{"gene":"CCNE2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2015,"finding":"CCNE2 is a direct target of miR-30d-5p; miR-30d-5p binds to CCNE2 and suppresses its expression, thereby inhibiting NSCLC cell proliferation, invasion, and migration. Re-introduction of CCNE2 antagonized the inhibitory effects of miR-30d-5p.","method":"Luciferase reporter assay, Western blot, functional rescue experiments in NSCLC cells","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct luciferase reporter validation plus functional rescue, single lab","pmids":["25843294"],"is_preprint":false},{"year":2015,"finding":"CCNE2 acts downstream of HMGA1 to regulate motility and invasiveness of basal-like breast cancer cells by promoting nuclear localization and activity of YAP (Hippo pathway mediator). MST1/2 and LATS1/2 kinases are required for HMGA1- and CCNE2-mediated regulation of YAP localization. CDK inhibitors induce translocation of YAP from nucleus to cytoplasm.","method":"Genetic epistasis (knockdown/overexpression), subcellular fractionation/localization of YAP, CDK inhibitor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments with defined pathway placement and localization readout, single lab","pmids":["26265440"],"is_preprint":false},{"year":2017,"finding":"CCNE2 overexpression contributes to acquired trastuzumab resistance in HER2+ breast cancer; silencing CCNE2 in trastuzumab-resistant BT474r cells restored sensitivity to trastuzumab. miR-26a and miR-30b regulate CCNE2 expression and trastuzumab response.","method":"siRNA knockdown of CCNE2, cell viability assays, miRNA overexpression in resistant cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined drug-resistance phenotype, single lab, two orthogonal methods","pmids":["28120942"],"is_preprint":false},{"year":2016,"finding":"miR-26a directly targets the 3' UTR of CCNE2 (and CCND2) to regulate mouse hepatocyte proliferation and cell cycle progression. Inhibition of miR-26a upregulated CCNE2 expression and increased hepatocyte proliferation.","method":"Dual-luciferase reporter assay, Western blot, flow cytometry, adenoviral overexpression/inhibition in hepatocyte cell line","journal":"Hepatobiliary & pancreatic diseases international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase validation of 3'UTR binding, functional cell cycle readout, single lab","pmids":["26818545"],"is_preprint":false},{"year":2016,"finding":"Beryllium induces p53-dependent transcriptional downregulation of CCNE2 mRNA (~90% reduction). However, reduction in CCNE2 mRNA did not lead to corresponding reductions in cyclin E2 protein, which had an unusually long half-life (>12 hours), indicating post-transcriptional stabilization of CCNE2 protein independent of p53.","method":"siRNA knockdown of p53, RT-PCR, Western blot, cycloheximide chase, proteasomal inhibition (MG-132)","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, cycloheximide chase, MG-132), single lab","pmids":["27611480"],"is_preprint":false},{"year":2020,"finding":"CARM1, an arginine methyltransferase, is recruited to the CCNE2 gene promoter and activates CCNE2 transcription. Asymmetric di-methylation marks H3R17me2a and H3R26me2a are enriched at the CCNE2 core promoter. Restoration of CCNE2 abolished CARM1-knockdown-mediated inhibition of cell proliferation, placing CCNE2 downstream of CARM1 in NSCLC.","method":"ChIP assay, luciferase reporter assay, shRNA knockdown, overexpression rescue experiments in vitro and in vivo","journal":"Aging","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP demonstrating histone methylation at CCNE2 promoter, luciferase reporter, and in vivo rescue, multiple orthogonal methods in single lab","pmids":["32487779"],"is_preprint":false},{"year":2021,"finding":"E2F1 transcription factor directly targets the CCNE2 promoter and activates its transcription in TGF-β1-induced human cardiac fibroblast differentiation. Luciferase reporter assay and immunoprecipitation confirmed CCNE2 as a direct target gene of E2F1. Silencing CCNE2 decreased cardiac fibroblast differentiation.","method":"Luciferase reporter assay, immunoprecipitation, siRNA knockdown, Western blot","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter-binding confirmed by luciferase and IP, functional knockdown readout, single lab","pmids":["34521301"],"is_preprint":false},{"year":2021,"finding":"MFA (methyl ferulic acid) attenuates cardiac fibroblast differentiation and myocardial fibrosis by suppressing the pRB-E2F1/CCNE2 pathway (as well as RhoA/ROCK2 pathway), reducing CCNE2-mediated proliferation and migration of human cardiac fibroblasts.","method":"Western blot, cell migration/proliferation assays, in vivo myocardial infarction mouse model","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from Western blot changes without direct mechanistic dissection of CCNE2 in this context, single lab","pmids":["34483923"],"is_preprint":false},{"year":2019,"finding":"miR-30a directly interacts with the CCNE2 3'UTR; nicotine-induced