Identification and Validation of MSX1 as a Key Candidate for Progestin Resistance in Endometrial Cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33235459", "kind": "science-record", "revision": 8, "content_hash": "sha256:b300a74560ab616dab6b6ced9cd0a9a50b25e6b699d41a06d33870ee94fa8408", "created_at": "2026-11-01T15:41:17Z", "updated_at": "2026-11-01T22:45:40Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification and Validation of MSX1 as a Key Candidate for Progestin Resistance in Endometrial Cancer.", "doi": "10.2147/OTT.S271494", "pmid": "33235459", "authors": ["Linlin Yang", "Yunxia Cui", "Ting Huang", "Xiao Sun", "Yudong Wang"], "journal": "OncoTargets and therapy", "year": 2020, "abstract": "PURPOSE: Progestin resistance is a critical obstacle for endometrial conservative therapy. Therefore, studies to acquire a more comprehensive understanding of the mechanisms are urgent. However, the pivotal molecules are still unexplored.\nMATERIALS AND METHODS: We downloaded GSE121367 from the GEO database. The \"limma\" R language package was applied to identify differentially expressed genes (DEGs). We conducted Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Protein-protein interaction was constructed by STRING and visualized in Cytoscape. The tumor immune microenvironment was explored by the TISIDB database. Methylation validation and overall survival analysis were conducted by the TCGA database. In addition, the upstream modulators of hub genes were predicted by miRTarBase and Network Analyst databases. The expression levels of candidate genes were validated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemical assay (IHC). Cell growth, clone formation, migration, invasion, and wound healing assays were studied to explore the role of MSX1 in progestin resistance in vitro.\nRESULTS: A total of 3,282 DEGs were identified and they were mostly enriched in the cell adhesion pathway. We screened out ten hub genes whose genomic alteration rates were low based on the current endometrial carcinoma sample sets. Has-miR-335-5p, has-miR-124-3p, MAZ, and TFDP1 were the most prominent upstream regulators. The methylation status of CDH1, JAG1, EPCAM, and MSX1 was decreased, corresponding to their high protein expression, which also predicted better overall survival. The homeobox protein of MSX1 showed significant tissue specificity and better prognostic value and its knockdown inhibited epithelial-mesenchymal transitions (EMT) and enhanced progesterone efficacy.\nCONCLUSION: Our study identified that the gene of MSX1 promised to be the specific indicator and therapeutic target for progestin resistance. This would shed new light on the underlying biological mechanism to overcome progestin resistance of endometrial cancer.", "claims": [{"id": "claim-data-access", "statement": "All data analyzed during this study are included in this published article.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33235459", "locator": "sections[32] \"Data Sharing Statement\" paragraph 2", "quote": "All data analyzed during this study are included in this published article."}], "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:33235459"], "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": "blocked", "blocked_on": "data:accession_absent", "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": [], "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": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33235459", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.2147/OTT.S271494", "sha256": "sha256:93c39d3e3f7f64d03a645b1aa55576357cb6b0c06ee30b8b2685cd77bda607f9", "bytes": 