{"gene":"CCDC34","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2015,"finding":"CCDC34 knockdown via lentivirus-mediated siRNA suppressed bladder cancer cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in nude mice. CCDC34 silencing decreased phosphorylation of MEK, ERK1/2, JNK, p38, and Akt, and reduced expression of c-Raf and c-Jun, indicating MAPK (ERK, p38, JNK) and PI3K/Akt pathways are involved in CCDC34-mediated proliferation and migration.","method":"Lentivirus-mediated siRNA knockdown, Western blot for pathway phosphorylation, in vitro proliferation/migration assays, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab","pmids":["26312564"],"is_preprint":false},{"year":2017,"finding":"CCDC34 inhibition in SW620 colorectal cancer cells led to reduced cell activity, increased apoptosis, and reduced invasion; mechanistically, BCL2, survivin, N-cadherin, and MMP-9 were decreased while E-cadherin increased, indicating CCDC34 promotes CRC invasion by suppressing apoptosis and promoting epithelial-to-mesenchymal transition.","method":"siRNA knockdown, Western blot for apoptosis/invasion-associated proteins, invasion assays, flow cytometry","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined molecular readouts, single lab, moderate mechanistic depth","pmids":["29115580"],"is_preprint":false},{"year":2020,"finding":"CCDC34 knockdown in hepatocellular carcinoma cells inhibited proliferation and metastasis both in vitro and in vivo; RNA sequencing and Western blot revealed CCDC34 inhibition reduced AKT activation and suppressed epithelial-mesenchymal transition (EMT).","method":"siRNA knockdown, RNA sequencing, Western blot, xenograft and lung metastasis mouse models, CCK-8 and Transwell assays","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — KD with in vivo validation and RNA-seq pathway identification, single lab","pmids":["32021254"],"is_preprint":false},{"year":2021,"finding":"RABL2A interacts with CCDC34 in its GTP-bound state in sorafenib-resistant HCC cells (Huh7/SR and Hep3B/SR), as confirmed by co-immunoprecipitation and immunofluorescent staining. RABL2A Q80L (GTP-locked) overexpression conferred sorafenib resistance and increased p-p38 and p-JNK, effects that were abrogated by CCDC34 depletion, placing CCDC34 downstream of active RABL2A in p38/MAPK and JNK/MAPK signaling.","method":"Co-immunoprecipitation, immunofluorescent staining, GTP/GDP-locked RABL2A mutants, siRNA knockdown, CCK-8, TUNEL, PI/Annexin V, Western blot, in vivo model","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP, mutant epistasis, in vitro and in vivo, single lab","pmids":["34767735"],"is_preprint":false},{"year":2023,"finding":"MNX1 directly binds to the CCDC34 promoter and transcriptionally activates CCDC34 expression, as demonstrated by luciferase reporter and chromatin immunoprecipitation assays. CCDC34 overexpression partially rescued the antitumor effect of MNX1 knockdown in lung adenocarcinoma cells, placing CCDC34 genetically downstream of MNX1.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression rescue, in vitro proliferation/migration/invasion assays, in vivo xenograft","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirm direct transcriptional regulation, epistasis confirmed by rescue, single lab","pmids":["37415626"],"is_preprint":false},{"year":2024,"finding":"A novel missense mutation in CCDC34 (c.848C>A, p.A283E) identified by whole-exome sequencing in a consanguineous Pakistani family with oligoasthenoteratozoospermia was associated with axonemal ultrastructural defects including lack of outer dynein arms, indicating CCDC34 plays a role in maintaining axonemal ultrastructure and assembly/stability of outer dynein arms in sperm flagella.","method":"Whole-exome sequencing, hematoxylin and eosin staining, transmission electron microscopy of sperm ultrastructure","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2-3 — human loss-of-function mutation with TEM ultrastructural readout, single family, no functional rescue","pmids":["38856307"],"is_preprint":false},{"year":2024,"finding":"CCDC34 promotes lung adenocarcinoma stemness properties through β-catenin-mediated regulation of ATG5-induced autophagy, contributing to acquired EGFR-TKI resistance. CCDC34 knockdown synergistically inhibited tumor growth when combined with EGFR-TKIs in vitro and in vivo.","method":"WGCNA bioinformatics, siRNA knockdown, overexpression, Western blot for