Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34539890", "kind": "science-record", "revision": 8, "content_hash": "sha256:61cf639af53761c0e2d47fe7a2f24756aca9ca6b76b48adcccf2805887189364", "created_at": "2026-11-01T15:41:53Z", "updated_at": "2026-11-01T22:47:33Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Overexpression of Nicotinamide N-methyltransferase mainly covers stroma of colorectal cancer and correlates with unfavorable survival by its product 1-MNA.", "doi": "10.7150/jca.56419", "pmid": "34539890", "authors": ["Jun Yang", "Qingchao Tong", "Ying Zhang", "Shijin Yuan", "Yuzhen Gao", "Ke Deng", "Yanzhong Wang", "Jie Lu", "Xinyou Xie", "Zhe Zhang", "Jun Zhang"], "journal": "Journal of Cancer", "year": 2021, "abstract": "Background: Accumulating evidence indicates that Nicotinamide N-methyltransferase (NNMT) is abnormally expressed in tumor tissues of several cancers including colorectal cancer (CRC) and associated with cancer progression. However, the distribution characteristics and the clinical value of each part of NNMT expression in CRC are still not fully understood. The purpose of this study is to determine the distribution of NNMT expression and its association with survival in CRC. Methods: By using the cancer genome atlas (TCGA) and clinical proteomic tumor analysis consortium (CPTAC), we firstly analyzed the difference of gene and protein levels of NNMT between CRC and normal colorectal tissue. Then, NNMT protein expressions were detected in 18 intraepithelial neoplastic samples and 177 CRC tumor samples through immunohistochemistry in our study cohort. Furthermore, the relationship between NNMT expression and clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) of CRC patients were analyzed by Pearson χ2 test and log-rank test, respectively, in public datasets and our study cohort. Lastly, the function of NNMT and its product 1-methyl-nicotinamide (1-MNA) on migration and invasion in colorectal cancer cells was analyzed by wound healing assay and transwell assay. Results: We determined that higher NNMT expression in CRC tissues than normal tissues in both gene and protein level in TCGA and CPTAC datasets (all p < 0.05). In addition, the strong relationships of NNMT expression with stromal cells were found in the TCGA cohort. Fortunately, our cohort could validate that the expression of NNMT in tumor stroma cell was significantly higher than that in tumor cell (p < 0.0001), and both of them were significantly higher than that in adjacent normal tissue (ANT) (p < 0.0001 and p < 0.0001, respectively). Furthermore, the positive NNMT expression in tumor cell and stromal cell were associated with series of unfavorable clinical characteristics, including advanced TNM stage, lymph node metastasis, distant metastasis (all p < 0.05). Also, higher NNMT was associated with unfavorable survival both in our study and public datasets, including TCGA and two Gene Expression Omnibus (GEO) datasets (GSE33113 and GSE17538). Moreover, the functional experiments showed that stromal cells with high NNMT expression can secret 1-MAN to promote migration and invasion of CRC cells in vitro. Conclusions: In CRC, NNMT is overexpressed in tumor cells and stroma cells, and then mainly expressed in tumor stroma cells. Overexpression of NNMT in tumor cell and stroma cell both are associated with metastasis and unfavorable survival. Besides, stromal cells with high NNMT expression secrets 1-MAN to promote migration and invasion of CRC cells. Therefore, NNMT may be a potential prognostic indicator in CRC patients.", "claims": [{"id": "claim-method", "statement": "The relationships between NNMT expression and clinicopathological attributes were analyzed using Pearson's χ2 test. Survival curves were plotted by the Kaplan-Meier method with log-rank test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34539890", "locator": "sections[12] \"Statistical analysis\" paragraph 2", "quote": "The relationships between NNMT expression and clinicopathological attributes were analyzed using Pearson's χ2 test."}, {"asset": "source:pmid:34539890", "locator": "sections[12] \"Statistical analysis\" paragraph 2", "quote": "Survival curves were plotted by the Kaplan-Meier method with log-rank test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "To identify the different expression of NNMT between colorectal cancers and normal tissue, the RNA transcriptome gene expression data of NNMT were extracted from the TCGA (downloaded from the XENA, https://xenabrowser.net/), and the proteomics data of that were downloaded from the project of “CPTAC Colon Cancer Confirmatory Study” (BioProject Accession: PRJNA514017 ID: 514017, https://cptac-data-portal.georgetown.edu/study-summary/S045).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34539890", "locator": "sections[3] \"Public Colorectal Dataset Collection\" paragraph 2", "quote": "To identify the different expression of NNMT between colorectal cancers and normal tissue, the RNA transcriptome gene expression data of NNMT were extracted from the TCGA (downloaded from the XENA, https://xenabrowser.net/), and the proteomics data of that were downloaded from the project of “CPTAC Colon Cancer Confirmatory Study” (BioProject Accession: PRJNA514017 ID: 514017, https://cptac-data-portal.georgetown.edu/study-summary/S045)."}], "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:34539890"], "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. 