Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33732011", "kind": "science-record", "revision": 8, "content_hash": "sha256:be9b8cee49653372607e891967e3ed9e5f26f2ef75516ecc584d11653f4c50bc", "created_at": "2026-11-01T15:41:29Z", "updated_at": "2026-11-01T22:46:19Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Using Integrated Bioinformatics Analysis to Identify Abnormally Methylated Differentially Expressed Genes in Hepatocellular Carcinoma.", "doi": "10.2147/IJGM.S294505", "pmid": "33732011", "authors": ["Qing-Lian Chen", "Qian Yan", "Kun-Liang Feng", "Chun-Feng Xie", "Chong-Kai Fang", "Ji-Nan Wang", "Li-Hua Liu", "Ya Li", "Chong Zhong"], "journal": "International journal of general medicine", "year": 2021, "abstract": "OBJECTIVE: For the identification of abnormally methylated differentially expressed genes (MDEGs) in hepatocellular carcinoma (HCC), this study integrated four microarray datasets to investigate the fundamental mechanisms of tumorigenesis.\nMETHODS: We obtained the expression (GSE76427, GSE57957) and methylation (GSE89852, GSE54503) profiles from Gene Expression Omnibus (GEO). The abnormally MDEGs were identified by using R software. We used the clusterProfiler package for the functional and pathway enrichment analysis. The String database was used to build the protein-protein interaction (PPI) network and visualize it in Cytoscape. MCODE was employed in the module analysis. Additionally, Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) were employed to validate results. Lastly, we used cBioPortal software to examine the hub genetic alterations.\nRESULTS: We identified 162 hypermethylated, down-regulated genes and 190 hypomethylated, up-regulated genes. Up-regulated genes with low methylation were enriched in biological processes, such as keratinocyte proliferation, and calcium homeostasis. Pathway analysis was enriched in the AMPK and PI3K-Akt signaling pathways. The PPI network identified PTK2, VWF, and ITGA2 as hypomethylated, high-expressing hub genes. Down-regulated genes with high methylation were related to responses to peptide hormones and estradiol, multi-multicellular organism process. Pathway analysis indicated enrichment in camp, oxytocin signaling pathways. The PPI network identified CFTR, ESR1, and CXCL12 as hypermethylated, low-expressing hub genes. Upon verification in TCGA databases, we found that the expression and methylation statuses of the hub genes changed significantly, and it was consistent with our results.\nCONCLUSION: The novel abnormally MDEGs and pathways in HCC were identified. These results helped us further understand the molecular mechanisms underlying HCC invasion, metastasis, and development. Hub genes can serve as biomarkers for an accurate diagnosis and treatment of HCC, and PTK2, VWF, ITGA2, CFTR, ESR1, and CXCL12 are included.", "claims": [{"id": "claim-method", "statement": "The methylation and expression profiling microarray datasets were analyzed to identify differential expression in the microarray data by using the limma package (v3.12) in R software (v3.6.1) (https://www.r-project.org/).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33732011", "locator": "sections[4] \"Data Acquisition and Processing\" paragraph 2", "quote": "The methylation and expression profiling microarray datasets were analyzed to identify differential expression in the microarray data by using the limma package (v3.12) in R software (v3.6.1) (https://www.r-project.org/)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33732011", "locator": "sections[20] \"Data Sharing Statement\" paragraph 2", "quote": "The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request."