upregulation of miR-30a downregulates CCNE2 expression and arrests human periodontal ligament cells in G1 phase. Inhibition of miR-30a restored CCNE2 expression downregulated by nicotine.","method":"Luciferase reporter assay, qRT-PCR, cell cycle analysis (flow cytometry), miR-30a inhibitor rescue","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR luciferase validation plus functional cell cycle readout and rescue experiment, single lab","pmids":["31689122"],"is_preprint":false},{"year":2019,"finding":"CircCCNB1 acts as a sponge for miR-449a to maintain CCNE2 expression; reduced CircCCNB1 inhibits CCNE2 expression via miR-449a, repressing cellular proliferation and triggering cellular senescence (increased SA-β-gal, p21, p53).","method":"Whole-transcriptome sequencing, functional knockdown of CircCCNB1, miR-449a activity assays, SA-β-gal assay, Western blot","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — circRNA sponge mechanism demonstrated by multiple functional assays, single lab","pmids":["31767812"],"is_preprint":false},{"year":2020,"finding":"circ-CSPP1 acts as a sponge for miR-577, positively regulating CCNE2 (a target of miR-577) in hepatocellular carcinoma. Knockdown of circ-CSPP1 downregulated CCNE2, p-Rb, E2F1, and c-myc. miR-577 inhibitor rescued suppressive effects of circ-CSPP1 knockdown, but was reversed by CCNE2 silencing.","method":"Dual luciferase assay, RNA immunoprecipitation, RNA FISH, knockdown/overexpression, xenograft model, Western blot","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal RIP and luciferase validation, cascade rescue experiment, in vivo confirmation, single lab","pmids":["32514247"],"is_preprint":false},{"year":2024,"finding":"ELF3 (ETS transcription factor) directly activates the CCNE2 promoter; ELF3 overexpression enhances CCNE2 promoter activity. ELF3 silencing reduces CCNE2 expression, induces cell cycle arrest, and suppresses malignant transformation of HPV16 E6/E7-immortalized keratinocytes.","method":"Dual luciferase reporter assay (promoter activity), bioinformatics binding site analysis, siRNA knockdown, CCK-8 assay, cell cycle analysis, Western blot","journal":"Journal of microbiology and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter activation by luciferase assay plus loss-of-function with cell cycle readout, single lab","pmids":["39572025"],"is_preprint":false},{"year":2026,"finding":"Knockdown of CCNE2 in rheumatoid arthritis synovial fibroblasts (RASFs) induced cellular senescence (elevated p16, p21, p53, SA-β-gal activity, H3K9me3) and apoptosis, and reduced cell viability. In vivo AAV-mediated intra-articular shCCNE2 reduced arthritis index and joint inflammation in CIA mice, also enhancing SASP factor secretion (MMP-3, IL-8).","method":"shRNA knockdown, flow cytometry (apoptosis), SA-β-gal assay, Western blot, AAV intra-articular injection in CIA mouse model","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined senescence and apoptosis readouts in vitro and in vivo, single lab","pmids":["40820921"],"is_preprint":false},{"year":2024,"finding":"CircHAS2 promotes CCNE2 activation via two axes: (1) sponging miR-1244 to relieve repression of CCNE2, and (2) binding USP10 to facilitate p53 nuclear export and degradation, thereby de-repressing CCNE2 expression. This bidirectional regulation promotes colorectal cancer cell proliferation.","method":"RNA sequencing, molecular biology (luciferase, RIP), patient-derived organoids, xenograft models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal axes validated by molecular assays plus organoid/xenograft confirmation, single lab","pmids":["38515149"],"is_preprint":false},{"year":2020,"finding":"Tigecycline suppresses CCNE2 expression in pancreatic ductal adenocarcinoma cells; CCNE2 overexpression significantly rescued tigecycline-inhibited cell proliferation and migration/invasion, placing CCNE2 as a downstream effector of tigecycline's anti-tumor action.","method":"Western blot, CCNE2 overexpression rescue, MTT/BrdU/soft agar assay, wound healing, transwell assay, xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — rescue experiment supports downstream role of CCNE2 but mechanism of how tigecycline suppresses CCNE2 not established, single lab","pmids":["32141702"],"is_preprint":false}],"current_model":"CCNE2 (Cyclin E2) is a cell cycle regulatory protein that promotes G1/S transition and cell proliferation; it is transcriptionally activated by E2F1 (directly binding the CCNE2 promoter) and by CARM1 (via H3R17me2a/H3R26me2a histone methylation at the CCNE2 promoter), post-transcriptionally regulated by multiple miRNAs (including miR-30d-5p, miR-30a, miR-26a, miR-144, miR-145, miR-577, miR-449a) targeting its 3'UTR, and subject to p53-dependent transcriptional repression; its protein stability is regulated post-transcriptionally and appears unusually long-lived in some cell types; beyond cell cycle control, CCNE2 acts downstream of HMGA1 to promote nuclear YAP localization via the Hippo pathway kinases MST1/2 and LATS1/2, thereby driving breast cancer cell invasiveness, and CCNE2 knockdown induces cellular senescence and apoptosis in synovial fibroblasts."