β-catenin/ATG5/autophagy markers, in vitro stemness assays, in vivo xenograft, drug combination assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with pathway placement via β-catenin/ATG5, in vivo validation, single lab","pmids":["39587349"],"is_preprint":false}],"current_model":"CCDC34 (coiled-coil domain-containing protein 34) functions as an oncogenic regulator that promotes cancer cell proliferation, survival, migration, and invasion through activation of MAPK (ERK, p38, JNK) and PI3K/AKT signaling pathways; it is transcriptionally activated by the homeobox transcription factor MNX1 via direct promoter binding; it interacts with GTP-bound RABL2A to mediate sorafenib resistance through p38/JNK signaling; it promotes stemness and EGFR-TKI resistance via β-catenin-mediated ATG5-dependent autophagy; and in sperm, it maintains axonemal ultrastructure and outer dynein arm assembly, as loss-of-function mutations cause oligoasthenoteratozoospermia."},"narrative":{"teleology":[{"year":2015,"claim":"The first functional investigation established that CCDC34, until then uncharacterized, is required for bladder cancer cell proliferation and migration through MAPK and PI3K/AKT signaling, answering whether this coiled-coil protein has signaling relevance in cancer.","evidence":"Lentiviral siRNA knockdown in bladder cancer cells with Western blot phospho-pathway analysis and nude mouse xenograft","pmids":["26312564"],"confidence":"Medium","gaps":["No direct enzymatic or scaffolding activity defined for CCDC34 itself","Single cancer type; generalizability unknown","Mechanism connecting a coiled-coil protein to MAPK/AKT activation unexplained"]},{"year":2017,"claim":"Extended the cancer-promoting role to colorectal cancer and revealed that CCDC34 suppresses apoptosis (via BCL2/survivin) and promotes EMT (via N-cadherin/E-cadherin switch), broadening its oncogenic mechanism beyond proliferation alone.","evidence":"siRNA knockdown in SW620 cells with Western blot for apoptosis and EMT markers, invasion assays, flow cytometry","pmids":["29115580"],"confidence":"Medium","gaps":["No direct protein interaction partners identified","EMT marker changes could be indirect consequences of proliferation effects","Single cell line tested"]},{"year":2020,"claim":"Confirmed AKT pathway engagement and EMT promotion in hepatocellular carcinoma with transcriptome-wide support and in vivo metastasis models, strengthening the case that CCDC34 is a general oncogenic factor across carcinomas.","evidence":"siRNA knockdown with RNA-seq, Western blot, xenograft and lung metastasis mouse models","pmids":["32021254"],"confidence":"Medium","gaps":["Still no direct biochemical mechanism linking CCDC34 to AKT activation","No identification of direct binding partners in this system"]},{"year":2021,"claim":"Identified the first direct physical interactor of CCDC34 — GTP-bound RABL2A — and placed CCDC34 as a downstream effector that transduces RABL2A signaling to p38/JNK MAPK to confer sorafenib resistance, answering how a coiled-coil protein connects to MAPK cascades.","evidence":"Reciprocal co-immunoprecipitation, GTP/GDP-locked RABL2A mutants, epistasis by siRNA in sorafenib-resistant HCC cells, in vivo model","pmids":["34767735"],"confidence":"Medium","gaps":["Whether CCDC34 directly activates kinases or acts as a scaffold/adaptor is unknown","RABL2A–CCDC34 interaction not confirmed by structural or biophysical methods","Relevance of RABL2A–CCDC34 axis outside drug resistance context untested"]},{"year":2023,"claim":"Demonstrated that CCDC34 is a direct transcriptional target of MNX1, establishing the first upstream regulatory mechanism for CCDC34 expression in cancer and answering why CCDC34 is upregulated in lung adenocarcinoma.","evidence":"ChIP and luciferase reporter for MNX1 binding to CCDC34 promoter; rescue of MNX1-knockdown phenotype by CCDC34 overexpression in lung adenocarcinoma cells and xenograft","pmids":["37415626"],"confidence":"Medium","gaps":["Whether MNX1–CCDC34 axis operates in other tumor types is untested","Additional transcription factors controlling CCDC34 expression not explored"]},{"year":2024,"claim":"Revealed a non-cancer physiological role for CCDC34: a loss-of-function missense mutation causes oligoasthenoteratozoospermia with outer dynein arm loss, establishing CCDC34 as required for axonemal assembly in human sperm and linking it to a Mendelian fertility disorder.","evidence":"Whole-exome sequencing in