}], "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:33732011"], "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:GSE54503"], "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:GSE54503"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33732011", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.2147/IJGM.S294505", "sha256": 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"reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[1]#t0001", "version": null, "note": "Gene Ontology Analysis of Aberrantly Methylated Differentially Expressed Genes in Hepatocellular Carcinoma", "structure": {"pmcid": "PMC7956867", "section_index": 11, "section_title": "Analysis of GO Functional and KEGG Pathway Enrichment", "row_count": 27, "column_count": 6}, "table": {"label": "Table 1", "caption": "Gene Ontology Analysis of Aberrantly Methylated Differentially Expressed Genes in Hepatocellular Carcinoma", "rows": [["Category", "ID", "Description", "Overlap Genes", "Count", "P value"], ["Hypomethylation and high expression"], ["Biological Process", "GO:0038065", "Collagen-activated signaling pathway", "COL4A1/COL4A2/ITGA2", "3", "9.44E-05"], ["Biological Process", "GO:0010839", "Negative regulation of keratinocyte proliferation", "EFNB2/SFN/CD109", "3", "0.000204"], ["Biological Process", "GO:0055074", "Calcium ion homeostasis", "HEXB/GPR4/TRIM24/GJA1/STC2/BCAP31/STC1/SCGN/PDPK1/KL/ATP2B4/JPH1", "12", "0.000319"], ["Biological Process", "GO:0043616", "Keratinocyte proliferation", "CDH13/EFNB2/SFN/CD109", "4", "0.000397"], ["Cellular Component", "GO:0030055", "Cell-substrate junction", "CDH13/RPL30/NOX4/PTK2/EFNB2/GJA1/ITGA2/PABPC1/ITGB4/ITGA4/PDPK1/FLNC", "12", "0.000179"], ["Cellular Component", "GO:0031225", "Anchored component of membrane", "CDH13/GPC3/RAB3B/PRND/GPIHBP1/CD109/RAB5A", "7", "0.000443"], ["Cellular Component", "GO:0005925", "Focal adhesion", "CDH13/RPL30/NOX4/PTK2/EFNB2/GJA1/ITGA2/PABPC1/ITGA4/PDPK1/FLNC", "11", "0.000583"], ["Cellular Component", "GO:0005924", "Cell-substrate adherens junction", "CDH13/RPL30/NOX4/PTK2/EFNB2/GJA1/ITGA2/PABPC1/ITGA4/PDPK1/FLNC", "11", "0.000621"], ["Molecular Function", "GO:0019838", "Growth factor binding", "COL4A1/ESM1/ITGB4/CRIM1/KL/CD109", "6", "0.001063"], ["Molecular Function", "GO:0035174", "Histone serine kinase activity", "MELK/VRK1", "2", "0.001521"], ["Molecular Function", "GO:0005520", "Insulin-like growth factor binding", "ESM1/ITGB4/CRIM1", "3", "0.001974"], ["Molecular Function", "GO:0030165", "PDZ domain binding", "GJA1/PDZK1/CRIM1/ATP2B4", "4", "0.006906"], ["Hypermethylation and low expression"], ["Biological Process", "GO:0032355", "Response to estradiol", "CRHBP/ESR1/OXT/SOCS2/PTGS2/LEP/GSTP1/GJB2", "8", "5.88E-06"], ["Biological Process", "GO:0044706", "Multi-multicellular organism process", "CRHBP/ESR1/OXT/PTGS2/ADRA2B/LEP/FOSL1/NODAL/GJB2/NRK", "10", "7.86E-06"], ["Biological Process", "GO:0007565", "Female pregnancy", "CRHBP/ESR1/OXT/PTGS2/ADRA2B/LEP/FOSL1/NODAL/GJB2", "9", "1.55E-05"], ["Biological Process", "GO:0043434", "Response to peptide hormone", "CRHBP/SRD5A2/OXT/SOCS2/CXCL12/PTGS2/NGFR/EGR2/LEP/GSTP1/GJB2/PRKCZ/INS-IGF2", "13", "2.86E-05"], ["Cellular Component", "GO:0005771", "Multivesicular body", "CRHBP/LRAT/SLC17A8/NAPSA", "4", "0.000293"], ["Cellular Component", "GO:0031941", "Filamentous actin", "SHROOM4/PRKCZ/ESPN", "3", "0.002814"], ["Cellular Component", "GO:0097449", "Astrocyte projection", "SLC17A8/GJB2", "2", "0.003053"], ["Cellular