date":"2008","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/18259738","citation_count":110,"is_preprint":false},{"pmid":"24680789","id":"PMC_24680789","title":"A model of TMS-induced I-waves in motor cortex.","date":"2014","source":"Brain stimulation","url":"https://pubmed.ncbi.nlm.nih.gov/24680789","citation_count":104,"is_preprint":false},{"pmid":"14677399","id":"PMC_14677399","title":"Pharmacology of TMS.","date":"2003","source":"Supplements to Clinical neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/14677399","citation_count":103,"is_preprint":false},{"pmid":"25730614","id":"PMC_25730614","title":"Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. 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ChIP and ChIP-seq confirmed FOXM1 binding to the TYMS promoter, and FOXM1 knockdown decreased TYMS expression, while FOXM1 overexpression increased it, contributing to 5-FU resistance.\",\n      \"method\": \"ChIP, ChIP-seq, siRNA knockdown, overexpression studies in colon cancer cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP and functional knockdown/overexpression in single lab with two orthogonal methods\",\n      \"pmids\": [\"30728402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXM1 binds the TYMS promoter and regulates TYMS expression upon 5-FU treatment in 5-FU-sensitive cholangiocarcinoma cells (KKU-D131), but not in highly resistant HuCCA cells, demonstrating that uncoupling of the FOXM1-TYMS regulatory axis underlies severe 5-FU resistance.\",\n      \"method\": \"ChIP, siRNA knockdown, RT-qPCR, Western blot, clonogenicity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional siRNA knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30538221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-433 post-transcriptionally represses TYMS expression by binding the 3'-UTR of TYMS mRNA, reducing TYMS protein levels and increasing 5-FU sensitivity in HeLa cells.\",\n      \"method\": \"Dual-luciferase reporter assay, RT-PCR, Western blot, WST-8 cell proliferation assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus Western blot and proliferation assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23915286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYC transcriptionally upregulates TYMS expression in gastrointestinal cancer cells; MYC-driven TYMS upregulation predetermines sensitivity to the TYMS inhibitor raltitrexed. NIPBL inactivation decreases RTX therapeutic responses by blocking MYC-driven TYMS transcription.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 knockout screening, cell-based functional assays, in vivo xenograft experiments\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screening plus in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"31648989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-140-3p directly targets the TYMS 3'-UTR (confirmed by dual-luciferase reporter assay) and suppresses TYMS expression; miR-140-3p upregulation inhibited proliferation, migration, invasion, and angiogenesis of lung adenocarcinoma cells, effects reversed by TYMS silencing.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot, colony formation, Scratch, Transwell, tube formation assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation plus multiple functional assays, single lab\",\n      \"pmids\": [\"34818974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Genetic engineering of loss of heterozygosity (LOH) at the TYMS locus (deletion of the short 2-repeat allele) in a diploid colorectal cancer cell line reduced TS protein expression and caused hypersensitivity to 5-FU and 5-fluoro-2'-deoxyuridine; re-introduction of exogenous TYMS cDNA restored resistance, directly linking TYMS copy number and expression level to 5-FU sensitivity.\",\n      \"method\": \"Genetic engineering (allele deletion), exogenous cDNA complementation, in vitro drug sensitivity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic reconstitution with deletion and cDNA complementation establishing direct causal link between TYMS copy number/expression and drug sensitivity\",\n      \"pmids\": [\"17018589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TYMS overexpression in an Ink4a/Arf-null mouse model cooperates with Ink4a/Arf loss to accelerate tumorigenesis and metastasis; TYMS-expressing tumors exhibited genomic instability (double-strand DNA damage, aneuploidy, loss of G1/S checkpoint). TYMS shRNA knockdown in vivo reduced tumor incidence, delayed progression, and prolonged survival.\",\n      \"method\": \"Genetically engineered mouse model, shRNA in vivo knockdown, flow cytometry, DNA damage assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo genetic mouse model with shRNA rescue, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"37106126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TYMS and DHFR are positive regulators of glioma cell growth; inhibition of DHFR/TYMS by pemetrexed combined with temozolomide (TMZ) produced synergistic anti-glioma activity in vitro and in U251 xenografts via activation of AMPK and subsequent suppression of the mTOR signaling pathway.\",\n      \"method\": \"Cell proliferation assays, xenograft in vivo model, Western blot for AMPK/mTOR pathway\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with pathway mechanistic readout, single lab\",\n      \"pmids\": [\"31542479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TYMS knockdown in triple-negative breast cancer cells suppressed proliferation and promoted ferroptosis, associated with increased ROS and Fe2+ accumulation, upregulation of ACSL4, and downregulation of GPX4; mechanistically linked to inhibition of PI3K/Akt/mTOR signaling pathway.