},"narrative":{"mechanistic_narrative":"CCNE2 (Cyclin E2) is a cell cycle regulator that drives G1/S progression and cell proliferation, and its expression is tightly controlled at both the transcriptional and post-transcriptional levels [PMID:32487779, PMID:34521301, PMID:31689122]. Transcription of CCNE2 is directly activated through promoter binding by E2F1 [PMID:34521301], the ETS factor ELF3 [PMID:39572025], and the arginine methyltransferase CARM1, which deposits the activating asymmetric dimethyl marks H3R17me2a and H3R26me2a at the CCNE2 core promoter [PMID:32487779]. CCNE2 is also constrained by a converging network of 3'UTR-targeting microRNAs—including miR-30d-5p, miR-30a, and miR-26a—whose loss derepresses CCNE2 and promotes proliferation and cell cycle entry [PMID:25843294, PMID:26818545, PMID:31689122]; these miRNAs are in turn titrated by sponging circular RNAs (circCCNB1/miR-449a, circ-CSPP1/miR-577, circHAS2/miR-1244), and circHAS2 additionally elevates CCNE2 by binding USP10 to promote p53 nuclear export and degradation [PMID:31767812, PMID:32514247, PMID:38515149]. Consistent with this, CCNE2 is subject to p53-dependent transcriptional repression, yet the cyclin E2 protein itself is unusually long-lived, indicating post-transcriptional stabilization that uncouples protein abundance from mRNA levels [PMID:27611480]. Functionally, CCNE2 acts as a proliferative effector across multiple disease contexts: it lies downstream of HMGA1 to promote nuclear localization and activity of YAP via the Hippo kinases MST1/2 and LATS1/2, driving breast cancer invasiveness [PMID:26265440], it contributes to trastuzumab resistance in HER2+ breast cancer [PMID:28120942], and its depletion induces cellular senescence and apoptosis in synovial fibroblasts [PMID:40820921].","teleology":[{"year":2015,"claim":"Established that CCNE2 is a directly repressible target of microRNA control, defining a post-transcriptional brake on its proliferative output.","evidence":"Luciferase reporter and functional rescue with miR-30d-5p in NSCLC cells","pmids":["25843294"],"confidence":"Medium","gaps":["Does not address how CCNE2 protein abundance translates to CDK activity","Single cancer-cell context"]},{"year":2015,"claim":"Placed CCNE2 in a signaling role beyond core cell-cycle timing, linking it to YAP nuclear localization via Hippo kinases in breast cancer invasion.","evidence":"Genetic epistasis, YAP subcellular fractionation, and CDK inhibitor treatment in basal-like breast cancer cells","pmids":["26265440"],"confidence":"Medium","gaps":["Molecular mechanism connecting CCNE2/CDK activity to MST1/2-LATS1/2 not resolved","No direct CCNE2-YAP biochemical interaction shown"]},{"year":2016,"claim":"Demonstrated that CCNE2 mRNA is transcriptionally repressed by p53 while the protein is uncoupled from mRNA by post-transcriptional stabilization, revealing dual-layer regulation.","evidence":"p53 siRNA, RT-PCR, cycloheximide chase, and MG-132 in beryllium-treated cells","pmids":["27611480"],"confidence":"Medium","gaps":["Stabilizing factor and degron not identified","Generality of long half-life across cell types unknown"]},{"year":2016,"claim":"Confirmed direct 3'UTR targeting by miR-26a as a controller of CCNE2-driven cell cycle progression in a non-cancer proliferative setting.","evidence":"Dual-luciferase reporter, flow cytometry, and adenoviral modulation in hepatocytes","pmids":["26818545"],"confidence":"Medium","gaps":["Does not establish CCNE2's CDK partner or substrate program here"]},{"year":2019,"claim":"Extended the miRNA-repression model with miR-30a and introduced circRNA sponges as upstream rheostats that maintain CCNE2 expression and forestall senescence.","evidence":"Luciferase, cell cycle analysis, and circCCNB1/miR-449a functional assays with SA-β-gal readouts","pmids":["31689122","31767812"],"confidence":"Medium","gaps":["Quantitative contribution of each ceRNA axis to CCNE2 levels unclear","Senescence linkage is correlative at the CCNE2 level"]},{"year":2020,"claim":"Identified CARM1-deposited histone arginine methylation at the CCNE2 promoter as a direct activating chromatin input, adding an epigenetic layer to CCNE2 transcriptional control.","evidence":"ChIP for H3R17me2a/H3R26me2a, luciferase reporter, shRNA, and in vivo rescue in NSCLC","pmids":["32487779"],"confidence":"High","gaps":["Whether CARM1 acts coordinately with E2F1 at the same promoter not tested","Direct CARM1-promoter recruitment mechanism not defined"]},{"year":2020,"claim":"Reinforced ceRNA control of CCNE2 (circ-CSPP1/miR-577) and connected it to the pRb-E2F1 axis and downstream proliferation in vivo.","evidence":"Luciferase, RIP, FISH, and xenograft in hepatocellular carcinoma","pmids":["32514247"],"confidence":"Medium","gaps":["Causal ordering of pRb/E2F1 changes relative to CCNE2 