{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:18:43Z","timestamp":1787239123959,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: In recent decades, the incidence of colorectal cancer (CRC) has been rising worldwide. CRC ranks second in cancer-related mortality. The identification of reliable biomarkers for early diagnosis and prognosis prediction, along with a deeper understanding of the underlying molecular events, holds substantial promise for improving patient outcomes. The tissue inhibitor of the metalloproteinase 1 (TIMP1) gene is overexpressed in various gastrointestinal malignancies and contributes to tumor progression. However, its role in regulating the CRC tumor immune microenvironment (TIME) and its potential as a clinically actionable prognostic biomarker remain unclear. Methods: To probe how TIMP1 acts as a prognosis-related candidate biomarker in colorectal carcinoma, TCGA-derived datasets were adopted to conduct Kaplan\u2013Meier survival assessment. We also investigated the connection between the expression abundance of TIMP1 and the infiltration of immune populations and intratumoral lymphocytes; furthermore, immune checkpoint-related genes were systematically assessed across multiple tumor types via the TISIDB and TIMER2.0 platforms, with particular emphasis on CRC. We adopted the ESTIMATE scoring system to figure out how TIMP1 gene expression correlates with the phenotypic properties of the colorectal-cancer TIME. We relied on the limma toolkit for the screening of differential transcripts from high-TIMP1 and low-TIMP1 cohorts. Enrichment assessments covering Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes entries were then carried out to predict the potential biological pathways associated with TIMP1. We constructed the protein\u2013protein interaction map for TIMP1-interacting partners via the STRING repository. To further explore TIMP1-correlated genes, we performed Venn diagram intersection analysis combined with Spearman\u2019s correlation test. Finally, quantitative reverse-transcription PCR was then implemented to detect TIMP1 messenger-RNA abundance inside the RKO colorectal carcinoma cell line as well as normal colonic epithelial CCD-18Co cells, which offered in vitro experimental verification for our bioinformatic outcomes. Results: According to outcome data, TIMP1 transcripts were markedly up-regulated in CRC specimens and cell lines relative to normal samples. Elevated TIMP1 expression served as a poor-prognosis indicator for overall survival (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.29\u20130.64, p &lt; 0.001) and disease-specific survival (HR = 0.39, 95% CI = 0.22\u20130.68, p = 0.001) among colorectal-carcinoma patients. TIMP1-high and TIMP1-low groups exhibited notable differences in immune cell infiltration (CD8+ T, macrophage, mast, neutrophil, B, monocyte, dendritic, and CD4+ T cells). TIMP1 expression was also significantly correlated with tumor-infiltrating lymphocytes, key immune checkpoint genes (e.g., CD274 [PD-L1] and CTLA4), and immunomodulatory chemokines (e.g., CCL3 and CCL5). Twelve TIMP1-interacting DEGs were selected: COL5A1, FN1, PRG4, and a cluster of nine MMPs (MMP1\/2\/3\/7\/8\/9\/11\/13\/14), all of which showed significant positive correlations with TIMP1 (r = 0.31\u20130.63, all p &lt; 0.001). Conclusions: TIMP1 expression correlates with features of the tumor immune microenvironment and extracellular matrix remodeling in CRC, suggesting that TIMP1 shows potential as a candidate biomarker. However, its potential as a therapeutic target warrants further experimental investigation.<\/jats:p>","DOI":"10.3390\/genes17080977","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:48:31Z","timestamp":1787219311000},"page":"977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Analysis of Multiple Databases Identifies Tissue Inhibitor of Metalloproteinase 1 Expression and Its Association with the Immune Microenvironment in Colorectal Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9836-3203","authenticated-orcid":false,"given":"Yun","family":"Xie","sequence":"first","affiliation":[{"name":"Faculty of Science, Inner Mongolia Agricultural University, Hohhot 010018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou 