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pmid:30813939
Comprehensive bioinformatics analysis of acquired progesterone resistance in endometrial cancer cell line.
Wenzhi Li · Shufen Wang · Chunping Qiu · Zhiming Liu · Qing Zhou · Deshui Kong · Xiaohong Ma · Jie Jiang
Journal of translational medicine · 2019 doi:10.1186/s12967-019-1814-6
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Complete file
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The aim of this study was to elucidate the molecular mechanisms of progesterone resistance and to identify the key genes and pathways mediating progesterone resistance in endometrial cancer using bioinformatics analysis.\nMETHODS: We developed a stable MPA (medroxyprogesterone acetate)-resistant endometrial cancer cell subline named IshikawaPR. Microarray analysis was used to identify differentially expressed genes (DEGs) from triplicate samples of Ishikawa and IshikawaPR cells. PANTHER, DAVID and Metascape were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and cBioPortal for progesterone receptor (PGR) coexpression analysis. GEO microarray (GSE17025) was utilized for validation. The protein-protein interaction network (PPI) and modular analyses were performed using Metascape and Cytoscape. Further validation were performed by real-time polymerase chain reaction (RT-PCR).\nRESULTS: In total, 821 DEGs were found and further analyzed by GO, KEGG pathway enrichment and PPI analyses. We found that lipid metabolism, immune system and inflammation, extracellular environment-related processes and pathways accounted for a significant portion of the enriched terms. PGR coexpression analysis revealed 7 PGR coexpressed genes (ANO1, SOX17, CGNL1, DACH1, RUNDC3B, SH3YL1 and CRISPLD1) that were also dramatically changed in IshikawaPR cells. Kaplan-Meier survival statistics revealed clinical significance for 4 out of 7 target genes. Furthermore, 8 hub genes and 4 molecular complex detections (MCODEs) were identified.\nCONCLUSIONS: Using microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of progesterone resistance. We offered several possible mechanisms of progesterone resistance and identified therapeutic and prognostic targets of progesterone resistance in endometrial cancer.", "claims": [{"id": "claim-method", "statement": "Kaplan–Meier curves for target genes were generated with the online tool Kaplan–Meier Plotter (http://www.kmplot.com/). A total of 542 RNA-seq data samples of uterine corpus endometrial carcinoma were interrogated. The patients were split into 2 groups (high vs. low) based on the expression level.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30813939", "locator": "sections[5] \"PGR coexpression analysis and validation by bioinformatics\" paragraph 3", "quote": "Kaplan–Meier curves for target genes were generated with the online tool Kaplan–Meier Plotter (http://www.kmplot.com/). A total of 542 RNA-seq data samples of uterine corpus endometrial carcinoma were interrogated. 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"section[13]/table-wrap[2]#Tab5", "version": null, "note": "Top 15 GO enrichments of the 4 MCODEs related genes", "structure": {"pmcid": "PMC6391799", "section_index": 13, "section_title": "Protein-protein interaction network (PPI) and modular analysis", "row_count": 16, "column_count": 3}, "table": {"label": "Table 5", "caption": "Top 15 GO enrichments of the 4 MCODEs related genes", "rows": [["GO term", "Description", "−Log10(p)"], ["GO:0002474", "Antigen processing and presentation of peptide antigen via MHC class I", "6.60"], ["GO:0006955", "Immune response", "3.98"], ["GO:0002480", "Antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent", "3.93"], ["GO:0006954", "Inflammatory response", "3.22"], ["GO:0090023", "Positive regulation of neutrophil chemotaxis", "3.13"], ["GO:0007218", "Neuropeptide signaling pathway", "3.08"], ["GO:0007186", "G-protein coupled receptor signaling pathway", "2.98"], ["GO:000693", "Chemotaxis", "2.84"], ["GO:0042612", "MHC class I protein complex", "3.82"], ["GO:0005622", "Intracellular", "3.57"], ["GO:0005887", "Integral component of plasma membrane", "3.38"], ["GO:0031090", "Organelle membrane", "3.37"], ["GO:0071556", "Integral component of lumenal side of endoplasmic reticulum membrane", "2.96"], ["GO:0008395", "Steroid hydroxylase activity", "4.85"], ["GO:0020037", "Heme binding", "3.96"]], "row_count": 16, "column_count": 3, "numeric_cells": 31, "header_rows": 1, "locator": "section[13]/table-wrap[2]#Tab5"}}, {"id": "asset:table:pmid:30813939:6", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:c0c41e51a5366de2646382e76d8b9bb042f088deab21f7e6327e6501cd5b1a13", "bytes": 779, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[13]/table-wrap[3]#Tab6", "version": null, "note": "Top 10 KEGG pathway enrichment of the 4 MCODEs related genes", "structure": {"pmcid": "PMC6391799", "section_index": 13, "section_title": "Protein-protein interaction network (PPI) and modular analysis", "row_count": 11, "column_count": 3}, "table": {"label": "Table 6", "caption": "Top 10 KEGG pathway enrichment of the 4 MCODEs related genes", "rows": [["KEGG pathway term", "Count", "−Log(p-value)"], ["hsa04612:Antigen processing and presentation", "5", "4.241909"], ["hsa04145:Phagosome", "6", "4.228601"], ["hsa05168:Herpes simplex infection", "6", "3.858941"], ["hsa04080:Neuroactive ligand-receptor interaction", "6", "3.025758"], ["hsa05332:Graft-versus-host disease", "3", "2.399844"], ["hsa05330:Allograft rejection", "3", "2.302013"], ["hsa04940:Type I diabetes mellitus", "3", "2.194244"], ["hsa05320:Autoimmune thyroid disease", "3", "2.014217"], ["hsa05134:Legionellosis", "3", "1.982622"], ["hsa05416:Viral myocarditis", "3", "1.93748"]], "row_count": 11, "column_count": 3, "numeric_cells": 30, "header_rows": 1, "locator": 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A total of 542 RNA-seq data samples of uterine corpus endometrial carcinoma were interrogated. The patients were split into 2 groups (high vs. low) based on the expression level."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["survival_km"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: kaplan_meier."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE121367", "GSE17025"], "resolved_accessions": ["GSE121367", "GSE17025"], "statements": ["The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request."], "basis": "The paper names GSE121367, GSE17025 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. 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