not dissected"]},{"year":2021,"claim":"Defined E2F1 as a direct transcriptional activator of CCNE2 in fibroblast differentiation, generalizing CCNE2's proliferative function beyond cancer.","evidence":"Luciferase reporter, immunoprecipitation, and siRNA in TGF-β1-induced cardiac fibroblasts","pmids":["34521301","34483923"],"confidence":"Medium","gaps":["pRB-E2F1/CCNE2 pathway placement in MFA context inferred from Western blot only","No direct CCNE2 mechanistic dissection in the fibrosis model"]},{"year":2024,"claim":"Added ELF3 as a second direct transcriptional activator and revealed a circHAS2 module that elevates CCNE2 both by miRNA sponging and by USP10-mediated p53 degradation, integrating the transcriptional and p53-repression arms.","evidence":"Luciferase promoter assays, RIP, organoids, and xenografts in keratinocyte and colorectal cancer models","pmids":["39572025","38515149"],"confidence":"Medium","gaps":["Relative dominance of the miR-1244 versus USP10/p53 axis on CCNE2 unquantified","Direct ELF3-CARM1-E2F1 promoter interplay untested"]},{"year":2026,"claim":"Showed that CCNE2 loss is sufficient to drive senescence and apoptosis in synovial fibroblasts in vitro and in vivo, establishing CCNE2 as a fate-determining proliferative factor in a non-malignant inflammatory disease.","evidence":"shRNA, SA-β-gal, apoptosis flow cytometry, and AAV intra-articular shCCNE2 in CIA mice","pmids":["40820921"],"confidence":"Medium","gaps":["CDK partner and direct substrates mediating the senescence phenotype not identified","Mechanism linking CCNE2 loss to SASP induction unresolved"]},{"year":null,"claim":"The biochemical core of CCNE2 function—its CDK partner, kinase substrates, and how stabilized protein abundance is converted into cell-cycle and Hippo-pathway outputs—remains uncharacterized in this corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct CDK-CCNE2 complex or substrate phosphorylation reported","No structural model","Mechanism of CCNE2 protein stabilization unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,8,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,11]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O96020","full_name":"G1/S-specific cyclin-E2","aliases":[],"length_aa":404,"mass_kda":46.8,"function":"Essential for the control of the cell cycle at the late G1 and early S phase","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O96020/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNE2","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCNE2","total_profiled":1310},"omim":[{"mim_id":"620012","title":"DEVELOPMENTAL DELAY, HYPOTONIA, AND IMPAIRED LANGUAGE; DEDHIL","url":"https://www.omim.org/entry/620012"},{"mim_id":"611375","title":"MICRO RNA 34C; MIR34C","url":"https://www.omim.org/entry/611375"},{"mim_id":"611374","title":"MICRO RNA 34B; MIR34B","url":"https://www.omim.org/entry/611374"},{"mim_id":"611172","title":"MICRO RNA 34A; MIR34A","url":"https://www.omim.org/entry/611172"},{"mim_id":"606278","title":"F-BOX AND WD40 DOMAIN PROTEIN 7; FBXW7","url":"https://www.omim.org/entry/606278"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":34.9},{"tissue":"brain","ntpm":17.4}],"url":"https://www.proteinatlas.org/search/CCNE2"},"hgnc":{"alias_symbol":["CYCE2"],"prev_symbol":[]},"alphafold":{"accession":"O96020","domains":[{"cath_id":"1.10.472.10","chopping":"126-233","consensus_level":"high","plddt":96.711,"start":126,"end":233},{"cath_id":"1.10.472.10","chopping":"243-377","consensus_level":"high","plddt":93.366,"start":243,"end":377}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O96020","model_url":"https://alphafold.ebi.ac.uk/files/AF-O96020-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O96020-F1-predicted_aligned_error_v6.png","plddt_mean":77.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNE2","jax_strain_url":"https://www.jax.org/strain/search?query=CCNE2"},"sequence":{"accession":"O96020","fasta_url":"https://rest.uniprot.org/uniprotkb/O96020.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O96020/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O96020"}},"corpus_meta":[{"pmid":"25843294","id":"PMC_25843294","title":"MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/25843294","citation_count":104,"is_preprint":false},{"pmid":"32102682","id":"PMC_32102682","title":"Exosomal microRNA-144 from bone marrow-derived mesenchymal stem cells inhibits the progression of non-small cell lung cancer by targeting CCNE1 and CCNE2.","date":"2020","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32102682","citation_count":76,"is_preprint":false},{"pmid":"28120942","id":"PMC_28120942","title":"The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28120942","citation_count":62,"is_preprint":false},{"pmid":"26265440","id":"PMC_26265440","title":"A novel HMGA1-CCNE2-YAP axis regulates breast cancer 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cells.","date":"2019","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/31689122","citation_count":8,"is_preprint":false},{"pmid":"35117009","id":"PMC_35117009","title":"LncRNA