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pmid:33632198
Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.
Li Liang · Mengling Liu · Xun Sun · Yitao Yuan · Ke Peng · Khalid Rashid · Yiyi Yu · Yuehong Cui · Yanjie Chen · Tianshu Liu
Cancer cell international · 2021 doi:10.1186/s12935-021-01829-8
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Complete file
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We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.\nMETHODS: A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.\nRESULTS: We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.\nCONCLUSIONS: SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.", "claims": [{"id": "claim-method", "statement": "Kaplan - Meier survival curve and Log - rank test analysis was applied to investigated the predictive valued of identified DEGs for patients with CRC and receiving cetuximab contained therapy.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33632198", "locator": "sections[13] \"Statistical analysis\" paragraph 2", "quote": "Kaplan - Meier survival curve and Log - rank test analysis was applied to investigated the predictive valued of identified DEGs for patients with CRC and receiving cetuximab contained therapy."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Public datasets of colon adenocarcinoma and rectum adenocarcinoma analyzed during the current study can be retrieved from The Cancer Genome Atlas (TCGA) at https://portal.gdc.cancer.gov/. GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. Other data that support the findings of this study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33632198", "locator": "sections[29] \"Availability of data and materials\" paragraph 2", "quote": "Public datasets of colon adenocarcinoma and rectum adenocarcinoma analyzed during the current study can be retrieved from The Cancer Genome Atlas (TCGA) at https://portal.gdc.cancer.gov/. GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. Other data that support the findings of this 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:33632198"], "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:GSE56386"], "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:GSE56386"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33632198", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12935-021-01829-8", "sha256": "sha256:678d56d7692e9406b1527d7d0fddbe67c69b980b717828fbdb5d37c512bd88fa", "bytes": 50326, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12935-021-01829-8", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7905896", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE56386", "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=GSE56386", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE56386", "version": null, "note": "Public datasets of colon adenocarcinoma and rectum adenocarcinoma analyzed during the current study can be retrieved from The Cancer Genome Atlas (TCGA) at https://portal.gdc.cancer.gov/. GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. Other data that support the findings of this study are available from the corresponding author on reasonable request.