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expression of NNMT in tumor cell and clinical pathological characteristics in 177 patients with CRC.", "structure": {"pmcid": "PMC8425209", "section_index": 15, "section_title": "The association of NNMT expression with clinicopathologic features and survival in CRC", "row_count": 26, "column_count": 5}, "table": {"label": "Table 1", "caption": "The relationship between positive expression of NNMT in tumor cell and clinical pathological characteristics in 177 patients with CRC.", "rows": [["Characteristics", "n", "", "Tumor cell", ""], ["NNMTP (%)", "Pearsonχ2", "P value"], ["Total", "177", "56(31.6)", "", ""], ["Gender", "", "", "0.655", "0.418"], ["Male", "119", "40(33.6)", "", ""], ["Female", "58", "16(27.6)", "", ""], ["Age", "", "", "0.14", "0.708"], ["<61", "88", "29(33.0)", "", ""], [">=61", "89", "27(30.3)", "", ""], ["TNM", "", "", "10.573", "0.001*"], ["Ⅰ-Ⅱ", "104", "23(22.1)", "", ""], ["Ⅲ-Ⅳ", "73", "33(45.2)", "", ""], ["T", "", "", "1.746", "0.186"], ["T1+T2", "21", "4(19.0)", "", ""], ["T3+T4", "156", "52(33.3)", "", ""], ["Lymph node metastasis", "", "", "10.607", "0.001*"], ["N0", "107", "24(42.9)", "", ""], ["N1-2", "70", "32(57.1)", "", ""], ["Distance metastasis", "", "", "15.259", "0.000*"], ["M0", "159", "43(27.0)", "", ""], ["M1", "18", "13(72.2)", "", ""], ["Histology", "", "", "3.664", "0.300"], ["Mucinous adenocarcinoma", "23", "5(21.7)", "", ""], ["Non-Mucinous adenocarcinoma", "148", "49(33.1)", "", ""], ["Squamous cell carcinoma", "5", "1(20.0)", "", ""], ["Signet-ring cell carcinoma", "1", "1(100.0)", "", ""]], "row_count": 26, "column_count": 5, "numeric_cells": 52, "header_rows": 2, "locator": "section[15]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:34539890:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:2db8f0203fe039b9787fc5c857ebdebb9abf7dc287a78d3ca9b7d787b64807af", "bytes": 1230, "access": "open", "state": "verified", "reader": "read_table", 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["BioProject Accession: PRJNA514017 ID: 514017", "GSE33113", "GSE17538"], "resolved_accessions": ["GSE33113", "GSE17538"], "statements": ["To identify the different expression of NNMT between colorectal cancers and normal tissue, the RNA transcriptome gene expression data of NNMT were extracted from the TCGA (downloaded from the XENA, https://xenabrowser.net/), and the proteomics data of that were downloaded from the project of “CPTAC Colon Cancer Confirmatory Study” (BioProject Accession: PRJNA514017 ID: 514017, https://cptac-data-portal.georgetown.edu/study-summary/S045)."], "basis": "The paper names GSE33113, GSE17538 in CPTAC Colon Cancer Confirmatory Study and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["survival_km"], "assets": ["source:pmid:34539890", "data:geo:GSE17538", "asset:table:pmid:34539890:1", "asset:table:pmid:34539890:2"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE17538"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:34:57Z", "independence": "single_reader"}, "evidence_check": {"method": "reordered", "availability": null}, "calls": 3, "usage": {"prompt_tokens": 37364, "completion_tokens": 2060, "cached_tokens": 784}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:34539890", "type": "paper", "label": "pmid:34539890"}, {"id": "source:pmid:34539890", "type": "manuscript", "label": "PMID 34539890 full text"}, {"id": "data:geo:GSE17538", "type": "dataset", "label": "GEO GSE17538"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34539890", "type": "paper", "label": "pmid:34539890"}, {"id": "source:pmid:34539890", "type": "manuscript", "label": "PMID 34539890 full text"}, {"id": "data:geo:GSE17538", "type": "dataset", "label": "GEO GSE17538"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34539890", "type": "extraction", "used": ["source:pmid:34539890"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE17538", "type": "accession_resolution", "used": ["data:geo:GSE17538"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:34539890", "parent_hash": "sha256:238cbe563cde1f0090c947b2c896b6b95bfe4b8b1f0d3cccdb3ecf2eb1d979f0", "fork_of": null, "generation": 7}, "gaps": ["asset:data:geo:GSE17538 licence not read", "asset:data:geo:GSE17538 not downloaded", "asset:data:geo:GSE33113 licence not read", "asset:data:geo:GSE33113 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"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": ["ic samples and 177 CRC tumor samples through immunohistochemistry in our study cohort. Furthermore, the relati", "hics Committee of Sir Run Run Shaw Hospital. Immunohistochemistry (IHC) analysis on paraffin tissue samples Th", "Run Run Shaw Hospital. Immunohistochemistry (IHC) analysis on paraffin tissue samples The tis", "sparency and sealing. Finally, the images of IHC were captured by digital slide scanning syst"], "order_basis": "paper_text_order:929", "id": "assay:1"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["China. In addition, colorectal cancer tissue microarray (TMA) (DC-Col01022), including 72 cancer tis"], "order_basis": "paper_text_order:3291", "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": ["or 10 mins. The sections were incubated with mouse monoclonal anti-human NNMT antibody (1E7 8,"], "order_basis": "paper_text_order:5064", "id": "assay:3"}, {"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": ["ulture Collection. All the cancer cells were cultured in RPMI-1640 medium (Gibco, Grand Island, NY, U", "(Gibco, Grand Island, NY, USA). CCD-18Co was cultured in Eagle's minimal essential medium. These medi"], "order_basis": "paper_text_order:7000", "id": "assay:4"}, {"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": ["The relationships between NNMT expression and clinicopathological attributes were analyzed using Pearson's χ2 test. Survival curves were plotted by the Kaplan-Meier method with log-rank test."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]}