MVIH knockdown inhibits the malignancy progression through downregulating miR-505 mediated HMGB1 and CCNE2 in acute myeloid leukemia.","date":"2019","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35117009","citation_count":7,"is_preprint":false},{"pmid":"25327794","id":"PMC_25327794","title":"[Evaluation of c-myc and CCNE2 amplification in breast cancer with quantitative multi-gene fluorescence in-situ hybridization].","date":"2014","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25327794","citation_count":4,"is_preprint":false},{"pmid":"32990223","id":"PMC_32990223","title":"[MicroRNA-200c-3p inhibits proliferation of nephroblastoma cells by targeting CCNE2].","date":"2020","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/32990223","citation_count":4,"is_preprint":false},{"pmid":"40820921","id":"PMC_40820921","title":"Targeting CCNE2 to alleviate rheumatoid arthritis through inducing senescence and apoptosis.","date":"2026","source":"Modern rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/40820921","citation_count":1,"is_preprint":false},{"pmid":"32669969","id":"PMC_32669969","title":"Correction to: Circular RNA circ-CSPP1 regulates CCNE2 to facilitate hepatocellular carcinoma cell growth via sponging miR-577.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32669969","citation_count":1,"is_preprint":false},{"pmid":"39572025","id":"PMC_39572025","title":"ELF3 Overexpression Contributes to the Malignant Transformation of HPV16 E6/E7-Immortalized Keratinocytes by Promoting CCNE2 Expression.","date":"2024","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39572025","citation_count":0,"is_preprint":false},{"pmid":"37032834","id":"PMC_37032834","title":"Retraction: Knockdown of long non-coding RNA KCNQ1OT1 restrained glioma cells' malignancy by activating miR-370/CCNE2 axis.","date":"2023","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37032834","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17053,"output_tokens":3777,"usd":0.053907,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11424,"output_tokens":3254,"usd":0.069235,"stage2_stop_reason":"end_turn"},"total_usd":0.123142,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"CCNE2 is a direct target of miR-30d-5p; miR-30d-5p binds to CCNE2 and suppresses its expression, thereby inhibiting NSCLC cell proliferation, invasion, and migration. Re-introduction of CCNE2 antagonized the inhibitory effects of miR-30d-5p.\",\n      \"method\": \"Luciferase reporter assay, Western blot, functional rescue experiments in NSCLC cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct luciferase reporter validation plus functional rescue, single lab\",\n      \"pmids\": [\"25843294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCNE2 acts downstream of HMGA1 to regulate motility and invasiveness of basal-like breast cancer cells by promoting nuclear localization and activity of YAP (Hippo pathway mediator). MST1/2 and LATS1/2 kinases are required for HMGA1- and CCNE2-mediated regulation of YAP localization. CDK inhibitors induce translocation of YAP from nucleus to cytoplasm.\",\n      \"method\": \"Genetic epistasis (knockdown/overexpression), subcellular fractionation/localization of YAP, CDK inhibitor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments with defined pathway placement and localization readout, single lab\",\n      \"pmids\": [\"26265440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCNE2 overexpression contributes to acquired trastuzumab resistance in HER2+ breast cancer; silencing CCNE2 in trastuzumab-resistant BT474r cells restored sensitivity to trastuzumab. miR-26a and miR-30b regulate CCNE2 expression and trastuzumab response.\",\n      \"method\": \"siRNA knockdown of CCNE2, cell viability assays, miRNA overexpression in resistant cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined drug-resistance phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"28120942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-26a directly targets the 3' UTR of CCNE2 (and CCND2) to regulate mouse hepatocyte proliferation and cell cycle progression. Inhibition of miR-26a upregulated CCNE2 expression and increased hepatocyte proliferation.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, flow cytometry, adenoviral overexpression/inhibition in hepatocyte cell line\",\n      \"journal\": \"Hepatobiliary & pancreatic diseases international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase validation of 3'UTR binding, functional cell cycle readout, single lab\",\n      \"pmids\": [\"26818545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Beryllium induces p53-dependent transcriptional downregulation of CCNE2 mRNA (~90% reduction). However, reduction in CCNE2 mRNA did not lead to corresponding reductions in cyclin E2 protein, which had an unusually long half-life (>12 hours), indicating post-transcriptional stabilization of CCNE2 protein independent of p53.