High expression of RRM2 as an independent predictive factor of poor prognosis in patients with lung adenocarcinoma.

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In this study, we evaluated whether RRM2 gene expression is associated with the prognosis of patients with lung adenocarcinoma (LUAD) using publicly available data from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and logistic regression were performed to evaluate the association between RRM2 expression and clinical features in patients with LUAD. Kaplan-Meier and Cox regression methods were used to examine the effect of RRM2 expression level in the overall survival, and a nomogram was performed to illustrate the correlation between the RRM2 gene expression and the risk of LUAD. TCGA data set was used for gene set enrichment analysis (GSEA). We also performed a further experiment in vitro to assess the effect of RRM2 expression on the proliferation and invasive abilities of LUAD cells and its key signaling pathway proteins. Our results revealed that the expression level of RRM2 in patients with LUAD was much higher than that in normal tissues (p = 3.99e-32). High expression of RRM2 was significantly associated with tumor stage (IV vs. I: OR = 3.02, p = 0.012) and TNM classification (T2 vs. T1: OR = 1.88, p = 0.001; N2 vs. N0: OR = 2.69, p < 0.001). Kaplan-Meier survival analysis showed that high expression of RRM2 was associated with a worse prognosis of LUAD compared low expression of RRM2 (p = 7.86e-04). Multivariate analysis showed that high RRM2 expression was an independent factor affecting overall survival (HR = 1.29, p < 0.001). The association between RRM2 gene expression and the risk of LUAD was presented in a nomogram. GSEA revealed that the cell cycle, p53 signaling pathway, DNA replication, small cell lung cancer, apoptosis, and pathways in cancer were differentially enriched in patients with high expression of RRM2. RRM2 over-expression promoted the proliferation and invasive abilities of LUAD cells. RRM2 over-expression increased the activation of Bcl-2 and E-cadherin signaling pathways, and reduced the activation of p53 signaling pathway. In summary, high RRM2 expression is an independent predictive factor of poor prognosis in patients with lung adenocarcinoma.", "claims": [{"id": "claim-method", "statement": "Kaplan-Meier survival analysis showed that high RRM2 expression was associated with poor prognosis (p = 7.86e-04), as shown in Figure 3A.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33411689", "locator": "sections[6] \"High expression of RRM2 is an independent risk factor for overall survival\" paragraph 2", "quote": "Kaplan-Meier survival analysis showed that high RRM2 expression was associated with poor prognosis (p = 7.86e-04), as shown in Figure 3A."}], "state": "complete"}, {"id": "claim-data-access", "statement": "mRNA expression data (535 samples, Workflow Type: HTSeq-FPKM) and clinical information were downloaded from TCGA database (https://cancergenome.nih.gov). 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"section_title": "Correlation between RRM2 expression and clinical features", "row_count": 28, "column_count": 7}, "table": {"label": "Table 2", "caption": "Logistic analysis of the association between RRM2 expression and clinical characteristics.", "rows": [["Clinical characteristics", "Total (N)", "RRM2 expression"], ["", "OR", "95%CI", "", "p-Value"], ["Age (>=65 vs. <65)", "503", "", "0.72", "0.50-1.03", "", "0.071"], ["Gender (Male vs. Female)", "503", "", "1.36", "0.96-1.93", "", "0.085"], ["Race (non-Asian vs. Asian)", "455", "", "0.99", "0.23-4.26", "", "0.995"], ["Stage", "495", "", "", "", "", ""], ["I", "", "", "Reference", "", ""], ["II", "", "", "1.56", "1.01-2.40", "", "0.043"], ["III", "", "", "2.18", "1.33-3.63", "", "0.002"], ["IV", "", "", "3.02", "1.31-7.58", "", "0.012"], ["Smoking status", "489", "", "", "", "", ""], ["Current smoker", "", "", "Reference", "", ""], ["Ever smoker", "", "", "0.40", "0.25-0.62", "", "4.66e-05"], ["Never smoker", "", "", "0.33", "0.18-0.60", "", "<0.001"], ["T (T2 vs. T1)", "436", "", "1.88", "1.28-2.79", "", "0.001"], ["M (M1 vs. M0)", "359", "", "2.25", "0.97-5.65", "", "0.066"], ["N classification", "489", "", "", "", "", ""], ["N0", "", "", "Reference", "", "", ""], ["N1", "", "", "1.78", "1.12-2.83", "", "0.015"], ["N2", "", "", "2.69", "1.59-4.65", "", "<0.001"], ["Location (central vs. peripheral)", "174", "", "1.60", "0.87-2.97", "", "0.135"], ["Radiation therapy (yes vs. no)", "157", "", "2.42", "0.75-9.25", "", "0.158"], ["New tumor event after initial treatment (yes vs. no)", "187", "", "2.28", "1.02-5.37", "", "0.049"], ["EGFR mutation (yes vs. no)", "272", "", "0.76", "0.45-1.28", "", "0.306"], ["KRAS mutation (yes vs. no)", "62", "", "0.50", "0.17-1.40", "", "0.191"], ["EML4-ALK translocation (yes