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Public datasets of colon adenocarcinoma and rectum adenocarcinoma analyzed during the current study can be retrieved from The Cancer Genome Atlas (TCGA) at https://portal.gdc.cancer.gov/. GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. 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GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. Other data that support the findings of this study are available from the corresponding author on reasonable request.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Public datasets of colon adenocarcinoma and rectum adenocarcinoma analyzed during the current study can be retrieved from The Cancer Genome Atlas (TCGA) at https://portal.gdc.cancer.gov/. GSE5851, GSE56368, and GSE59857 datasets can be retrieved from the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/. 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"open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#Tab1", "version": null, "note": "The expression of the top 20 upregulated and downregulated genes in the cetuximab resistant CACO2", "structure": {"pmcid": "PMC7905896", "section_index": 15, "section_title": "Model establishment and screening of DEGs", "row_count": 45, "column_count": 10}, "table": {"label": "Table 1", "caption": "The expression of the top 20 upregulated and downregulated genes in the cetuximab resistant CACO2", "rows": [["Gene symbol", "Normalized Signal Value", "Log [fold change]", "P value", "Adjustive p value"], ["Sensitive", "Resistant"], ["Sam.1", "Sam.2", "Sam.3", "Sam.1", "Sam.2", "Sam.3"], ["Top 20 of up-regulated genes"], ["DRD2", "1.253", "1.265", "1.252", "7.414", "7.471", "7.331", "6.149", "2.76E–09", "5.19E–05"], ["SLC2A5", "8.931", "9.006", "9.037", "13.002", "12.996", "12.980", "4.001", "2.62E–08", "9.87E–05"], ["CADM1", "4.659", "4.421", "4.556", "9.133", "9.344", "9.152", "4.664", "4.91E–08", "1.11E–04"], ["RTP3", "1.232", "1.300", "1.161", "4.731", "4.881", "4.823", "3.581", "8.34E–08", "1.14E–04"], ["NPR2", "6.365", "6.349", "6.191", "10.112", "10.297", "10.310", "3.938", "9.25E–08", "1.16E–04"], ["SERPINF1", "10.281", "10.168", "10.135", "13.543", "13.716", "13.685", "3.453", "1.29E–07", "1.26E–04"], ["BASP1", "6.890", "6.446", "6.407", "11.922", "12.156", "12.069", "5.468", "1.33E–07", "1.26E–04"], ["LAMA1", "6.237", "6.392", "6.334", "9.733", "9.873", "9.949", "3.531", "1.42E–07", "1.26E–04"], ["THPO", "1.271", "1.275", "1.418", "4.485", "4.429", "4.562", "3.171", "1.75E–07", "1.26E–04"], ["ACTA1", "4.330", "3.837", "4.273", "9.829", "9.596", "9.503", "5.496", "1.80E–07", "1.26E–04"], ["SERPINF2", "11.096", "11.257", "10.992", "14.287", "14.346", "14.294", "3.194", "2.59E–07", "1.35E–04"], ["ANXA8", "9.699", "9.805", "9.662", "12.950", "13.168", "12.871", "3.274", "3.77E–07", "1.73E–04"], ["DPYSL3", "7.688", "7.165", "7.810", "12.588", "12.744", "12.676", "5.115", "4.15E–07", "1.82E–04"], ["PDGFRA", "1.312", "1.304", "1.231", "5.091", "5.216", "4.782", "3.748", "4.25E–07", "1.82E–04"], ["SDC2", "4.645", "4.510", "4.744", "7.533", "7.547", "7.725", "2.968", "5.37E–07", "2.10E–04"], ["ORM1", "12.007", "12.089", "11.909", "14.634", "14.613", "14.758", "2.667", "5.43E–07", "2.10E–04"], ["ORM2", "12.062", "12.209", "12.006", "14.728", "14.646", "14.739", "2.612", "5.85E–07", "2.10E–04"], ["ADM", "10.696", "10.620", "10.518", "13.201", "13.321", "13.175", "2.621", "5.92E–07", "2.10E–04"], ["ADAM19", "9.666", "9.526", "9.323", "12.874", "12.710", "12.676", "3.248", "6.38E–07", "2.22E–04"], ["CCDC3", "9.139", "9.112", "8.781", "12.448", "12.206", "12.351", "3.324", "9.05E–07", "2.59E–04"], ["Top 