a consanguineous family; transmission electron microscopy of sperm axonemes","pmids":["38856307"],"confidence":"Medium","gaps":["No functional rescue experiment to confirm causality of the p.A283E variant","Mechanism by which CCDC34 contributes to outer dynein arm assembly is unknown","Single family; independent replication needed"]},{"year":2024,"claim":"Connected CCDC34 to cancer stemness and drug resistance by showing it drives β-catenin-mediated ATG5-dependent autophagy, providing a mechanistic basis for EGFR-TKI resistance in lung adenocarcinoma.","evidence":"Knockdown and overexpression with Western blot for β-catenin/ATG5/autophagy markers, stemness assays, EGFR-TKI combination in vitro and in vivo","pmids":["39587349"],"confidence":"Medium","gaps":["How CCDC34 activates β-catenin is mechanistically undefined","Relationship between RABL2A–CCDC34 axis and β-catenin/autophagy axis not explored","No structural or biochemical data on CCDC34 protein activity"]},{"year":null,"claim":"The intrinsic molecular activity of CCDC34 — whether it functions as a scaffold, adaptor, or has enzymatic activity — remains unknown, as does how a single coiled-coil protein participates in both axonemal dynein arm assembly and cytoplasmic oncogenic signaling.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No biochemical or structural characterization of CCDC34 protein","No reconstitution of CCDC34 activity in vitro","Relationship between ciliary/flagellar and oncogenic functions unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["RABL2A","MNX1"],"other_free_text":[]},"mechanistic_narrative":"CCDC34 (coiled-coil domain-containing protein 34) functions as a pro-proliferative and pro-survival factor in multiple cancer types and is required for axonemal integrity in sperm flagella. In cancer cells, CCDC34 sustains MAPK (ERK, p38, JNK) and PI3K/AKT signaling to promote proliferation, suppress apoptosis, and drive epithelial-to-mesenchymal transition and invasion; it is transcriptionally activated by the homeobox factor MNX1 via direct promoter binding and acts downstream of GTP-bound RABL2A to activate p38/JNK signaling that confers sorafenib resistance [PMID:26312564, PMID:34767735, PMID:37415626]. CCDC34 also promotes cancer stemness and EGFR-TKI resistance through β-catenin-mediated ATG5-dependent autophagy [PMID:39587349]. A homozygous missense mutation in CCDC34 (p.A283E) causes oligoasthenoteratozoospermia with loss of outer dynein arms and disrupted axonemal ultrastructure, establishing a requirement for CCDC34 in sperm motility and flagellar assembly [PMID:38856307]."},"prefetch_data":{"uniprot":{"accession":"Q96HJ3","full_name":"Coiled-coil domain-containing protein 34","aliases":["Renal carcinoma antigen NY-REN-41"],"length_aa":373,"mass_kda":43.2,"function":"Involved in spermatogenesis. Has a probable role in anterograde intraflagellar transport which is essential for the formation of sperm flagella","subcellular_location":"Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q96HJ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC34","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCDC34","total_profiled":1310},"omim":[{"mim_id":"620084","title":"SPERMATOGENIC FAILURE 76; SPGF76","url":"https://www.omim.org/entry/620084"},{"mim_id":"618788","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 134; CCDC134","url":"https://www.omim.org/entry/618788"},{"mim_id":"612324","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 34; CCDC34","url":"https://www.omim.org/entry/612324"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Calyx","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":48.3}],"url":"https://www.proteinatlas.org/search/CCDC34"},"hgnc":{"alias_symbol":["NY-REN-41","L15","RAMA3"],"prev_symbol":[]},"alphafold":{"accession":"Q96HJ3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HJ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HJ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HJ3-F1-predicted_aligned_error_v6.png","plddt_mean":68.