51313, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.2147/OTT.S271494", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7679365", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:33235459:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:13d19fd3e68b70821e463b01660a33861283752358c484a8d3bc98037779c1d6", "bytes": 1163, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[1]#t0001", "version": null, "note": "The Related Databases and Their Functions in This Study", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 13, "column_count": 2}, "table": {"label": "Table 1", "caption": "The Related Databases and Their Functions in This Study", "rows": [["Databases", "Functions"], ["Gene Expression Omnibus (GEO)", "Extraction of gene expression microarray data"], ["The Cancer Genome Atlas (TCGA) database", "Extraction of gene expression data and survival data"], ["The Database for Annotation, Visualization, and Integrated Discovery (DAVID)", "Gene functional annotation"], ["Metascape", "Pathway enrichment analysis"], ["Search Tool for the Retrieval of Interacting Genes (STRING)", "Functional interactions between proteins"], ["Gene Expression Profiling Interactive Analysis (GEPIA)", "Hub genes expression analysis and survival analysis"], ["cBioPortal for Cancer Genomics", "Mutation and DNA copy-number alterations analysis"], ["UALCAN", "Evaluate gene 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Factors (TFs) of Hub Genes", "row_count": 37, "column_count": 2}, "table": {"label": "Table 2", "caption": "Sequences of Primers Used for Amplification of Target Genes", "rows": [["Gene", "Primer Nucleotide Sequence"], ["CDH1", "Forward: 5ʹ-GAACGCATTGCCACATACAC-3’"], ["", "Reverse: 5ʹ-TGGTGTAAGCGATGGCGGCA-3"], ["EPCAM", "Forward: 5′-AATCGTCAATGCCAGTGTACTT-3′"], ["", "Reverse: 5′-TCTCATCGCAGTCAGGATCATAA-3′"], ["MSX1", "Forward: 5′-CCTCTTTGCTCCCTGAGTTCA-3′"], ["", "Reverse: 5′-GGGACTCTTCCAGCCACTTTTT-3′"], ["KRT19", "Forward: 5ʹ-GCGAGCTAGAGGTGAAGATC-3’"], ["", "Reverse: 5ʹ-CGGAAGTCATCTGCAGCCA-3’"], ["OAS1", "Forward: 5′-CGTGTTTCCGCATGCAAAT-3′"], ["", "Reverse: 5′-ACCTCGGAAGCACCTTTCCT-3′"], ["JAG1", "Forward: 5ʹ-ATCGTGCTGCCTTTCAGTTT-3′"], ["", "Reverse: 5ʹ-GATCATGCCCGAGTGAGAA-3′"], ["TBX1", "Forward: 5ʹ-CTGACCAATAACCTGCTGGATGA-3′"], ["", "Reverse: 5ʹ-GGCTGATATCTGTGCATGGAGTT-3′"], ["DAB2", "Forward: 5ʹ-GTAGAAACAAGTGCAACCAATGG-3’"], ["", "Reverse: 5ʹ-GCCTTTGAACCTTGCTAAGAGA-3’"], ["E-cadherin", "Forward: 5′-CGAGAGCTACACGTTCACGG-3′"], ["", "Reverse: 5′-GGGTGTCGAGGGAAAAATAGG-3′"], ["N-cadherin", "Forward: 5′-TGCGGTACAGTGTAACTGGG-3′"], ["", "Reverse: 5′-GAAACCGGGCTATCTGCTCG-3′"], ["Vimentin", "Forward: 5′-TGCCGTTGAAGCTGCTAACTA-3′"], ["", "Reverse: 5′-CCAGAGGGAGTGAATCCAGATTA-3′"], ["Snail", "Forward: 5′-ACTGCAACAAGGAATACCTCAG-3′"], ["", "Reverse: 5′-GCACTGGTACTTCTTGACATCTG-3′"], ["Twist", "Forward: 5′-ATTCAAAGAAACAGGGCGTGG-3′"], ["", "Reverse: 5′-CCTTTCAGTGGCTGATTGGC-3′"], ["MMP9", "Forward: 5′-TTGACAGCGACAAGAAGTGG-3′"], ["", "Reverse: 5′-GCCATTCACGTCGTCCTTAT-3′"], ["MMP2", "Forward: 5′-TCTCCTGACATTGACCTTGGC-3′"], ["", "Reverse: 5′-CAAGGTGCTGGCTGAGTAGATC-3′"], ["CCND1", "Forward:5ʹ-AAACAGATCATCCGCAAACAC-3’"], ["", "Reverse:5ʹ-GTTGGGGCTCCTCAGGTTC-3’"], ["MYC", "Forward:5ʹ-CCTGGTGCTCCATGAGGAGA-3’"], ["", "Reverse:5ʹ-TCCAGCAGAAGGTGATCCAGAC-3’"], ["GAPDH", "Forward: 5ʹ-ACCCAGAAGACTGTGGATGG-3’"], ["", "Reverse: 5ʹ-TCAGCTCAGGGATGACCTTG-3’"]], "row_count": 37, "column_count": 2, "numeric_cells": 37, "header_rows": 1, "locator": "section[8]/table-wrap[2]#t0002"}}, {"id": "asset:table:pmid:33235459:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:cc731fa430280b12264472ad24804862a765fa6cdac3403605b86ca632ccd764", "bytes": 1559, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[3]#t0003", "version": null, "note": "GO