20 of down-regulated genes"], ["GC", "6.719", "6.693", "6.902", "1.271", "1.278", "1.263", "–5.500", "8.90E–09", "6.23E–05"], ["SCIN", "6.839", "6.926", "7.093", "1.350", "1.309", "1.335", "–5.621", "9.94E–09", "6.23E–05"], ["ST6GALNAC1", "7.759", "7.546", "7.389", "1.269", "1.309", "1.356", "–6.253", "1.39E–08", "6.51E–05"], ["PADI2", "8.533", "8.655", "8.104", "1.339", "1.256", "1.373", "–7.108", "3.18E–08", "9.95E–05"], ["MUC13", "14.179", "13.905", "14.478", "7.486", "7.521", "7.534", "–6.674", "4.05E–08", "1.09E–04"], ["SULF2", "9.285", "8.985", "9.273", "3.737", "3.522", "3.850", "–5.478", "5.92E–08", "1.11E–04"], ["COL17A1", "8.492", "8.749", "8.525", "2.545", "2.030", "2.235", "–6.319", "6.07E–08", "1.11E–04"], ["FAM83E", "10.754", "10.695", "10.635", "6.944", "7.056", "6.897", "–3.729", "6.48E–08", "1.11E–04"], ["HLA-DMB", "5.666", "5.548", "5.337", "1.177", "1.237", "1.244", "–4.298", "8.23E–08", "1.14E–04"], ["NPAS2", "5.506", "5.310", "5.640", "1.250", "1.186", "1.173", "–4.282", "8.47E–08", "1.14E–04"], ["PNLIPRP2", "9.009", "8.923", "8.898", "4.505", "4.836", "4.560", "–4.310", "1.04E–07", "1.22E–04"], ["LCN2", "11.287", "11.659", "11.027", "4.564", "4.442", "4.834", "–6.711", "1.24E–07", "1.26E–04"], ["SRPX", "9.803", "9.612", "9.507", "5.937", "5.942", "5.842", "–3.734", "1.53E–07", "1.26E–04"], ["HOXB9", "10.762", "10.582", "10.682", "7.503", "7.485", "7.573", "–3.155", "1.66E–07", "1.26E–04"], ["BTNL3", "5.120", "5.170", "5.485", "1.188", "1.231", "1.215", "–4.047", "1.77E–07", "1.26E–04"], ["TMC5", "7.201", "6.746", "7.401", "1.274", "1.203", "1.339", "–5.844", "1.77E–07", "1.26E–04"], ["APOBEC1", "6.060", "5.632", "6.092", "1.210", "1.170", "1.156", "–4.749", "1.78E–07", "1.26E–04"], ["S100A9", "10.469", "10.404", "9.896", "3.540", "3.948", "3.972", "–6.436", "2.00E–07", "1.31E–04"], ["DDIT4L", "6.599", "6.789", "7.249", "1.229", "1.281", "1.306", "–5.607", "2.07E–07", "1.31E–04"], ["PI3", "13.824", "13.941", "13.611", "9.571", "9.226", "9.378", "–4.400", "2.12E–07", "1.31E–04"]], "row_count": 45, "column_count": 10, "numeric_cells": 373, "header_rows": 3, "locator": "section[15]/table-wrap[1]#Tab1"}}, {"id": "asset:table:pmid:33632198:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:d78d18b8e9b362d25640960ca3b9ac3c37dbe3ef300da5cee98bcd9e987473e7", "bytes": 6363, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[2]#Tab2", "version": null, "note": "GO term and KEGG pathway enrichment analyses of differentially expressed genes", "structure": {"pmcid": "PMC7905896", "section_index": 15, "section_title": "Model establishment and screening of DEGs", "row_count": 85, "column_count": 6}, "table": {"label": "Table 2", "caption": "GO term and KEGG pathway enrichment analyses of differentially expressed genes", "rows": [["Term", "Description", "Count", "%", "Log10 [p value]", "Log10 [q value]"], ["GO Biological process"], ["GO:0006935", "Chemotaxis", "117", "5.89", "−15.44", "−11.44"], ["GO:0010817", "Regulation of