Identification of novel transcription factor-microRNA-mRNA co-regulatory networks in pulmonary large-cell neuroendocrine carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33569435", "kind": "science-record", "revision": 8, "content_hash": "sha256:aa2de0c7a83e78cf34396de8e60c4d9a24493d4ad978e08f7b43662279a07c81", "created_at": "2026-11-01T15:41:25Z", "updated_at": "2026-11-01T22:03:06Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification of novel transcription factor-microRNA-mRNA co-regulatory networks in pulmonary large-cell neuroendocrine carcinoma.", "doi": "10.21037/atm-20-7759", "pmid": "33569435", "authors": ["Cunliang Cai", "Qianli Zeng", "Guiliang Zhou", "Xiangdong Mu"], "journal": "Annals of translational medicine", "year": 2021, "abstract": "BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare neuroendocrine neoplasm. Previous studies have shown that microRNAs (miRNAs) are widely involved in tumor regulation through targeting critical genes. However, it is unclear which miRNAs play vital roles in the pathogenesis of LCNEC, and how they interact with transcription factors (TFs) to regulate cancer-related genes.\nMETHODS: To determine the novel TF-miRNA-target gene feed-forward loop (FFL) model of LCNEC, we integrated multi-omics data from Gene Expression Omnibus (GEO), Transcriptional Regulatory Relationships Unraveled by Sentence-Based Text Mining (TRRUST), Transcriptional Regulatory Element Database (TRED), and The experimentally validated microRNA-target interactions database (miRTarBase database). First, expression profile datasets for mRNAs (GSE1037) and miRNAs (GSE19945) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. The target genes of the FFL were obtained from the miRTarBase database, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on the target genes. Then, we screened for key miRNAs in the FFL and performed gene regulatory network analysis based on key miRNAs. Finally, the TF-miRNA-target gene FFLs were constructed by the hypergeometric test.\nRESULTS: A total of 343 DEGs and 60 DEMs were identified in LCNEC tissues compared to normal tissues, including 210 down-regulated and 133 up-regulated genes, and 29 down-regulated and 31 up-regulated miRNAs. Finally, the regulatory network of TF-miRNA-target gene was established. The key regulatory network modules included ETS1-miR195-CD36, TAOK1-miR7-1-3P-GRIA1, E2F3-miR195-CD36, and TEAD1-miR30A-CTHRC1.\nCONCLUSIONS: We constructed the TF-miRNA-target gene regulatory network, which is helpful for understanding the complex LCNEC regulatory mechanisms.", "claims": [{"id": "claim-method", "statement": "Finally, the TF-miRNA-target gene FFLs were constructed by the hypergeometric test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33569435", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Finally, the TF-miRNA-target gene FFLs were constructed by the hypergeometric test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The mRNA expression profile (GSE1037) and the miRNA expression profile (GSE19945) datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/gds/). The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset. There were 19 normal and 8 LCNEC tissues included in the GSE1037 dataset, while 20 Barrett’s esophagus, 8 normal, and 11 LCNEC tissues were included in the GSE19945 dataset.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33569435", "locator": "sections[3] \"Collection of datasets\" paragraph 2", "quote": "The mRNA expression profile (GSE1037) and the miRNA expression profile (GSE19945) datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/gds/)."}, {"asset": "source:pmid:33569435", "locator": "sections[9] \"Microarray datasets from the GEO\" paragraph 2", "quote": "The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset."}, {"asset": "source:pmid:33569435", "locator": "sections[9] \"Microarray datasets from the GEO\" paragraph 2", "quote": "There were 19 normal and 8 LCNEC tissues included in the GSE1037 dataset, while 20 Barrett’s esophagus, 8 normal, and 11 LCNEC tissues were included in the GSE19945 dataset."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:33569435"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE1037"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "blocked", "blocked_on": "method:student_t", "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE1037"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:run_analysis blocked on method:student_t"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33569435", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.21037/atm-20-7759", "sha256": "sha256:23599138067b0384ad797c5e01d535b22f7ebd29a9c8069f6db1f597d6127030", "bytes": 26585, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.21037/atm-20-7759", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7867924", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE1037", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE1037", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE1037", "version": null, "note": "The mRNA expression profile (GSE1037) and the miRNA expression profile (GSE19945) datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/gds/). The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset. There were 19 normal and 8 LCNEC tissues included in the GSE1037 dataset, while 20 Barrett’s esophagus, 8 normal, and 11 LCNEC tissues were included in the GSE19945 dataset.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The mRNA expression profile (GSE1037) and the miRNA expression profile (GSE19945) datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/gds/). The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset. 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The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset. There were 19 normal and 8 LCNEC tissues included in the GSE1037 dataset, while 20 Barrett’s esophagus, 8 normal, and 11 LCNEC tissues were included in the GSE19945 dataset.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The mRNA expression profile (GSE1037) and the miRNA expression profile (GSE19945) datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/gds/). The mRNA expression profiles were obtained from the GSE1037 dataset, and miRNA profiles were obtained from the GSE19945 dataset. 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"section_title": "Screening LCNEC-related TFs and miRNAs", "row_count": 211, "column_count": 3}, "table": {"label": "Table 1", "caption": "Prediction of differentially expressed miRNA transcription factors", "rows": [["Transcription factor", "Fold enrichment", "P value"], ["SPZ1", "3.491981474", "1"], ["TFCP2L1", "3.491981474", "1"], ["PLAG1", "3.491981474", "1"], ["UBP1", "3.491981474", "1"], ["SMAD1", "2.418351505", "0.592451271"], ["CEBPA", "2.331854739", "1"], ["FOXJ1", "2.253290851", "0.007366364"], ["HOXD10", "2.110026715", "0.000910034"], ["HOXA10", "2.095886932", "0.702502302"], ["FOXK1", "2.077990133", "2.60309E-10"], ["FOXO1", "2.018878514", "4.36494E-15"], ["PLAGL1", "1.997552883", "1"], ["SOX1", "1.935828721", "1.11214E-18"], ["FOXJ2", "1.915387049", "1.87936E-19"], ["HOXB6", "1.902265495", "3.17735E-07"], ["NR1H4", "1.858898701", "0.008388385"], ["WT1", "1.849662145", "1"], ["SIX1", "1.838755106", "1"], ["RUNX1", "1.793638688", "0.619373949"], ["POU3F3", "1.775874666", "0.054495145"], ["CEBPG", "1.754677258", "1"], ["ELF5", "1.746784009", "1"], ["TLX2", "1.746281687", "0.079372394"], ["HMX1", "1.731514167", "9.22283E-10"], ["HOXB8", "1.722789491", "7.18956E-09"], ["MAFK", "1.718848158", "0.00013488