and Pathway Enrichment Analysis of DEGs", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 21, "column_count": 3}, "table": {"label": "Table 3", "caption": "GO and Pathway Enrichment Analysis of DEGs", "rows": [["Category", "Term", "P-value"], ["GOTERM_BP_DIRECT", "GO:0021983~pituitary gland development", "2.52E-04"], ["GOTERM_BP_DIRECT", "GO:0043392~negative regulation of DNA binding", "2.52E-04"], ["GOTERM_BP_DIRECT", "GO:0060337~type I interferon signaling pathway", "7.45E-04"], ["GOTERM_BP_DIRECT", "GO:0010628~positive regulation of gene expression", "7.56E-04"], ["GOTERM_BP_DIRECT", "GO:0001764~neuron migration", "0.001169"], ["GOTERM_CC_DIRECT", "GO:0031225~anchored component of membrane", "0.000235"], ["GOTERM_CC_DIRECT", "GO:0005615~extracellular space", "0.000690"], ["GOTERM_CC_DIRECT", "GO:0005771~multivesicular body", "0.001670"], ["GOTERM_CC_DIRECT", "GO:0005576~extracellular region", "0.002465"], ["GOTERM_CC_DIRECT", "GO:0016324~apical plasma membrane", "0.004640"], ["GOTERM_MF_DIRECT", "GO:0046983~protein dimerization activity", "0.006223"], ["GOTERM_MF_DIRECT", "GO:0008201~heparin binding", "0.008454"], ["GOTERM_MF_DIRECT", "GO:0005112~Notch binding", "0.016286"], ["GOTERM_MF_DIRECT", "GO:0046872~metal ion binding", "0.016772"], ["GOTERM_MF_DIRECT", "GO:0005215~transporter activity", "0.023963"], ["KEGG_PATHWAY", "hsa04514:Cell adhesion molecules", "0.0046"], ["KEGG_PATHWAY", "hsa04612:Antigen processing and presentation", "0.0096"], ["KEGG_PATHWAY", "hsa05168:Herpes simplex infection", "0.0153"], ["KEGG_PATHWAY", "hsa04144:Endocytosis", "0.0166"], ["KEGG_PATHWAY", "hsa04145:Phagosome", "0.0246"]], "row_count": 21, "column_count": 3, "numeric_cells": 40, "header_rows": 1, "locator": "section[8]/table-wrap[3]#t0003"}}, {"id": "asset:table:pmid:33235459:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:8b554a0c889521dd78b920760a502f1dc1d687c053c2dfd8ea3a8f981e2b2e2a", "bytes": 929, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[4]#t0004", "version": null, "note": "Upregulated Gene Sets in the IshikawaPR Cell Line", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 11, "column_count": 6}, "table": {"label": "Table 4", "caption": "Upregulated Gene Sets in the IshikawaPR Cell Line", "rows": [["Gene Sets", "Size", "ES", "NES", "NOM P-value", "FDR q-value"], ["Interferon gamma response", "196", "0.55", "2.07", "0.00", "0.00"], ["TNF-a signaling via NF-KB", "196", "0.46", "1.72", "0.00", "0.01"], ["Epithelial mesenchymal transition", "195", "0.43", "1.62", "0.00", "0.01"], ["Hypoxia", "191", "0.39", "1.47", "0.00", "0.04"], ["Complement", "193", "0.44", "1.67", "0.00", "0.01"], ["Negative regulation of regulated secretory pathway", "23", "0.68", "1.73", "0.00", "0.27"], ["Chronic inflammatory response", "18", "0.69", "1.72", "0.01", "0.27"], ["Interleukin1 production", "90", "0.49", "1.69", "0.00", "0.30"], ["Interferon gamma mediated signaling pathway", "87", "0.51", "1.74", "0.00", "0.30"], ["Negative regulation of response to drug", "25", "0.63", "1.68", "0.00", "0.30"]], "row_count": 11, "column_count": 6, "numeric_cells": 50, "header_rows": 1, "locator": "section[8]/table-wrap[4]#t0004"}}, {"id": "asset:table:pmid:33235459:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:e6de91159a00ff31b71840ebbc9e7e002b1a1fb61c55d46108ac89f287420a48", "bytes": 1080, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[5]#t0005", "version": null, "note": "Upregulated Gene Sets in the Ishikawa Cell Line", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 11, "column_count": 6}, "table": {"label": "Table 5", "caption": "Upregulated Gene Sets in the Ishikawa Cell Line", "rows": [["Gene