Integrative bioinformatics approaches for identifying potential biomarkers and pathways involved in non-obstructive azoospermia.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33532314", "kind": "science-record", "revision": 6, "content_hash": "sha256:ea5b5b5e750eceffd4fc188bf27ffa6c75c1b6bfbcc17153523b8e5e43153d6f", "created_at": "2026-11-01T15:41:24Z", "updated_at": "2026-11-01T22:03:02Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Integrative bioinformatics approaches for identifying potential biomarkers and pathways involved in non-obstructive azoospermia.", "doi": "10.21037/tau-20-1029", "pmid": "33532314", "authors": ["Tengfei Hu", "Shaoge Luo", "Yu Xi", "Xuchong Tu", "Xiaojian Yang", "Hui Zhang", "Jiarong Feng", "Chunlin Wang", "Yan Zhang"], "journal": "Translational andrology and urology", "year": 2021, "abstract": "BACKGROUND: Non-obstructive azoospermia (NOA) is a disease related to spermatogenic disorders. Currently, the specific etiological mechanism of NOA is unclear. This study aimed to use integrated bioinformatics to screen biomarkers and pathways involved in NOA and reveal their potential molecular mechanisms.\nMETHODS: GSE145467 and GSE108886 gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between NOA tissues and matched obstructive azoospermia (OA) tissues were identified using the GEO2R tool. Common DEGs in the two datasets were screened out by the VennDiagram package. For the functional annotation of common DEGs, DAVID v.6.8 was used to perform Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In accordance with data collected from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, a protein-protein interaction (PPI) network was constructed by Cytoscape. Cytohubba in Cytoscape was used to screen the hub genes. Furthermore, the hub genes were validated based on a separate dataset, GSE9210. Finally, potential micro RNAs (miRNAs) of hub genes were predicted by miRWalk 3.0.\nRESULTS: A total of 816 common DEGs, including 52 common upregulated and 764 common downregulated genes in two datasets, were screened out. Some of the more important of these pathways, including focal adhesion, PI3K-Akt signaling pathway, cell cycle, oocyte meiosis, AMP-activated protein kinase (AMPK) signaling pathway, FoxO signaling pathway, and Huntington disease, were involved in spermatogenesis. We further identified the top 20 hub genes from the PPI network, including CCNB2, DYNLL2, HMMR, NEK2, KIF15, DLGAP5, NUF2, TTK, PLK4, PTTG1, PBK, CEP55, CDKN3, CDC25C, MCM4, DNAI1, TYMS, PPP2R1B, DNAI2, and DYNLRB2, which were all downregulated genes. In addition, potential miRNAs of hub genes, including hsa-miR-3666, hsa-miR-130b-3p, hsa-miR-15b-5p, hsa-miR-6838-5p, and hsa-miR-195-5p, were screened out.\nCONCLUSIONS: Taken together, the identification of the above hub genes, miRNAs and pathways will help us better understand the mechanisms associated with NOA, and provide potential biomarkers and therapeutic targets for NOA.", "claims": [{"id": "claim-method", "statement": "The Wilcox test was used to determine whether there were differences in the expression of hub genes between the two subgroups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33532314", "locator": "sections[7] \"Analysis of hub genes in the NOA subgroup\" paragraph 2", "quote": "The Wilcox test was used to determine whether there were differences in the expression of hub genes between the two subgroups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The GSE145467 dataset, which was contributed by Hodžić et al. (11), is based on the GPL4133 platform of the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) and includes 10 NOA samples and 10 OA testicular samples.