"], ["PAX4", "1.716160943", "1.4468E-06"], ["FOXD1", "1.704224125", "6.25808E-13"], ["HOXC6", "1.694497234", "1.21095E-08"], ["MAFB", "1.686519617", "5.38403E-13"], ["MSX1", "1.686375909", "2.57832E-08"], ["ALX1", "1.683956787", "0.309670898"], ["FOXD3", "1.68316583", "3.19157E-13"], ["DBX2", "1.677564983", "7.75995E-15"], ["TP53", "1.670869884", "1"], ["FOXC1", "1.670643009", "1.8709E-10"], ["T", "1.670474076", "0.934293791"], ["CUX1", "1.666226182", "3.75078E-12"], ["FOXA1", "1.654805116", "1.00367E-28"], ["DBX1", "1.651097554", "1.28079E-07"], ["POU5F1", "1.638378804", "6.15565E-12"], ["CEBPD", "1.637996088", "0.005794963"], ["DLX2", "1.63378421", "6.86485E-05"], ["POU3F4", "1.631550373", "1.93335E-11"], ["RUNX2", "1.629650476", "1.19591E-09"], ["ESX1", "1.61478381", "1.3111E-07"], ["SRF", "1.602422009", "2.19434E-13"], ["HOXC10", "1.595336802", "0.168294861"], ["MSX2", "1.593779283", "2.04468E-09"], ["BARX1", "1.590638194", "1.88744E-10"], ["MEIS2", "1.590312278", "8.11158E-15"], ["PDX1", "1.586462162", "5.28493E-10"], ["EOMES", "1.584057161", "1.49715E-07"], ["BARX2", "1.580894015", "1.3101E-07"], ["HOXB3", "1.574054871", "1.59887E-08"], ["ONECUT1", "1.572663985", "5.28929E-15"], ["TFAP2A", "1.570112673", "2.95514E-06"], ["HOXB13", "1.566781141", "1.2731E-13"], ["HOXA3", "1.566245194", "6.39409E-15"], ["PRRX1", "1.56201562", "1.26796E-09"], ["HOXA13", "1.559588244", "2.22792E-07"], ["PAX7", "1.555356559", "1.76924E-11"], ["POU3F2", "1.553491613", "3.52034E-20"], ["HOXB9", "1.5476928", "5.34779E-13"], ["NKX3-1", "1.545950166", "1"], ["NOBOX", "1.54077687", "7.63787E-15"], ["ISL2", "1.539221985", "4.96908E-12"], ["HOXB7", "1.539042169", "8.4588E-09"], ["GFI1", "1.537266387", "6.97499E-13"], ["NKX2-1", "1.527462565", "2.31111E-16"], ["POU6F1", "1.52477309", "8.28794E-15"], ["CDX2", "1.518330825", "5.83258E-05"], ["PAX6", "1.517197962", "4.84278E-12"], ["ZFP161", "1.507988341", "2.02524E-25"], ["FEV", "1.507033544", "7.4113E-11"], ["ATF6", "1.504340104", "0.00220223"], ["EGR1", "1.503241757", "4.57094E-85"], ["HOXA5", "1.502031223", "1.46359E-19"], ["POU4F3", "1.489331293", "1.5136E-13"], ["TBX5", "1.489325563", "0.002477807"], ["RORA", "1.485903128", "5.54899E-24"], ["EN1", "1.483760545", "1.30534E-08"], ["HOXD8", "1.481210524", "1.0198E-15"], ["ELF3", "1.478344872", "7.98561E-08"], ["LMO2", "1.47696946", "2.79805E-11"], ["POU2F1", "1.474893113", "1.33454E-47"], ["ATF4", "1.474456227", "2.81165E-05"], ["VAX2", "1.472471901", "1.45559E-07"], ["RBPJ", "1.47117606", "0.001214947"], ["LHX4", "1.469890725", "1.16956E-06"], ["PHOX2A", "1.469522124", "1.27912E-07"], ["CACD", "1.467486855", "6.03042E-09"], ["HOXA9", "1.461007763", "8.18167E-13"], ["PBX1", "1.460910348", "4.84252E-13"], ["HOXA7", "1.457791777", "8.3229E-09"], ["ELF1", "1.456519375", "7.71995E-10"], ["PRRX2", "1.45648868", "4.61243E-10"], ["NKX6-1", "1.455833442", "4.69109E-26"], ["VSX2", "1.45551558", "5.56645E-10"], ["GATA1", "1.453421391", "2.27659E-12"], ["PAX5", "1.453176104", "0.093698746"], ["YY1", "1.445064824", "4.8313E-23"], ["HOXC9", "1.444363151", "4.33266E-09"], ["OTX2", "1.444277761", "0.000103525"], ["MYC", "1.440541634", "3.43948E-18"], ["BARHL1", "1.433879586", "1.45299E-07"], ["IRF1", "1.433847611", "9.58287E-13"], ["NR5A2", "1.429886696", "4.89954E-07"], ["ZEB1", "1.428193515", "1.38122E-05"], ["LHX8", "1.425071674", "0.012186295"], ["ARNT", "1.421105882", "2.04387E-05"], ["NANOG", "1.420858694", "0.028373957"], ["HNF1A", "1.420349524", "2.80572E-12"], ["BSX", "1.420323497", "0.002842563"], ["ARID3A", "1.416364291", "5.08411E-19"], ["MEF2A", "1.415833776", "1.97674E-29"], ["DMBX1", "1.413929403", "0.000111663"], ["HOXB4", "1.410439336", "6.30315E-10"], ["GBX1", "1.403916576", "0.058544479"], ["LHX3", 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