Sets", "Size", "ES", "NES", "NOM P-value", "FDR q-value"], ["ATP dependent microtubule motor activity plus end directed", "26", "−0.65", "−1.76", "0.00", 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"uri": null, "sha256": "sha256:e00f6221a0e75f3940eec01983cb76285f25eb99ea752038ea619feb2b0cae3e", "bytes": 1291, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[6]#t0006", "version": null, "note": "Identification of Hub Genes by cytoHubba", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 11, "column_count": 13}, "table": {"label": "Table 6", "caption": "Identification of Hub Genes by cytoHubba", "rows": [["Name", "Betweenness", "BottleNeck", "Closeness", "ClusteringCoefficient", "Degree", "DMNC", "EcCentricity", "EPC", "MCC", "MNC", "Radiality", "Stress"], ["CDH1", "7,440.58", "76", "66.299", "0.085", "27", "0.227", "0.100", "43.793", "96", "17", "11.806", "17,516"], ["JAG1", "1,707.27", "14", "52.316", "0.321", "8", "0.428", "0.100", "39.736", "26", "6", "11.457", "3,744"], ["PTGES", "510.00", "1", "38.399", "1.000", "2", "0.308", "0.082", "21.129", "2", "2", "10.558", "500"], ["EPCAM", "423.05", "6", "52.267", "0.378", "10", "0.339", "0.090", "41.186", "58", "10", "11.312", "1,750"], ["CNTNAP2", "2,582.66", "10", "38.916", "0.000", "5", "0.000", "0.100", "15.668", "5", "1", "10.609", "4,672"], ["TBX1", "1,156.20", "12", "52.016", "0.333", "7", "0.454", "0.100", "39.344", "20", "5", "11.438", "3,108"], ["MSX1", "944.50", "4", "43.892", "0.167", "4", "0.308", "0.100", "25.883", "4", "2", "11.039", "1,976"], ["KRT19", "405.98", "5", "49.634", "0.389", "9", "0.334", "0.090", "39.797", "46", "9", "11.198", "1,452"], ["OAS1", "81.05", "1", "39.275", "0.500", "8", "0.408", "0.100", "29.613", "58", "8", "10.419", "450"], ["DAB2", "751.752", "2", "45.945", "0.267", "6", "0.379", "0.112", "32.237", "10", "4", "11.191", "1,378"]], "row_count": 11, "column_count": 13, "numeric_cells": 121, "header_rows": 1, "locator": "section[8]/table-wrap[6]#t0006"}}, {"id": "asset:table:pmid:33235459:7", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:ec1f964c3b4f2c87ffc197f8cbb85c23dbd2db8d5c219b3e7b09e10c7b78a6ac", "bytes": 758, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[7]#t0007", "version": null, "note": "The Information of Ten Hub Genes", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs and Transcriptional Factors (TFs) of Hub Genes", "row_count": 11, "column_count": 3}, "table": {"label": "Table 7", "caption": "The Information of Ten Hub Genes", "rows": [["Gene Name", "logFC", "P-value"], ["CDH1(cadherin 1)", "−5.41", "2.16E-10"], ["JAG1(jagged 1)", "−5.44", "2.35E-10"], ["PTGES(prostaglandin E synthase)", "7.77", "2.42E-11"], ["EPCAM(epithelial cell adhesion molecule)", "−5.39", "2.66E-10"], ["CNTNAP2(contactin associated protein-like 2)", "−7.10", "1.76E-11"], ["TBX1(T-box 1)", "7.61", "2.71E-10"], ["MSX1(msh homeobox 1)", "−5.45", "5.79E-10"], ["KRT19(keratin 19)", "−6.60", "4.00E-10"], ["OAS1(2ʹ-5ʹ-oligoadenylate synthetase 1)", "5.83", "1.24E-10"], ["DAB2(disabled homolog 2, mitogen-responsive phosphoprotein)", "9.00", "3.02E-10"]], "row_count": 11, "column_count": 3, "numeric_cells": 28, "header_rows": 1, "locator": "section[8]/table-wrap[7]#t0007"}}, {"id": "asset:table:pmid:33235459:8", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:a214f59d710118823c4782a5897b52a745e70f3673189087700c1212dc93ee30", "bytes": 494, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[8]#t0008", "version": null, "note": "The Main Related MicroRNAs of Hub Genes", "structure": {"pmcid": "PMC7679365", "section_index": 8, "section_title": "Prediction of Relevant MicroRNAs 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