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33532314", "locator": "sections[3] \"Microarray data source\" paragraph 3", "quote": "The GSE145467 dataset, which was contributed by Hodžić et al. (11), is based on the GPL4133 platform of the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) and includes 10 NOA samples and 10 OA testicular samples."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "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:33532314"], "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:GSE108886"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "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:GSE108886"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33532314", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.21037/tau-20-1029", "sha256": "sha256:9ef1586877c1eb8f1bd7a38f50650aa2d83d797f3e27429501b4af6e41b033cd", "bytes": 34021, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.21037/tau-20-1029", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7844508", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE108886", "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=GSE108886", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE108886", "version": null, "note": "The GSE145467 dataset, which was contributed by Hodžić et al. (11), is based on the GPL4133 platform of the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) and includes 10 NOA samples and 10 OA testicular samples.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The GSE145467 dataset, which was contributed by Hodžić et al. 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(11), is based on the GPL4133 platform of the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) and includes 10 NOA samples and 10 OA testicular samples.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The GSE145467 dataset, which was contributed by Hodžić et al. 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"GSM233026", "GSM233027"], "sample_count": 58, "group_sizes": null, "group_sizes_basis": null, "platform": "887", "taxon": "Homo sapiens", "title": "A testicular gene expression profile for NOA patients, and ART3 as a genetic susceptibility gene for NOA", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:33532314:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:8247ef6c61968cd5f37887e526e1aa5b1ef08582ab580b9341537773bd2f1316", "bytes": 2470, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[13]/table-wrap[1]#t1", "version": null, "note": "Gene ontology analysis of common upregulated and downregulated DEGs", "structure": {"pmcid": "PMC7844508", "section_index": 13, "section_title": "GO enrichment analysis", "row_count": 33, "column_count": 5}, "table": {"label": "Table 1", "caption": "Gene ontology analysis of common upregulated and downregulated DEGs", "rows": [["Category", "Term", "Count", "Gene ratio", "P value"], ["Upregulated", "", "", "", ""], ["BP", "GO:0030198~extracellular matrix organization", "6", "0.0775294", "2.59E-04"], ["BP", "GO:0008285~negative regulation of cell proliferation", "6", "0.0775294", "0.005787"], ["BP", "GO:0007155~cell adhesion", "6", "0.0775294", "0.0105986"], ["BP", "GO:0044267~cellular protein metabolic process", "5", "0.0646078", "3.85E-04"], ["BP", "GO:0043066~negative regulation of apoptotic process", "5", "0.0646078", "0.04328502"], ["CC", "GO:0070062~extracellular exosome", "25", "0.3230392", "5.98E-08"], ["CC", "GO:0005615~extracellular space", "20", "0.2584313", "9.39E-10"], ["CC", "GO:0005576~extracellular region", "18", "0.2325882", "6.52E-07"], ["CC", "GO:0031012~extracellular matrix", "11", "0.1421372", "6.35E-09"], ["CC", "GO:0005578~proteinaceous extracellular matrix", "6", "0.0775294", "8.18E-04"], ["MF", "GO:0005102~receptor