Component", "GO:0016323", "Basolateral plasma membrane", "PTH1R/TACSTD2/SHROOM4/CD81/SLC26A5/SLCO4C1", "6", "0.005589"], ["Molecular Function", "GO:0008514", "Organic anion transmembrane transporter activity", "SLC13A5/SLC17A8/SLC26A5/CFTR/SLCO4C1/SLC16A5/SLC25A42/SLC6A20", "8", "0.000398"], ["Molecular Function", "GO:0000978", "RNA polymerase II proximal promoter sequence-specific DNA binding", "ESR1/LHX2/PER1/EGR2/LRRFIP1/TBX15/FOSL1/JDP2/CUX2/SIX2/NFIC", "11", "0.000556"], ["Molecular Function", "GO:0016019", "Peptidoglycan receptor activity", "PGLYRP2/PGLYRP1", "2", "0.000579"], ["Molecular Function", "GO:0000987", "Proximal promoter sequence-specific DNA binding", "ESR1/LHX2/PER1/EGR2/LRRFIP1/TBX15/FOSL1/JDP2/CUX2/SIX2/NFIC", "11", "0.000734"]], "row_count": 27, "column_count": 6, "numeric_cells": 87, "header_rows": 1, "locator": "section[11]/table-wrap[1]#t0001"}}, {"id": "asset:table:pmid:33732011:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:66ae095b4887363c49cd8cf674ce7dcececab13e741b64bf51ba15c8643aa6e6", "bytes": 1035, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#t0002", "version": null, "note": "KEGG Pathway Analysis of Aberrantly Methylated Differentially Expressed Genes in Hepatocellular Carcinoma", "structure": {"pmcid": "PMC7956867", "section_index": 12, "section_title": "Analysis of KEGG Pathway", "row_count": 9, "column_count": 5}, "table": {"label": "Table 2", "caption": "KEGG Pathway Analysis of Aberrantly Methylated Differentially Expressed Genes in Hepatocellular Carcinoma", "rows": [["Pathway ID", "Term", "Count", "P value", "Gene"], ["Hypomethylation and high expression"], ["hsa04512", "ECM-receptor interaction", "7", "1.82E-05", "COL4A1, COL4A2, VWF, THBS4, ITGA2, ITGB4, ITGA4"], ["hsa04510", "Focal adhesion", "10", "3.12E-05", "COL4A1, COL4A2, PTK2, VWF, THBS4, ITGA2, ITGB4, ITGA4, PDPK1, FLNC"], ["hsa04151", "PI3K-Akt signaling pathway", "10", "0.00305631", "COL4A1, COL4A2, PTK2, VWF, THBS4, ITGA2, ITGB4, ITGA4, PDPK1, PPP2R2C"], ["Hypermethylation and low expression"], ["sa04080", "Neuroactive ligand-receptor interaction", "8", "0.004872722", "PTH1R, OXT, ADRA1B, ADRA2B, LEP, CHRNA4, GABBR1, NPY1R"], ["hsa04360", "Axon guidance", "5", "0.0139185759", "CAMK2B, CXCL12, FES, PRKCZ, EPHA6"], ["hsa04310", "Wnt signaling pathway", "4", "0.035983231", "CAMK2B, PRICKLE1, FOSL1, FZD8"]], "row_count": 9, "column_count": 5, "numeric_cells": 19, "header_rows": 1, "locator": "section[12]/table-wrap[1]#t0002"}}, {"id": "asset:table:pmid:33732011:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:de323f824a5f2072f13e705bebc86f5dfeabe964882312f734cd97ef8019c55f", "bytes": 1227, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[13]/table-wrap[1]#t0003", "version": null, "note": "Hub Genes Among the Aberrantly Methylated Differentially Expressed Genes Ranked in cytoHubba", "structure": {"pmcid": "PMC7956867", "section_index": 13, "section_title": "Construction of PPI Network and cytoHubba Analysis", "row_count": 11, "column_count": 3}, "table": {"label": "Table 3", "caption": "Hub Genes Among the Aberrantly Methylated Differentially Expressed Genes Ranked in cytoHubba", "rows": [["Category", "Rank Methods in cytoHubba", "Top10 Genes"], ["Hypomethylation and high expression", "Betweenness", "VWF, ITGA2, PSMA3, SSB, LRR1, GJA1, PTK2, EFNB2, SNRPA, MELK"], ["Closeness", "ITGA2, VWF, PTK2, ITGB4, ITGA4, LRR1, SSB, COL4A1, PSMA3, COL4A2"], ["Degree", "PTK2, ITGA2, ITGB4, VWF, COL4A1, ITGA4, COL4A2, PSMA3, PABPC1, RAB5A"], ["EcCentricity", "VWF, PLVAP, GJA1, PSMA3, ITGA4, PTK2, PABPC1, ITGA2, ITGB4, SFN"], ["", "Edge