014010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuwei","family":"Yan","sequence":"additional","affiliation":[{"name":"Faculty of Science, Inner Mongolia Agricultural University, Hohhot 010018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenguang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Inner Mongolia Engineering Research Center of Genomic Big Data for Agriculture, Inner Mongolia Agricultural University, Hohhot 010018, China"},{"name":"Institute for Rural Revitalization, Inner Mongolia Agricultural University, Hohhot 010018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","first-page":"145","article-title":"Colorectal Cancer Statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA A Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1007\/s12664-024-01631-0","article-title":"Clinical Audit of Endoscopic Sub-Mucosal Dissection Performed for Complex Lateral Spreading Colorectal Tumors from a Region Non-Endemic for Colorectal Cancer","volume":"43","author":"Ansari","year":"2024","journal-title":"Indian J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/S0140-6736(19)32319-0","article-title":"Colorectal Cancer","volume":"394","author":"Dekker","year":"2019","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.2174\/0929867329666220823112731","article-title":"Physiological Properties, Functions, and Trends in the Matrix MetalloproteinaseInhibitors in Inflammation-Mediated Human Diseases","volume":"30","author":"Kim","year":"2023","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Abdolahi, F., Shahraki, A., Sheervalilou, R., and Mortazavi, S.S. (2023). Identification of Differentially Expressed Genes Associated with the Pathogenesis of Gastric Cancer by Bioinformatics Analysis. BMC Med. Genom., 16.","DOI":"10.1186\/s12920-023-01720-7"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yang, W., Wu, Z., Cai, S., Li, Z., Wang, W., Wu, J., Luo, H., and Ye, X. (2024). Tumor Lymphangiogenesis Index Reveals the Immune Landscape and Immunotherapy Response in Lung Adenocarcinoma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1354339"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108094","DOI":"10.1016\/j.clineuro.2023.108094","article-title":"Systematic Identification of Key Basement Membrane Related Genes as Potential New Biomarkers in Alzheimer\u2019s Disease","volume":"236","author":"Lin","year":"2024","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, H., and Dou, L. (2024). Single-Cell RNA Sequencing Reveals Hub Genes of Myocardial Infarction-Associated Endothelial Cells. BMC Cardiovasc. Disord., 24.","DOI":"10.1186\/s12872-024-03727-z"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Dittmer, A., and Dittmer, J. (2022). A CAF-Fueled TIMP-1\/CD63\/ITGB1\/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells. Cancers, 14.","DOI":"10.3390\/cancers14204983"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12014-023-09447-4","article-title":"Quantification of Putative Ovarian Cancer Serum Protein Biomarkers Using a Multiplexed Targeted Mass Spectrometry Assay","volume":"21","author":"Ryu","year":"2024","journal-title":"Clin. Proteom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1038\/s41388-022-02218-9","article-title":"Extravesicular TIMP-1 Is a Non-Invasive Independent Prognostic Marker and Potential Therapeutic Target in Colorectal Liver Metastases","volume":"41","author":"Rao","year":"2022","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1038\/s41598-023-29344-y","article-title":"Novel Biomarkers for Neoplastic Progression from Ulcerative Colitis to Colorectal Cancer: A Systems Biology Approach","volume":"13","author":"Shahnazari","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e17878","DOI":"10.1111\/jcmm.17878","article-title":"Screening of the Shared Pathogenic Genes of Ulcerative Colitis and Colorectal Cancer by Integrated Bioinformatics Analysis","volume":"28","author":"Shi","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"177","DOI":"10.21037\/atm-23-276","article-title":"Identification of Ferroptosis-Related Genes in Ulcerative Colitis: A Diagnostic Model with Machine Learning","volume":"11","author":"Qian","year":"2023","journal-title":"Ann. Transl. Med."