hormone levels", "102", "5.13", "−15.05", "−11.33"], ["GO:1,901,615", "Organic hydroxy compound metabolic process", "100", "5.03", "−13.61", "−10.01"], ["GO:0043062", "Extracellular structure organization", "82", "4.13", "−12.37", "−8.87"], ["GO:0015711", "Organic anion transport", "85", "4.28", "−10.60", "−7.25"], ["GO:0072006", "Nephron development", "37", "1.86", "−9.56", "−6.40"], ["GO:0048514", "Blood vessel morphogenesis", "105", "5.28", "−9.29", "−6.20"], ["GO:0009611", "Response to wounding", "105", "5.28", "−9.25", "−6.20"], ["GO:0051047", "Positive regulation of secretion", "75", "3.77", "−9.14", "−6.11"], ["GO:0006869", "Lipid transport", "66", "3.32", "−9.03", "−6.06"], ["GO:0008285", "Negative regulation of cell proliferation", "113", "5.69", "−8.91", "−6.01"], ["GO:0052548", "Regulation of endopeptidase activity", "73", "3.67", "−8.70", "−5.86"], ["GO:0032787", "Monocarboxylic acid metabolic process", "97", "4.88", "−8.15", "−5.36"], ["GO:0008610", "Lipid biosynthetic process", "103", "5.18", "−7.83", "−5.11"], ["GO:0003013", "Circulatory system process", "83", "4.18", "−7.17", "−4.54"], ["GO:0048598", "Embryonic morphogenesis", "87", "4.38", "−6.84", "−4.26"], ["GO:0030155", "Regulation of cell adhesion", "99", "4.98", "−6.68", "−4.14"], ["GO:0046683", "Response to organophosphorus", "31", "1.56", "−6.68", "−4.14"], ["GO:0035272", "Exocrine system development", "17", "0.86", "−6.62", "−4.11"], ["GO:0015718", "Monocarboxylic acid transport", "35", "1.76", "−6.53", "−4.04"], ["GO molecular function"], ["GO:0008289", "Lipid binding", "104", "5.23", "−6.90", "−3.45"], ["GO:0004857", "Enzyme inhibitor activity", "62", "3.12", "−6.81", "−3.45"], ["GO:0005509", "Calcium ion binding", "97", "4.88", "−6.45", "−3.37"], ["GO:0008201", "Heparin binding", "34", "1.71", "−6.05", "−3.17"], ["GO:0008514", "Organic anion transmembrane transporter activity", "39", "1.96", "−5.75", "−3.06"], ["GO:0048018", "Receptor ligand activity", "70", "3.52", "−5.72", "−3.06"], ["GO:0000987", "Proximal promoter sequence-specific DNA binding", "84", "4.23", "−5.16", "−2.65"], ["GO:0016491", "Oxidoreductase activity", "95", "4.78", "−4.82", "−2.41"], ["GO:0005201", "Extracellular matrix structural constituent", "30", "1.51", "−4.52", "−2.18"], ["GO:0016298", "Lipase activity", "25", "1.26", "−4.46", "−2.16"], ["GO:0033293", "Monocarboxylic acid binding", "18", "0.91", "−4.39", "−2.14"], ["GO:0043178", "Alcohol binding", "19", "0.96", "−4.39", "−2.14"], ["GO:0015144", "Carbohydrate transmembrane transporter activity", "12", "0.60", "−4.35", "−2.12"], ["GO:0033764", "Steroid dehydrogenase activity", "10", "0.50", "−4.05", "−1.90"], ["GO:0030515", "snoRNA binding", "10", "0.50", "−4.05", "−1.90"], ["GO:0042803", "Protein homodimerization activity", "81", "4.08", "−4.04", "−1.90"], ["GO:0008233", "Peptidase activity", "78", "3.93", "−3.82", "−1.73"], ["GO:0004745", "Retinol dehydrogenase activity", "8", "0.40", "−3.80", "−1.73"], ["GO:0019955", "Cytokine binding", "24", "1.21", "−3.69", "−1.63"], ["GO:0015250", "Water channel activity", "6", "0.30", "−3.50", "−1.46"], ["GO cellular component"], ["GO:0031012", "Extracellular matrix", "98", "4.93", "−13.46", "−10.17"], ["GO:0016324", "Apical plasma membrane", "68", "3.42", "−11.60", "−8.79"], ["GO:0044420", "Extracellular