percolated component", "ITGA2, ITGA4, PTK2, ITGB4, VWF, COL4A2, COL4A1, FLNC, THBS4, GJA1"], ["Hypermethylation and low expression", "Betweenness", "CFTR, ESR1, SLC26A5, CXCL12, GJB2, COL11A2, LEP, ADAMTS2, PROM1, CYP26A1"], ["Bottleneck", "CXCL12, CFTR, ESR1, SLC26A5, EOMES, NODAL, GJB2, PTGS2, SULT1A1, CYP26A1"], ["Closeness", "ESR1, CXCL12, LEP, PTGS2, OXT, PROM1, GABBR1, CFTR, NPY1R, ADRA2B"], ["Radiality", "CXCL12, ESR1, CFTR, LEP, PTGS2, PROM1, OXT, GABBR1, NPY1R, PRKAG2"], ["Stress", "CXCL12, CFTR, ESR1, SLC26A5, GJB2, LEP, COL11A2, OXT, ADAMTS2, PTGS2"]], "row_count": 11, "column_count": 3, "numeric_cells": 6, "header_rows": 1, "locator": "section[13]/table-wrap[1]#t0003"}}, {"id": "asset:table:pmid:33732011:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:cac62580c8dc153e985ea3132ed89919f7d21ccaa96261bb56c5513a05b71fad", "bytes": 1130, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[14]/table-wrap[1]#t0004", "version": null, "note": "Module Analysis of the Protein–Protein Interaction Network", "structure": {"pmcid": "PMC7956867", "section_index": 14, "section_title": "Module Analysis", "row_count": 12, "column_count": 6}, "table": {"label": "Table 4", "caption": "Module Analysis of the Protein–Protein Interaction Network", "rows": [["Category", "Module", "Score", "Nodes", "Enrichment and Pathway Description", "Genes"], ["Hypomethylation and high expression", "1", "6.75", "9", "GO:0030198—extracellular matrix organization", "THBS4, VWF, COL4A2, PTK2"], ["GO:0007229—integrin-mediated signaling pathway", "ITGB4, ITGA2, COL4A1"], ["hsa04510—Focal adhesion", "ITGA2, PTK2, VWF"], ["hsa04512—ECM-receptor interaction", "ITGA2, VWF"], ["", "", "", "hsa04151—PI3K-Akt signaling pathway", "ITGA2, PTK2, VWF"], ["2", "4", "4", "GO:0044265—cellular macromolecule catabolic process", "UBD, PSMA3, PSMD2, RPL30"], ["", "", "", "", "hsa03050—Proteasome", "PSMA3, PSMD2"], ["Hypermethylation and low expression", "1", "4.4", "6", "GO:0007186—G protein-coupled receptor signaling pathway", "GABBR1, LEP, ESR1, OXT"], ["GO:0007610—behavior", "CXCL12, NPY1R"], ["hsa04915—Estrogen signaling pathway", "ESR1, GABBR1"], ["hsa04060—Cytokine-cytokine receptor interaction", "CXCL12, LEP"]], "row_count": 12, "column_count": 6, "numeric_cells": 23, "header_rows": 1, "locator": "section[14]/table-wrap[1]#t0004"}}, {"id": "asset:table:pmid:33732011:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:aed4995549ad85e8ee8fd1b554b4367ea0470bf2a4ae83e874ba51e3eaf846f8", "bytes": 745, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#t0005", "version": null, "note": "Validation of the Hub Genes in TCGA", "structure": {"pmcid": "PMC7956867", "section_index": 15, "section_title": "Identification and Validation of Six Selected Genes", "row_count": 7, "column_count": 6}, "table": {"label": "Table 5", "caption": "Validation of the Hub Genes in TCGA", "rows": [["Category", "Hub Gene", "Expression Status", "P value", "Methylation Status", "P value"], ["Hypomethylation and high expression", "VWF", "Upregulated", "3.488E-13", "Hypomethylated", "1.77E-70"], ["ITGA2", "Upregulated", "4.262E-15", "Hypomethylated", "5.929E-38"], ["", "PTK2", "Upregulated", "9.802E-34", "Hypomethylated", "1.012E-40"], ["Hypermethylation and low expression", "CFTR", "Downregulated", "2.588E-54", "Hypermethylated", "2.911E-66"], ["ESR1", "Downregulated", "1.398E-69", "Hypermethylated", "2.826E-08"], ["CXCL12", "Downregulated", "4.464E-102", "Hypermethylated", "2.643E-34"]], "row_count": 7, "column_count": 6, 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