\",\n      \"method\": \"siRNA knockdown of p53, RT-PCR, Western blot, cycloheximide chase, proteasomal inhibition (MG-132)\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, cycloheximide chase, MG-132), single lab\",\n      \"pmids\": [\"27611480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CARM1, an arginine methyltransferase, is recruited to the CCNE2 gene promoter and activates CCNE2 transcription. Asymmetric di-methylation marks H3R17me2a and H3R26me2a are enriched at the CCNE2 core promoter. Restoration of CCNE2 abolished CARM1-knockdown-mediated inhibition of cell proliferation, placing CCNE2 downstream of CARM1 in NSCLC.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, shRNA knockdown, overexpression rescue experiments in vitro and in vivo\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP demonstrating histone methylation at CCNE2 promoter, luciferase reporter, and in vivo rescue, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32487779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E2F1 transcription factor directly targets the CCNE2 promoter and activates its transcription in TGF-β1-induced human cardiac fibroblast differentiation. Luciferase reporter assay and immunoprecipitation confirmed CCNE2 as a direct target gene of E2F1. Silencing CCNE2 decreased cardiac fibroblast differentiation.\",\n      \"method\": \"Luciferase reporter assay, immunoprecipitation, siRNA knockdown, Western blot\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter-binding confirmed by luciferase and IP, functional knockdown readout, single lab\",\n      \"pmids\": [\"34521301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MFA (methyl ferulic acid) attenuates cardiac fibroblast differentiation and myocardial fibrosis by suppressing the pRB-E2F1/CCNE2 pathway (as well as RhoA/ROCK2 pathway), reducing CCNE2-mediated proliferation and migration of human cardiac fibroblasts.\",\n      \"method\": \"Western blot, cell migration/proliferation assays, in vivo myocardial infarction mouse model\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from Western blot changes without direct mechanistic dissection of CCNE2 in this context, single lab\",\n      \"pmids\": [\"34483923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-30a directly interacts with the CCNE2 3'UTR; nicotine-induced upregulation of miR-30a downregulates CCNE2 expression and arrests human periodontal ligament cells in G1 phase. Inhibition of miR-30a restored CCNE2 expression downregulated by nicotine.\",\n      \"method\": \"Luciferase reporter assay, qRT-PCR, cell cycle analysis (flow cytometry), miR-30a inhibitor rescue\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR luciferase validation plus functional cell cycle readout and rescue experiment, single lab\",\n      \"pmids\": [\"31689122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CircCCNB1 acts as a sponge for miR-449a to maintain CCNE2 expression; reduced CircCCNB1 inhibits CCNE2 expression via miR-449a, repressing cellular proliferation and triggering cellular senescence (increased SA-β-gal, p21, p53).\",\n      \"method\": \"Whole-transcriptome sequencing, functional knockdown of CircCCNB1, miR-449a activity assays, SA-β-gal assay, Western blot\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — circRNA sponge mechanism demonstrated by multiple functional assays, single lab\",\n      \"pmids\": [\"31767812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"circ-CSPP1 acts as a sponge for miR-577, positively regulating CCNE2 (a target of miR-577) in hepatocellular carcinoma. Knockdown of circ-CSPP1 downregulated CCNE2, p-Rb, E2F1, and c-myc. miR-577 inhibitor rescued suppressive effects of circ-CSPP1 knockdown, but was reversed by CCNE2 silencing.\",\n      \"method\": \"Dual luciferase assay, RNA immunoprecipitation, RNA FISH, knockdown/overexpression, xenograft model, Western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RIP and luciferase validation, cascade rescue experiment, in vivo confirmation, single lab\",\n      \"pmids\": [\"32514247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELF3 (ETS transcription factor) directly activates the CCNE2 promoter; ELF3 overexpression enhances CCNE2 promoter activity. ELF3 silencing reduces CCNE2 expression, induces cell cycle arrest, and suppresses malignant transformation of HPV16 E6/E7-immortalized keratinocytes.\",\n      \"method\": \"Dual luciferase reporter assay (promoter activity), bioinformatics binding site analysis, siRNA knockdown, CCK-8 assay, cell cycle analysis, Western blot\",\n      \"journal\": \"Journal of microbiology and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter activation by luciferase assay plus loss-of-function with cell cycle readout, single lab\",\n      \"pmids\": [\"39572025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of CCNE2 in rheumatoid arthritis synovial fibroblasts (RASFs) induced cellular senescence (elevated p16, p21, p53, SA-β-gal activity, H3K9me3) and apoptosis, and reduced cell viability. In vivo AAV-mediated intra-articular shCCNE2 reduced arthritis index and joint inflammation in CIA mice, also enhancing SASP factor secretion (MMP-3, IL-8).