vs. no)", "242", "", "1.16", "0.56-2.41", "", "0.692"], ["Person neoplasm cancer status (with tumor vs tumor free)", "407", "", "1.73", "1.12-2.71", "", "0.014"], ["Primary therapy outcomes (SD+PD vs. CR+PR)", "151", "", "1.44", "0.55-3.94", "", "0.463"]], "row_count": 28, "column_count": 7, "numeric_cells": 78, "header_rows": 0, "locator": "section[5]/table-wrap[1]#t2"}}, {"id": "asset:table:pmid:33411689:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:d394e4f932667dc64ecf5125f74155d54f0cfc17f0e4074dbf284d5c6064269d", "bytes": 1534, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[6]/table-wrap[1]#t3", "version": null, "note": "Univariate and multivariate Cox regression analyses of clinical characteristics associated with overall survival.", "structure": {"pmcid": "PMC7906179", "section_index": 6, "section_title": "High expression of RRM2 is an independent risk factor for overall survival", "row_count": 19, "column_count": 8}, "table": {"label": "Table 3", "caption": "Univariate and multivariate Cox regression analyses of clinical characteristics associated with overall survival.", "rows": [["Clinical characteristics", "Univariate analysis", "", "Multivariate analysis"], ["HR", "95%CI", "p-Value", "", "HR", "95%CI", "p-Value"], ["Age", "1.18", "0.86-1.63", "0.309", "", "1.36", "0.96-1.93", "0.083"], ["Gender", "1.04", "0.76-1.43", "0.789", "", "1.13", "0.80-1.59", "0.487"], ["Race", "2.01", "0.28-14.35", "0.488", "", "", "", ""], ["Stage", "1.67", "1.44-1.93", "1.12e-11", "", "1.28", "1.01-1.64", "0.043"], ["Smoking status", "0.92", "0.72-1.19", "0.540", "", "0.84", "0.65-1.10", "0.207"], ["T", "1.53", "1.25-1.86", "3.12e-05", "", "1.16", "0.90-1.51", "0.245"], ["M", "0.92", "0.77-1.11", "0.386", "", "1.13", "0.91-1.39", "0.259"], ["N", "1.72", "1.44-2.06", "1.82e-09", "", "1.39", "1.05-1.84", "0.022"], ["Location", "0.95", "0.57-1.58", "0.829", "", "", "", ""], ["Radiation therapy", "2.87", "1.32-6.23", "0.007", "", "", "", ""], ["New tumor event after initial treatment", "2.3", "1.31-4.05", "0.003", "", "", "", ""], ["EGFR mutation", "1.33", "0.82-2.15", "0.242", "", "", "", ""], ["KRAS mutation", "2.21", "0.85-5.76", "0.103", "", "", "", ""], ["EML4-ALK translocation", "1.96", "1.06-3.63", "0.031", "", "", "", ""], ["Primary therapy outcomes", "2.44", "0.90-6.59", "0.078", "", "", "", ""], ["Person neoplasm cancer status", "4.74", "3.27-6.87", "2.08e-16", "", "1.69", "1.37-2.08", "7.20e-07"], ["RRM2 expression", "1.34", "1.16-1.54", "4.86e-05", "", "1.29", "1.11-1.50", "<0.001"]], "row_count": 19, "column_count": 8, "numeric_cells": 80, "header_rows": 0, "locator": "section[6]/table-wrap[1]#t3"}}, {"id": "asset:table:pmid:33411689:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:34cfb899324ed01925e00e64c6697aa318ff7780ad9454676ea0af805aea9a6b", "bytes": 650, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[1]#t4", "version": null, "note": "Gene sets enriched in the high RRM2 expression phenotype.", "structure": {"pmcid": "PMC7906179", "section_index": 8, "section_title": "GSEA identifies a RRM2-related signaling pathway", "row_count": 7, "column_count": 6}, "table": {"label": "Table 4", "caption": "Gene sets enriched in the high RRM2 expression phenotype.", "rows": [["Gene set name", "SIZE", "ES", "NES", "NOM p-Val", "FDR q-Val"], ["KEGG_CELL_CYCLE", "124", "0.839", "2.697", "<0.001", "<0.001"], ["KEGG_P53_SIGNALING_PATHWAY", "66", "0.666", "2.49", "<0.001", "<0.001"], ["KEGG_DNA_REPLICATION", "36", "0.942", "2.242", "<0.001", "1.56e-04"], ["KEGG_SMALL_CELL_LUNG_CANCER", "84", "0.553", "2.077", "<0.001", "0.003"], ["KEGG_APOPTOSIS", "86", "0.454", "1.758", "0.013", "0.032"], ["KEGG_PATHWAYS_IN_CANCER", "324", "0.44", "1.863", "0.004", "0.018"]], "row_count": 7, "column_count": 6, "numeric_cells": 31, "header_rows": 0, "locator": "section[8]/table-wrap[1]#t4"}}], "gaps": ["asset:data:geo:GSE30219 not downloaded", 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Transfection was performe", "i-NC), and un-transfected group (O-Control). Transfection was performed as described previously [50]."], "order_basis": "paper_text_order:3793", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["on (ATCC; Manassas, VA, USA). All cells were cultured in Dulbecco's Modified Eagle's medium (DMEM; Gi", ", except SPCA-1, PG49, and HaCaT, which were cultured in Roswell Park Memorial Institute-1640 (RPMI-1", "control), and human lung cancer cell lines (A549, SPCA-1, 95-D, and NCI-H292) were obtained f", "lidated by qRT-PCR. Finally, the transfected A549 lung cancer cells were collected for subsequ"], "order_basis": "paper_text_order:3959", "id": "assay:3"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Kaplan-Meier survival analysis showed that high RRM2 expression was associated with poor prognosis (p = 7.86e-04), as shown in Figure 3A."], "order_basis": "consumes_earlier_output", "id": "assay:4"}]}