\",\n      \"method\": \"siRNA knockdown, Western blot, flow cytometry (ROS/apoptosis), xenograft tumor model, IHC\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro knockdown with in vivo xenograft, pathway-level mechanistic readout, single lab\",\n      \"pmids\": [\"38961034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TYMS knockdown in hepatocellular carcinoma cells inhibited growth and invasion, decreased DNA synthesis, and reduced extracellular matrix (ECM) degradation, implicating TYMS in HCC metastasis via these mechanisms.\",\n      \"method\": \"siRNA knockdown, cell invasion assay, DNA synthesis assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method class (knockdown with phenotypic readout), limited mechanistic depth from abstract\",\n      \"pmids\": [\"34858842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TYMS knockdown in colorectal cancer cells inhibited proliferation, migration, and invasion, and reduced spheroid formation. TYMS promotes CRC progression by regulating EMT-related proteins (E-cadherin, Vimentin, MMP-9) and stem cell biomarkers (CD133, CD44) via a TYMS-TM4SF4 axis; TM4SF4 was identified as a downstream target of TYMS.\",\n      \"method\": \"siRNA knockdown, cell functional assays (CCK-8, migration, invasion, spheroid), RNA sequencing, Western blot\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus RNA-seq plus downstream target identification, single lab, multiple methods\",\n      \"pmids\": [\"35411242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The rs7911488 C-allele in pre-miR-1307 leads to downregulation of miR-1307-3p, which directly targets TYMS; reduced miR-1307-3p results in elevated TYMS expression, conferring resistance to capecitabine/5-FU in colon cancer cells in vitro and in vivo.\",\n      \"method\": \"Patient genotyping, in vitro 5-FU resistance assays, in vivo xenograft, miRNA-target functional analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional validation of miRNA-TYMS axis, single lab\",\n      \"pmids\": [\"29088787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The TYMS 3'UTR insertion/deletion polymorphism (ins/del) is significantly associated with red blood cell folate and homocysteine concentrations in non-smokers; del/del homozygotes had substantially higher RBC folate and lower homocysteine compared to ins/ins or ins/del individuals, indicating a functional role of this polymorphism in folate metabolism.\",\n      \"method\": \"Population genetic association study with biochemical measurements (RBC folate, homocysteine)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — population association without direct functional/enzymatic experiment on the protein mechanism\",\n      \"pmids\": [\"15682292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TYMS-derived HLA-A2-binding peptides were recognized by cytotoxic T lymphocytes (CTLs) from colon cancer patients, demonstrating that TYMS protein is presented as a tumor-associated antigen on HLA-A2+ colon cancer cells and can elicit tumor-reactive CTL responses.\",\n      \"method\": \"Gene expression cloning, HLA-A2 peptide binding assay, CTL cytotoxicity assay with tumor-infiltrating lymphocytes\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct CTL functional assay with peptide identification, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15355913\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TYMS encodes thymidylate synthase, a folate-dependent enzyme essential for de novo dTMP synthesis and DNA replication; its expression is transcriptionally upregulated by FOXM1 (via direct promoter binding) and MYC, post-transcriptionally repressed by miR-433 and miR-140-3p (via 3'-UTR binding), and its copy number directly determines 5-FU sensitivity; elevated TYMS promotes tumor cell proliferation, EMT, and genomic instability, while TYMS knockdown triggers ferroptosis via PI3K/Akt/mTOR inhibition and increases sensitivity to fluoropyrimidine and antifolate chemotherapy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TYMS encodes thymidylate synthase, an enzyme whose expression level directly determines tumor cell sensitivity to fluoropyrimidine chemotherapy: genetic deletion of a TYMS allele in colorectal cancer cells lowers protein expression and confers hypersensitivity to 5-FU and 5-fluoro-2'-deoxyuridine, with resistance restored by re-introduction of exogenous TYMS cDNA [#5]. TYMS expression is controlled at multiple levels — transcriptionally activated by FOXM1, which binds the TYMS promoter to drive expression and 5-FU resistance [#0, #1], and by MYC, whose activation predetermines sensitivity to the TYMS inhibitor raltitrexed [#3] — and post-transcriptionally repressed through 3'-UTR targeting by miR-433 [#2], miR-140-3p [#4], and miR-1307-3p, the last of which is itself modulated by a pre-miRNA polymorphism that elevates TYMS and confers capecitabine/5-FU resistance [#11]. Beyond its canonical role in nucleotide synthesis, elevated TYMS acts oncogenically: in an Ink4a/Arf-null mouse model TYMS overexpression accelerates tumorigenesis and metastasis and produces genomic instability, double-strand DNA damage, aneuploidy, and loss of the G1/S checkpoint, while in vivo shRNA knockdown reduces tumor incidence and prolongs survival [#6]. TYMS promotes proliferation, migration, invasion, and EMT in colorectal cancer through a TYMS-TM4SF4 axis [#10], and its knockdown suppresses proliferation while promoting ferroptosis via inhibition of PI3K/Akt/mTOR signaling with ACSL4 upregulation and GPX4 downregulation [#8]. TYMS-derived peptides are presented on HLA-A2 and recognized by tumor-reactive cytotoxic T lymphocytes, marking the protein as a tumor-associated antigen [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that TYMS protein is not only an enzyme but can serve as a tumor-associated antigen, opening an immunological dimension to its role in cancer.