binding", "6", "0.0775294", "0.00290085"], ["MF", "GO:0005509~calcium ion binding", "6", "0.0775294", "0.04816598"], ["MF", "GO:0005518~collagen binding", "5", "0.0646078", "2.29E-05"], ["MF", "GO:0008201~heparin binding", "5", "0.0646078", "0.00100954"], ["MF", "GO:0017147~Wnt-protein binding", "3", "0.0387647", "0.00335112"], ["Downregulated", "", "", "", ""], ["BP", "GO:0007283~spermatogenesis", "68", "0.0747565", "1.86E-33"], ["BP", "GO:0007275~multicellular organism development", "50", "0.054968", "2.82E-13"], ["BP", "GO:0030154~cell differentiation", "44", "0.0483718", "1.24E-11"], ["BP", "GO:0007286~spermatid development", "24", "0.0263846", "1.21E-17"], ["BP", "GO:0030317~sperm motility", "21", "0.0230866", "1.32E-17"], ["CC", "GO:0005634~nucleus", "221", "0.2429586", "3.59E-05"], ["CC", "GO:0005737~cytoplasm", "197", "0.216574", "0.00769222"], ["CC", 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"state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[14]/table-wrap[1]#t2", "version": null, "note": "KEGG pathway analysis of common upregulated and downregulated DEGs", "structure": {"pmcid": "PMC7844508", "section_index": 14, "section_title": "KEGG pathway enrichment analysis", "row_count": 17, "column_count": 6}, "table": {"label": "Table 2", "caption": "KEGG pathway analysis of common upregulated and downregulated DEGs", "rows": [["Pathway", "ID", "Count", "Fold Enrichment", "P value", "Genes"], ["Upregulated", "", "", "", "", ""], ["Focal adhesion", "hsa04510", "6", "7.155686546", "1.08E-03", "LAMA2, COL6A3, PDGFRA, IGF1, COL6A1, SHC1"], ["PI3K-Akt signaling pathway", "hsa04151", "6", "4.272670807", "9.99E-03", "LAMA2, COL6A3, PDGFRA, IGF1, COL6A1, GNG11"], ["Glioma", "hsa05214", "3", "11.33901099", "2.65E-02", "PDGFRA, IGF1, SHC1"], ["ECM-receptor interaction", "hsa04512", "3", "8.471674877", "4.52E-02", "LAMA2, COL6A3, COL6A1"], ["Protein digestion and absorption", "hsa04974", "3", "8.375405844", "4.62E-02", "COL6A3, CPA3, COL6A1"], ["Downregulated", "", "", "", "", ""], ["Oocyte meiosis", "hsa04114", "9", "4.323695789", "1.02E-03", "PPP2R1B, PGR, PLCZ1, SPDYA, MAPK1, CCNB2, PPP3R2, PTTG1, CDC25C"], ["Glycolysis/gluconeogenesis", "hsa00010", "7", "5.5713294", "1.46E-03", "GAPDHS, LDHC, LDHAL6B, PFKP, PGAM2, PDHA2, PGK2"], ["Cell cycle", "hsa04110", "8", "3.44036009", "8.15E-03", "CCNB2, CDC14A, DBF4, TTK, PTTG1, CCNA1, CDC25C, MCM4"], ["Progesterone-mediated oocyte maturation", "hsa04914", "6", "3.677626303", "2.26E-02", "PGR, SPDYA, MAPK1, CCNB2, CCNA1, CDC25C"], ["AMPK signaling pathway", "hsa04152", "7", "3.034789185", "2.68E-02", "PPP2R1B, CPT1B, CAB39L, PFKP, CCNA1, PPP2R2B, PPP2R3C"], ["Glucagon signaling pathway", "hsa04922", "6", "3.231853418", "3.68E-02", "LDHC, CPT1B, LDHAL6B, PPP3R2, PGAM2, PDHA2"], ["Metabolic pathways", "hsa01100", "32", "1.399851193", "3.76E-02", "INPP1, LDHC, PLCZ1, KYNU, GCNT3, SGMS2, GK2, OLAH, COX7B2, NT5C1B, ACSBG2, PGAM2, TKTL2, CERS3, AZIN2, STT3B, ALDH1A2, TYMS, GALNTL5, PHOSPHO2, PDHA2, COX6B2, PRPS1L1, PCYT2, SPAM1, ADSSL1, LDHAL6B, SI, PFKP, GAPDHS, INPP4B, PGK2"], ["Protein processing in endoplasmic reticulum", "hsa04141", "8", "2.524287877", "3.78E-02", "HSPA1L, NGLY1, STT3B, DNAJC5B, UBQLNL, HSPA4L, UBQLN3, DNAJC5G"], ["Biosynthesis of amino acids", "hsa01230", "5", "3.703165375", "4.46E-02", "PFKP, PGAM2, TKTL2, PRPS1L1, PGK2"]], "row_count": 17, "column_count": 6, "numeric_cells": 61, "header_rows": 1, "locator": "section[14]/table-wrap[1]#t2"}}, {"id": "asset:table:pmid:33532314:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:dd18fd717fdab0c77ec3e4938d887041576a261c2db088dde5f64bd63c04ca01", "bytes": 1269, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#t3", "version": null, "note": "Degree values and