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC34","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC34"},"sequence":{"accession":"Q96HJ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HJ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HJ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HJ3"}},"corpus_meta":[{"pmid":"16261607","id":"PMC_16261607","title":"Quantitative analysis of messenger RNA abundance for ribosomal protein L-15, cyclophilin-A, phosphoglycerokinase, beta-glucuronidase, glyceraldehyde 3-phosphate dehydrogenase, beta-actin, and histone H2A during bovine oocyte maturation and early embryogenesis in vitro.","date":"2006","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/16261607","citation_count":109,"is_preprint":false},{"pmid":"16608517","id":"PMC_16608517","title":"Overexpression of ribosomal protein L15 is associated with cell proliferation in gastric cancer.","date":"2006","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16608517","citation_count":86,"is_preprint":false},{"pmid":"33123156","id":"PMC_33123156","title":"Lactobacillus plantarum L15 Alleviates Colitis by Inhibiting LPS-Mediated NF-κB Activation and Ameliorates DSS-Induced Gut Microbiota Dysbiosis.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33123156","citation_count":81,"is_preprint":false},{"pmid":"3309345","id":"PMC_3309345","title":"Ribosomal proteins EL11 from Escherichia coli and L15 from Saccharomyces cerevisiae bind to the same site in both yeast 26 S and mouse 28 S rRNA.","date":"1987","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3309345","citation_count":72,"is_preprint":false},{"pmid":"863909","id":"PMC_863909","title":"Isolation of eukaryotic ribosomal proteins. 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proliferation and migration, induced G2/M cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in nude mice. CCDC34 silencing decreased phosphorylation of MEK, ERK1/2, JNK, p38, and Akt, and reduced expression of c-Raf and c-Jun, indicating MAPK (ERK, p38, JNK) and PI3K/Akt pathways are involved in CCDC34-mediated proliferation and migration.\",\n      \"method\": \"Lentivirus-mediated siRNA knockdown, Western blot for pathway phosphorylation, in vitro proliferation/migration assays, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"26312564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCDC34 inhibition in SW620 colorectal cancer cells led to reduced cell activity, increased apoptosis, and reduced invasion; mechanistically, BCL2, survivin, N-cadherin, and MMP-9 were decreased while E-cadherin increased, indicating CCDC34 promotes CRC invasion by suppressing apoptosis and promoting epithelial-to-mesenchymal transition.\",\n      \"method\": \"siRNA knockdown, Western blot for apoptosis/invasion-associated proteins, invasion assays, flow cytometry\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined molecular readouts, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"29115580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC34 knockdown in hepatocellular carcinoma cells inhibited proliferation and metastasis both in vitro and in vivo; RNA sequencing and Western blot revealed CCDC34 inhibition reduced AKT activation and suppressed epithelial-mesenchymal transition (EMT).\",\n      \"method\": \"siRNA knockdown, RNA sequencing, Western blot, xenograft and lung metastasis mouse models, CCK-8 and Transwell assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with in vivo validation and RNA-seq pathway identification, single lab\",\n      \"pmids\": [\"32021254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RABL2A interacts with CCDC34 in its GTP-bound state in sorafenib-resistant HCC cells (Huh7/SR and Hep3B/SR), as confirmed by co-immunoprecipitation and immunofluorescent staining. RABL2A Q80L (GTP-locked) overexpression conferred sorafenib resistance and increased p-p38 and p-JNK, effects that were abrogated by CCDC34 depletion, placing CCDC34 downstream of active RABL2A in p38/MAPK and JNK/MAPK signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescent staining, GTP/GDP-locked RABL2A mutants, siRNA knockdown, CCK-8, TUNEL, PI/Annexin V, Western blot, in vivo model\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, mutant epistasis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"34767735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MNX1 directly binds to the CCDC34 promoter and transcriptionally activates CCDC34 expression, as demonstrated by luciferase reporter and chromatin immunoprecipitation assays. CCDC34 overexpression partially rescued the antitumor effect of MNX1 knockdown in lung adenocarcinoma cells, placing CCDC34 genetically downstream of MNX1.