\",\n      \"method\": \"shRNA knockdown, flow cytometry (apoptosis), SA-β-gal assay, Western blot, AAV intra-articular injection in CIA mouse model\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined senescence and apoptosis readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"40820921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CircHAS2 promotes CCNE2 activation via two axes: (1) sponging miR-1244 to relieve repression of CCNE2, and (2) binding USP10 to facilitate p53 nuclear export and degradation, thereby de-repressing CCNE2 expression. This bidirectional regulation promotes colorectal cancer cell proliferation.\",\n      \"method\": \"RNA sequencing, molecular biology (luciferase, RIP), patient-derived organoids, xenograft models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal axes validated by molecular assays plus organoid/xenograft confirmation, single lab\",\n      \"pmids\": [\"38515149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tigecycline suppresses CCNE2 expression in pancreatic ductal adenocarcinoma cells; CCNE2 overexpression significantly rescued tigecycline-inhibited cell proliferation and migration/invasion, placing CCNE2 as a downstream effector of tigecycline's anti-tumor action.\",\n      \"method\": \"Western blot, CCNE2 overexpression rescue, MTT/BrdU/soft agar assay, wound healing, transwell assay, xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — rescue experiment supports downstream role of CCNE2 but mechanism of how tigecycline suppresses CCNE2 not established, single lab\",\n      \"pmids\": [\"32141702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNE2 (Cyclin E2) is a cell cycle regulatory protein that promotes G1/S transition and cell proliferation; it is transcriptionally activated by E2F1 (directly binding the CCNE2 promoter) and by CARM1 (via H3R17me2a/H3R26me2a histone methylation at the CCNE2 promoter), post-transcriptionally regulated by multiple miRNAs (including miR-30d-5p, miR-30a, miR-26a, miR-144, miR-145, miR-577, miR-449a) targeting its 3'UTR, and subject to p53-dependent transcriptional repression; its protein stability is regulated post-transcriptionally and appears unusually long-lived in some cell types; beyond cell cycle control, CCNE2 acts downstream of HMGA1 to promote nuclear YAP localization via the Hippo pathway kinases MST1/2 and LATS1/2, thereby driving breast cancer cell invasiveness, and CCNE2 knockdown induces cellular senescence and apoptosis in synovial fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNE2 (Cyclin E2) is a cell cycle regulator that drives G1/S progression and cell proliferation, and its expression is tightly controlled at both the transcriptional and post-transcriptional levels [#5, #6, #8]. Transcription of CCNE2 is directly activated through promoter binding by E2F1 [#6], the ETS factor ELF3 [#11], and the arginine methyltransferase CARM1, which deposits the activating asymmetric dimethyl marks H3R17me2a and H3R26me2a at the CCNE2 core promoter [#5]. CCNE2 is also constrained by a converging network of 3'UTR-targeting microRNAs—including miR-30d-5p, miR-30a, and miR-26a—whose loss derepresses CCNE2 and promotes proliferation and cell cycle entry [#0, #3, #8]; these miRNAs are in turn titrated by sponging circular RNAs (circCCNB1/miR-449a, circ-CSPP1/miR-577, circHAS2/miR-1244), and circHAS2 additionally elevates CCNE2 by binding USP10 to promote p53 nuclear export and degradation [#9, #10, #13]. Consistent with this, CCNE2 is subject to p53-dependent transcriptional repression, yet the cyclin E2 protein itself is unusually long-lived, indicating post-transcriptional stabilization that uncouples protein abundance from mRNA levels [#4]. Functionally, CCNE2 acts as a proliferative effector across multiple disease contexts: it lies downstream of HMGA1 to promote nuclear localization and activity of YAP via the Hippo kinases MST1/2 and LATS1/2, driving breast cancer invasiveness [#1], it contributes to trastuzumab resistance in HER2+ breast cancer [#2], and its depletion induces cellular senescence and apoptosis in synovial fibroblasts [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that CCNE2 is a directly repressible target of microRNA control, defining a post-transcriptional brake on its proliferative output.\",\n      \"evidence\": \"Luciferase reporter and functional rescue with miR-30d-5p in NSCLC cells\",\n      \"pmids\": [\"25843294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address how CCNE2 protein abundance translates to CDK activity\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed CCNE2 in a signaling role beyond core cell-cycle timing, linking it to YAP nuclear localization via Hippo kinases in breast cancer invasion.