matrix component", "17", "0.86", "−6.08", "−3.57"], ["GO:0016323", "Basolateral plasma membrane", "41", "2.06", "−5.91", "−3.52"], ["GO:0031253", "Cell projection membrane", "56", "2.82", "−5.90", "−3.52"], ["GO:0005604", "Basement membrane", "23", "1.16", "−5.55", "−3.21"], ["GO:0031526", "Brush border membrane", "16", "0.81", "−5.25", "−2.97"], ["GO:0031091", "Platelet alpha granule", "21", "1.06", "−4.93", "−2.72"], ["GO:0030684", "Pre-ribosome", "19", "0.96", "−4.87", "−2.70"], ["GO:0005667", "Transcription factor complex", "53", "2.67", "−4.60", "−2.46"], ["GO:0070161", "Anchoring junction", "71", "3.57", "−3.64", "−1.68"], ["GO:0044452", "Nucleolar part", "29", "1.46", "−3.61", "−1.67"], ["GO:0005911", "Cell-cell junction", "53", "2.67", "−3.49", "−1.60"], ["GO:0005773", "Vacuole", "93", "4.68", "−3.40", "−1.56"], ["GO:0005777", "Peroxisome", "24", "1.21", "−3.40", "−1.56"], ["GO:0034358", "Plasma lipoprotein particle", "10", "0.50", "−3.32", "−1.52"], ["GO:0000940", "Condensed chromosome outer kinetochore", "6", "0.30", "−3.29", "−1.52"], ["GO:0071438", "Invadopodium membrane", "4", "0.20", "−3.22", "−1.48"], ["GO:0048471", "Perinuclear region of cytoplasm", "85", "4.28", "−3.20", "−1.47"], ["GO:0005593", "FACIT collagen trimer", "4", "0.20", "−2.88", "−1.25"], ["KEGG pathway"], ["hsa04974", "Protein digestion and absorption", "23", "1.16", "−6.16", "−3.46"], ["hsa04060", "Cytokine-cytokine receptor interaction", "45", "2.26", "−5.38", "−2.98"], ["hsa00830", "Retinol metabolism", "17", "0.86", "−4.86", "−2.64"], ["hsa04510", "Focal adhesion", "34", "1.71", "−4.45", "−2.36"], ["hsa04918", "Thyroid hormone synthesis", "17", "0.86", "−4.08", "−2.08"], ["hsa04610", "Complement and coagulation cascades", "17", "0.86", "−3.71", "−1.85"], ["hsa04310", "Wnt signaling pathway", "24", "1.21", "−3.21", "−1.49"], ["hsa03320", "PPAR signaling pathway", "15", "0.75", "−3.18", "−1.49"], ["hsa05323", "Rheumatoid arthritis", "17", "0.86", "−3.02", "−1.36"], ["hsa05146", "Amoebiasis", "17", "0.86", "−2.70", "−1.27"], ["hsa04540", "Gap junction", "16", "0.81", "−2.69", "−1.27"], ["hsa00471", "D-Glutamine and D-glutamate metabolism", "3", "0.15", "−2.68", "−1.27"], ["hsa04978", "Mineral absorption", "11", "0.55", "−2.60", "−1.21"], ["hsa04146", "Peroxisome", "15", "0.75", "−2.53", "−1.16"], ["hsa04621", "NOD-like receptor signaling pathway", "25", "1.26", "−2.49", "−1.14"], ["hsa04390", "Hippo signaling pathway", "23", "1.16", "−2.42", "−1.13"], ["hsa00590", "Arachidonic acid metabolism", "12", "0.60", "−2.38", "−1.13"], ["hsa00564", "Glycerophospholipid metabolism", "16", "0.81", "−2.35", "−1.12"], ["hsa04976", "Bile secretion", "13", "0.65", "−2.32", "−1.10"], ["hsa05412", "Arrhythmogenic right ventricular cardiomyopathy", "13", "0.65", "−2.26", "−1.06"]], "row_count": 85, "column_count": 6, "numeric_cells": 402, "header_rows": 1, "locator": "section[15]/table-wrap[2]#Tab2"}}, {"id": "asset:table:pmid:33632198:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:3297a1ec256c668469513d721300990d955757ed6ad8d4b9015ebca8cb4f0805", "bytes": 2882, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#Tab3", "version": null, "note": "Gene set enrichment analysis of upregulated and downregulated gene sets in the cetuximab