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression rescue, in vitro proliferation/migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirm direct transcriptional regulation, epistasis confirmed by rescue, single lab\",\n      \"pmids\": [\"37415626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel missense mutation in CCDC34 (c.848C>A, p.A283E) identified by whole-exome sequencing in a consanguineous Pakistani family with oligoasthenoteratozoospermia was associated with axonemal ultrastructural defects including lack of outer dynein arms, indicating CCDC34 plays a role in maintaining axonemal ultrastructure and assembly/stability of outer dynein arms in sperm flagella.\",\n      \"method\": \"Whole-exome sequencing, hematoxylin and eosin staining, transmission electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — human loss-of-function mutation with TEM ultrastructural readout, single family, no functional rescue\",\n      \"pmids\": [\"38856307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC34 promotes lung adenocarcinoma stemness properties through β-catenin-mediated regulation of ATG5-induced autophagy, contributing to acquired EGFR-TKI resistance. CCDC34 knockdown synergistically inhibited tumor growth when combined with EGFR-TKIs in vitro and in vivo.\",\n      \"method\": \"WGCNA bioinformatics, siRNA knockdown, overexpression, Western blot for β-catenin/ATG5/autophagy markers, in vitro stemness assays, in vivo xenograft, drug combination assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with pathway placement via β-catenin/ATG5, in vivo validation, single lab\",\n      \"pmids\": [\"39587349\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC34 (coiled-coil domain-containing protein 34) functions as an oncogenic regulator that promotes cancer cell proliferation, survival, migration, and invasion through activation of MAPK (ERK, p38, JNK) and PI3K/AKT signaling pathways; it is transcriptionally activated by the homeobox transcription factor MNX1 via direct promoter binding; it interacts with GTP-bound RABL2A to mediate sorafenib resistance through p38/JNK signaling; it promotes stemness and EGFR-TKI resistance via β-catenin-mediated ATG5-dependent autophagy; and in sperm, it maintains axonemal ultrastructure and outer dynein arm assembly, as loss-of-function mutations cause oligoasthenoteratozoospermia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC34 (coiled-coil domain-containing protein 34) functions as a pro-proliferative and pro-survival factor in multiple cancer types and is required for axonemal integrity in sperm flagella. In cancer cells, CCDC34 sustains MAPK (ERK, p38, JNK) and PI3K/AKT signaling to promote proliferation, suppress apoptosis, and drive epithelial-to-mesenchymal transition and invasion; it is transcriptionally activated by the homeobox factor MNX1 via direct promoter binding and acts downstream of GTP-bound RABL2A to activate p38/JNK signaling that confers sorafenib resistance [PMID:26312564, PMID:34767735, PMID:37415626]. CCDC34 also promotes cancer stemness and EGFR-TKI resistance through β-catenin-mediated ATG5-dependent autophagy [PMID:39587349]. A homozygous missense mutation in CCDC34 (p.A283E) causes oligoasthenoteratozoospermia with loss of outer dynein arms and disrupted axonemal ultrastructure, establishing a requirement for CCDC34 in sperm motility and flagellar assembly [PMID:38856307].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The first functional investigation established that CCDC34, until then uncharacterized, is required for bladder cancer cell proliferation and migration through MAPK and PI3K/AKT signaling, answering whether this coiled-coil protein has signaling relevance in cancer.\",\n      \"evidence\": \"Lentiviral siRNA knockdown in bladder cancer cells with Western blot phospho-pathway analysis and nude mouse xenograft\",\n      \"pmids\": [\"26312564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct enzymatic or scaffolding activity defined for CCDC34 itself\",\n        \"Single cancer type; generalizability unknown\",\n        \"Mechanism connecting a coiled-coil protein to MAPK/AKT activation unexplained\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the cancer-promoting role to colorectal cancer and revealed that CCDC34 suppresses apoptosis (via BCL2/survivin) and promotes EMT (via N-cadherin/E-cadherin switch), broadening its oncogenic mechanism beyond proliferation alone.