\",\n      \"evidence\": \"Genetic epistasis, YAP subcellular fractionation, and CDK inhibitor treatment in basal-like breast cancer cells\",\n      \"pmids\": [\"26265440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting CCNE2/CDK activity to MST1/2-LATS1/2 not resolved\", \"No direct CCNE2-YAP biochemical interaction shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CCNE2 mRNA is transcriptionally repressed by p53 while the protein is uncoupled from mRNA by post-transcriptional stabilization, revealing dual-layer regulation.\",\n      \"evidence\": \"p53 siRNA, RT-PCR, cycloheximide chase, and MG-132 in beryllium-treated cells\",\n      \"pmids\": [\"27611480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stabilizing factor and degron not identified\", \"Generality of long half-life across cell types unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed direct 3'UTR targeting by miR-26a as a controller of CCNE2-driven cell cycle progression in a non-cancer proliferative setting.\",\n      \"evidence\": \"Dual-luciferase reporter, flow cytometry, and adenoviral modulation in hepatocytes\",\n      \"pmids\": [\"26818545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish CCNE2's CDK partner or substrate program here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the miRNA-repression model with miR-30a and introduced circRNA sponges as upstream rheostats that maintain CCNE2 expression and forestall senescence.\",\n      \"evidence\": \"Luciferase, cell cycle analysis, and circCCNB1/miR-449a functional assays with SA-β-gal readouts\",\n      \"pmids\": [\"31689122\", \"31767812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each ceRNA axis to CCNE2 levels unclear\", \"Senescence linkage is correlative at the CCNE2 level\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CARM1-deposited histone arginine methylation at the CCNE2 promoter as a direct activating chromatin input, adding an epigenetic layer to CCNE2 transcriptional control.\",\n      \"evidence\": \"ChIP for H3R17me2a/H3R26me2a, luciferase reporter, shRNA, and in vivo rescue in NSCLC\",\n      \"pmids\": [\"32487779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CARM1 acts coordinately with E2F1 at the same promoter not tested\", \"Direct CARM1-promoter recruitment mechanism not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced ceRNA control of CCNE2 (circ-CSPP1/miR-577) and connected it to the pRb-E2F1 axis and downstream proliferation in vivo.\",\n      \"evidence\": \"Luciferase, RIP, FISH, and xenograft in hepatocellular carcinoma\",\n      \"pmids\": [\"32514247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of pRb/E2F1 changes relative to CCNE2 not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined E2F1 as a direct transcriptional activator of CCNE2 in fibroblast differentiation, generalizing CCNE2's proliferative function beyond cancer.\",\n      \"evidence\": \"Luciferase reporter, immunoprecipitation, and siRNA in TGF-β1-induced cardiac fibroblasts\",\n      \"pmids\": [\"34521301\", \"34483923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pRB-E2F1/CCNE2 pathway placement in MFA context inferred from Western blot only\", \"No direct CCNE2 mechanistic dissection in the fibrosis model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added ELF3 as a second direct transcriptional activator and revealed a circHAS2 module that elevates CCNE2 both by miRNA sponging and by USP10-mediated p53 degradation, integrating the transcriptional and p53-repression arms.\",\n      \"evidence\": \"Luciferase promoter assays, RIP, organoids, and xenografts in keratinocyte and colorectal cancer models\",\n      \"pmids\": [\"39572025\", \"38515149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative dominance of the miR-1244 versus USP10/p53 axis on CCNE2 unquantified\", \"Direct ELF3-CARM1-E2F1 promoter interplay untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that CCNE2 loss is sufficient to drive senescence and apoptosis in synovial fibroblasts in vitro and in vivo, establishing CCNE2 as a fate-determining proliferative factor in a non-malignant inflammatory disease.\",\n      \"evidence\": \"shRNA, SA-β-gal, apoptosis flow cytometry, and AAV intra-articular shCCNE2 in CIA mice\",\n      \"pmids\": [\"40820921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK partner and direct substrates mediating the senescence phenotype not identified\", \"Mechanism linking CCNE2 loss to SASP induction unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical core of CCNE2 function—its CDK partner, kinase substrates, and how stabilized protein abundance is converted into cell-cycle and Hippo-pathway outputs—remains uncharacterized in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct CDK-CCNE2 complex or substrate phosphorylation reported\", \"No structural model\", \"Mechanism of CCNE2 protein stabilization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 8, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}