\",\n      \"evidence\": \"Gene expression cloning, HLA-A2 peptide binding and CTL cytotoxicity assays with patient tumor-infiltrating lymphocytes\",\n      \"pmids\": [\"15355913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address enzymatic or proliferative function\", \"Clinical relevance of CTL recognition for tumor control untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that a TYMS 3'-UTR insertion/deletion polymorphism has functional consequences for systemic folate metabolism, linking germline TYMS variation to a measurable biochemical phenotype.\",\n      \"evidence\": \"Population genetic association study with RBC folate and homocysteine measurements\",\n      \"pmids\": [\"15682292\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association without direct enzymatic experiment on the protein\", \"Mechanism connecting 3'-UTR variant to expression not demonstrated here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved whether TYMS copy number/expression is causally rather than correlatively linked to fluoropyrimidine sensitivity, by directly manipulating the locus and rescuing the phenotype.\",\n      \"evidence\": \"Engineered LOH (allele deletion) plus exogenous cDNA complementation with in vitro drug sensitivity assays in a diploid colorectal cancer line\",\n      \"pmids\": [\"17018589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single cell-line context\", \"Does not address transcriptional/post-transcriptional regulators that set expression in tumors\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the first post-transcriptional brake on TYMS, showing that miRNA-mediated 3'-UTR repression lowers TYMS protein and sensitizes cells to 5-FU.\",\n      \"evidence\": \"Dual-luciferase reporter, Western blot, and proliferation assays in HeLa cells (miR-433)\",\n      \"pmids\": [\"23915286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Endogenous regulation of miR-433 in tumors not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the transcriptional inputs that drive TYMS, establishing FOXM1 as a direct promoter-binding activator and MYC as an activator whose status predetermines antifolate response.\",\n      \"evidence\": \"ChIP/ChIP-seq with siRNA knockdown and overexpression (FOXM1, colorectal and cholangiocarcinoma); genome-scale CRISPR screen with xenograft validation (MYC/NIPBL/raltitrexed)\",\n      \"pmids\": [\"30728402\", \"30538221\", \"31648989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of FOXM1 vs MYC to TYMS levels unresolved\", \"How regulatory uncoupling arises in highly resistant cells not mechanistically defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TYMS (with DHFR) to growth signaling, showing combined antifolate inhibition acts through AMPK activation and mTOR suppression.\",\n      \"evidence\": \"Proliferation assays, U251 xenografts, and AMPK/mTOR Western blot (pemetrexed + temozolomide in glioma)\",\n      \"pmids\": [\"31542479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AMPK/mTOR effects are direct TYMS consequences or secondary to drug combination unclear\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended TYMS function beyond nucleotide supply to invasion and EMT, identifying a downstream TYMS-TM4SF4 axis controlling EMT and stemness markers.\",\n      \"evidence\": \"siRNA knockdown with functional assays, RNA-seq, and Western blot in colorectal cancer; additional knockdown/invasion/DNA-synthesis assays in HCC\",\n      \"pmids\": [\"35411242\", \"34858842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TYMS regulates TM4SF4 not defined\", \"HCC findings rest on a single method class\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided in vivo genetic proof that TYMS overexpression is oncogenic and drives genomic instability, not merely a proliferation marker.\",\n      \"evidence\": \"Ink4a/Arf-null genetically engineered mouse model with in vivo shRNA knockdown, flow cytometry, and DNA damage assays\",\n      \"pmids\": [\"37106126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of TYMS-induced double-strand breaks and checkpoint loss not defined\", \"Cooperation specific to Ink4a/Arf loss context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TYMS loss to a regulated cell death program, showing knockdown promotes ferroptosis through PI3K/Akt/mTOR inhibition with ACSL4/GPX4 remodeling.\",\n      \"evidence\": \"siRNA knockdown, ROS/Fe2+ and Western blot readouts, xenograft and IHC in triple-negative breast cancer\",\n      \"pmids\": [\"38961034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ferroptosis follows from nucleotide depletion or a distinct TYMS function unresolved\", \"Direct link between TYMS and PI3K/Akt/mTOR not biochemically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TYMS enzymatic output and its non-canonical oncogenic and signaling roles are mechanistically coupled remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural/biochemical account in the corpus linking TYMS catalysis to genomic instability or EMT\", \"Direct molecular connection of TYMS to PI3K/Akt/mTOR and AMPK/mTOR signaling unestablished\", \"Mechanism of the TYMS-TM4SF4 axis undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}