\",\n      \"evidence\": \"siRNA knockdown in SW620 cells with Western blot for apoptosis and EMT markers, invasion assays, flow cytometry\",\n      \"pmids\": [\"29115580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct protein interaction partners identified\",\n        \"EMT marker changes could be indirect consequences of proliferation effects\",\n        \"Single cell line tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed AKT pathway engagement and EMT promotion in hepatocellular carcinoma with transcriptome-wide support and in vivo metastasis models, strengthening the case that CCDC34 is a general oncogenic factor across carcinomas.\",\n      \"evidence\": \"siRNA knockdown with RNA-seq, Western blot, xenograft and lung metastasis mouse models\",\n      \"pmids\": [\"32021254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Still no direct biochemical mechanism linking CCDC34 to AKT activation\",\n        \"No identification of direct binding partners in this system\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the first direct physical interactor of CCDC34 — GTP-bound RABL2A — and placed CCDC34 as a downstream effector that transduces RABL2A signaling to p38/JNK MAPK to confer sorafenib resistance, answering how a coiled-coil protein connects to MAPK cascades.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, GTP/GDP-locked RABL2A mutants, epistasis by siRNA in sorafenib-resistant HCC cells, in vivo model\",\n      \"pmids\": [\"34767735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CCDC34 directly activates kinases or acts as a scaffold/adaptor is unknown\",\n        \"RABL2A–CCDC34 interaction not confirmed by structural or biophysical methods\",\n        \"Relevance of RABL2A–CCDC34 axis outside drug resistance context untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that CCDC34 is a direct transcriptional target of MNX1, establishing the first upstream regulatory mechanism for CCDC34 expression in cancer and answering why CCDC34 is upregulated in lung adenocarcinoma.\",\n      \"evidence\": \"ChIP and luciferase reporter for MNX1 binding to CCDC34 promoter; rescue of MNX1-knockdown phenotype by CCDC34 overexpression in lung adenocarcinoma cells and xenograft\",\n      \"pmids\": [\"37415626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MNX1–CCDC34 axis operates in other tumor types is untested\",\n        \"Additional transcription factors controlling CCDC34 expression not explored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-cancer physiological role for CCDC34: a loss-of-function missense mutation causes oligoasthenoteratozoospermia with outer dynein arm loss, establishing CCDC34 as required for axonemal assembly in human sperm and linking it to a Mendelian fertility disorder.\",\n      \"evidence\": \"Whole-exome sequencing in a consanguineous family; transmission electron microscopy of sperm axonemes\",\n      \"pmids\": [\"38856307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional rescue experiment to confirm causality of the p.A283E variant\",\n        \"Mechanism by which CCDC34 contributes to outer dynein arm assembly is unknown\",\n        \"Single family; independent replication needed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CCDC34 to cancer stemness and drug resistance by showing it drives β-catenin-mediated ATG5-dependent autophagy, providing a mechanistic basis for EGFR-TKI resistance in lung adenocarcinoma.\",\n      \"evidence\": \"Knockdown and overexpression with Western blot for β-catenin/ATG5/autophagy markers, stemness assays, EGFR-TKI combination in vitro and in vivo\",\n      \"pmids\": [\"39587349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How CCDC34 activates β-catenin is mechanistically undefined\",\n        \"Relationship between RABL2A–CCDC34 axis and β-catenin/autophagy axis not explored\",\n        \"No structural or biochemical data on CCDC34 protein activity\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic molecular activity of CCDC34 — whether it functions as a scaffold, adaptor, or has enzymatic activity — remains unknown, as does how a single coiled-coil protein participates in both axonemal dynein arm assembly and cytoplasmic oncogenic signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical or structural characterization of CCDC34 protein\",\n        \"No reconstitution of CCDC34 activity in vitro\",\n        \"Relationship between ciliary/flagellar and oncogenic functions unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RABL2A\",\n      \"MNX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}