resistant group", "structure": {"pmcid": "PMC7905896", "section_index": 16, "section_title": "Gene set enrichment", "row_count": 37, "column_count": 7}, "table": {"label": "Table 3", "caption": "Gene set enrichment analysis of upregulated and downregulated gene sets in the cetuximab resistant group", "rows": [["Name", "Size", "Es", "Nes", "Non p value", "FDR q value", "FWER p value"], ["Up-regulation in Resistant Group", "", "", "", ""], ["HALLMARK_PEROXISOME", "19", "−0.36", "−1.32", "0.00", "0.49", "0.39"], ["HALLMARK_UV_RESPONSE_UP", "24", "−0.17", "−1.00", "0.38", "1.00", "1.00"], ["HALLMARK_MYOGENESIS", "38", "−0.48", "−0.93", "0.79", "1.00", "1.00"], ["HALLMARK_KRAS_SIGNALING_DN", "27", "−0.24", "−0.92", "0.54", "1.00", "1.00"], ["HALLMARK_ADIPOGENESIS", "24", "−0.17", "−0.80", "0.51", "1.00", "1.00"], ["HALLMARK_INTERFERON_GAMMA_RESPONSE", "31", "−0.21", "−0.77", "0.91", "1.00", "1.00"], ["HALLMARK_INTERFERON_ALPHA_RESPONSE", "24", "−0.28", "−0.76", "0.91", "0.98", "1.00"], ["HALLMARK_P53_PATHWAY", "24", "−0.14", "−0.68", "0.91", "0.92", "1.00"], ["Down-regulation in Resistant Group", "", "", "", ""], ["HALLMARK_COMPLEMENT", "30", "0.34", "1.59", "0.00", "0.27", "0.09"], ["HALLMARK_BILE_ACID_METABOLISM", "21", "0.38", "1.57", "0.00", "0.19", 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"section_index": 17, "section_title": "Common DEGs and PPI network construction", "row_count": 21, "column_count": 6}, "table": {"label": "Table 5", "caption": "Cetuximab resistance-related genes from the Genomics of Drug Sensitivity in Cancer database", "rows": [["Cancer feature", "Effect size", "p value", "FDR%", "No. of altered cell lines", "Tissue analysis"], ["SRGAP3_mut", "−1.310", "0.0382", "99.7", "3", "COREAD"], ["PBRM1_mut", "−0.971", "0.0791", "99.7", "4", "COREAD"], ["B2M_mut", "−0.722", "0.0879", "99.7", "7", "COREAD"], ["FBXW7_mut", "−0.575", "0.0998", "99.7", "13", "COREAD"], ["BRAF_mut", "0.580", "0.109", "99.7", "10", "COREAD"], ["cnaCOREAD47", "0.737", "0.111", "99.7", "6", "COREAD"], ["cnaCOREAD18", "0.611", "0.124", "99.7", "8", "COREAD"], ["MGA_mut", "−0.688", "0.132", "99.7", "6", "COREAD"], ["cnaCOREAD14", "0.892", "0.147", "99.7", "3", "COREAD"], ["CTCF_mut", "−0.560", "0.17", "99.7", "7", "COREAD"], ["cnaCOREAD37", "0.634", "0.172", "99.7", "6", "COREAD"], 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Meanwhile, public data from the Gene Expres", "atients with colorectal cancer in the tissue microarray. Additional file 4: Figure S2. SATB-2, ORP-1"], "order_basis": "paper_text_order:530", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["dated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2", "Methods Validation in clinical samples by immunohistochemistry staining Patients with advanced CRC (n = 102", "they were blocked with bovine serum albumin, immunostained with primary antibodies against SATB-2 (2130"], "order_basis": "paper_text_order:2017", "id": "assay:2"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["and incubated with goat anti-rabbit or anti-mouse secondary antibody (1:200) for about 30 min"], "order_basis": "paper_text_order:3874", "id": "assay:3"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["e 1: Table S1. 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