descriptions of the top 20 hub genes", "structure": {"pmcid": "PMC7844508", "section_index": 15, "section_title": "PPI network and hub gene analysis", "row_count": 21, "column_count": 4}, "table": {"label": "Table 3", "caption": "Degree values and descriptions of the top 20 hub genes", "rows": [["Rank", "Gene symbol", "Gene description", "Degree"], ["1", "CCNB2", "Cyclin B2", "25"], ["2", "DYNLL2", "Dynein light chain LC8-type 2", "22"], ["3", "HMMR", "Hyaluronan mediated motility receptor", "21"], ["4", "KIF15", "Kinesin family member 15", "20"], ["4", "NEK2", "NIMA related kinase 2", "20"], ["6", "DLGAP5", "DLG associated protein 5", "19"], ["7", "PTTG1", "Pituitary tumor-transforming 1", "18"], ["7", "PLK4", "Polo like kinase 4", "18"], ["7", "TTK", "TTK protein kinase", "18"], ["7", "NUF2", "NUF2, NDC80 kinetochore complex component", "18"], ["11", "PBK", "PDZ binding kinase", "17"], ["12", "CEP55", "Centrosomal protein 55", "16"], ["13", "CDKN3", "Cyclin dependent kinase inhibitor 3", "15"], ["14", "CDC25C", "Cell division cycle 25C", "14"], ["15", "DNAI1", "Dynein axonemal intermediate chain 1", "13"], ["15", "MCM4", "Minichromosome maintenance complex component 4", "13"], ["17", "DNAI2", "Dynein axonemal intermediate chain 2", "12"], ["17", "PPP2R1B", "Protein phosphatase 2 scaffold subunit Abeta", "12"], ["17", "TYMS", "Thymidylate synthetase", "12"], ["20", "DYNLRB2", "Dynein light chain roadblock-type 2", "11"]], "row_count": 21, "column_count": 4, "numeric_cells": 58, "header_rows": 1, "locator": "section[15]/table-wrap[1]#t3"}}, {"id": "asset:table:pmid:33532314:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:1038435750bc179bba8c44e55b013a4bba16de7ccce35aa34c6e90604c5b7a2e", "bytes": 1028, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[18]/table-wrap[1]#t4", "version": null, "note": "Hub genes and corresponded target miRNAs", "structure": {"pmcid": "PMC7844508", "section_index": 18, "section_title": "Integrated network analysis of miRNA–mRNA interactions", "row_count": 5, "column_count": 2}, "table": {"label": "Table 4", "caption": "Hub genes and corresponded target miRNAs", "rows": [["Gene", "miRNA"], ["NEK2", "hsa-miR-216a-3p"], ["CEP55", "hsa-miR-130b-3p hsa-miR-6838-5p hsa-miR-3666 hsa-miR-15b-5p"], ["PPP2R1B", "hsa-miR-382-5p hsa-miR-497-5p hsa-miR-125a-5p hsa-miR-6838-5p hsa-miR-15b-5p hsa-miR-195-5p hsa-miR-125b-5p hsa-miR-4319"], ["DYNLL2", "hsa-miR-193a-3p hsa-miR-148a-3p hsa-miR-139-5p hsa-miR-329-3p hsa-miR-330-3p hsa-miR-296-5p hsa-miR-19b-3p hsa-miR-129-2-3p hsa-miR-204-5p hsa-miR-4644 hsa-miR-1306-5p hsa-miR-130a-3p hsa-miR-130b-3p hsa-miR-150-5p hsa-miR-6088 hsa-miR-181c-5p hsa-miR-185-5p hsa-miR-148b-3p hsa-miR-193b-3p hsa-miR-195-5p hsa-miR-200a-3p hsa-miR-211 -5p hsa-miR-454-3p hsa-miR-331-3p hsa-miR-141-3p hsa-miR-103a-3p hsa-miR-129-1-3p hsa-miR-212-3p hsa-miR-328-3p hsa-miR-301b-3p hsa-miR-3666 hsa-miR-4295 hsa-miR-532-3p hsa-miR-152-3p hsa-miR-181d-5p hsa-miR-107 hsa-miR-132-3p hsa-miR-6835-3p"]], "row_count": 5, "column_count": 2, "numeric_cells": 5, "header_rows": 1, "locator": "section[18]/table-wrap[1]#t4"}}, {"id": "asset:table:pmid:33532314:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:3354b0f414bf6dab8364c3e8da04de6613fe3cd5f410a272d11e1c1521f06ad9", "bytes": 933, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[19]/table-wrap[1]#t5", "version": null, "note": "Several hub genes play a functional role in spermatogenesis", "structure": {"pmcid": "PMC7844508", "section_index": 19, "section_title": "Discussion", "row_count": 10, "column_count": 3}, "table": {"label": "Table 5", "caption": "Several hub genes play a functional role in spermatogenesis", "rows": [["Gene", 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