},{"key":"ref_16","first-page":"899","article-title":"Elevated Tissue Inhibitor of Metalloproteinase 1 RNA in Colorectal Cancer Stroma Correlates with Lymph Node and Distant Metastases","volume":"1","author":"Zeng","year":"1995","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Leng, X., Yang, J., Liu, T., Zhao, C., Cao, Z., Li, C., Sun, J., and Zheng, S. (2022). A Bioinformatics Framework to Identify the Biomarkers and Potential Drugs for the Treatment of Colorectal Cancer. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1017539"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"43","DOI":"10.21037\/cco-22-69","article-title":"A Prospective Cohort Study of TIMP1 as Prognostic Biomarker in Gastric and Colon Cancer","volume":"11","author":"Macedo","year":"2022","journal-title":"Chin. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41571-021-00473-5","article-title":"PD-L1 as a Biomarker of Response to Immune-Checkpoint Inhibitors","volume":"18","author":"Doroshow","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e10859","DOI":"10.7717\/peerj.10859","article-title":"Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) as a Prognostic Biomarker in Gastrointestinal Cancer: A Meta-Analysis","volume":"9","author":"Qin","year":"2021","journal-title":"PeerJ"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2205574119","DOI":"10.1073\/pnas.2205574119","article-title":"Epithelial Chemerin\u2013CMKLR1 Signaling Restricts Microbiota-Driven Colonic Neutrophilia and Tumorigenesis by up-Regulating Lactoperoxidase","volume":"119","author":"Lin","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e17415","DOI":"10.1002\/advs.202517415","article-title":"In Situ Assembly of Transformable Monopeptide on Activated Neutrophils Attenuates NETs-Induced Hepatocellular Carcinoma Metastasis by Disrupting NE Nuclear Translocation","volume":"13","author":"Chen","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_23","first-page":"e92609","article-title":"Acute Myeloid Leukemia With RUNX1::RUNX1T1 Fusion Transformed from JAK2V617F-Mutated Polycythemia Vera: A Case Report","volume":"17","author":"Tsukiji","year":"2025","journal-title":"Cureus"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zhang, J., Zhang, Y., Song, Z., Bian, J., Yi, H., and Ma, Z. (2023). Identifying Neutrophil-Associated Subtypes in Ulcerative Colitis and Confirming Neutrophils Promote Colitis-Associated Colorectal Cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1095098"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12026-023-09414-z","article-title":"Immune Cells and Hypertension","volume":"72","author":"Gan","year":"2024","journal-title":"Immunol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40824-023-00389-4","article-title":"Copper-Induced Injectable Hydrogel with Nitric Oxide for Enhanced Immunotherapy by Amplifying Immunogenic Cell Death and Regulating Cancer Associated Fibroblasts","volume":"27","author":"Shen","year":"2023","journal-title":"Biomater. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Batalha, S., Gomes, C.M., and Brito, C. (2023). Immune Microenvironment Dynamics of HER2 Overexpressing Breast Cancer under Dual Anti-HER2 Blockade. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1267621"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1007\/s00262-023-03406-6","article-title":"M2 Tumor-Associated Macrophages Resist to Oxidative Stress through Heme Oxygenase-1 in the Colorectal Cancer Tumor Microenvironment","volume":"72","author":"Ito","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000513582","article-title":"Novel Strategies to Target Mast Cells in Disease","volume":"13","author":"Paivandy","year":"2021","journal-title":"J. Innate Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41388-022-02543-z","article-title":"Mast Cells Inhibit Colorectal Cancer Development by Inducing ER Stress through Secreting Cystatin C","volume":"42","author":"Song","year":"2023","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s13578-023-01144-x","article-title":"Single-Cell Analysis Unveils Activation of Mast Cells in Colorectal Cancer Microenvironment","volume":"13","author":"Xie","year":"2023","journal-title":"Cell Biosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176565","DOI":"10.1016\/j.ejphar.2024.176565","article-title":"GSK0660 Enhances Antitumor Immunotherapy by Reducing PD-L1 Expression","volume":"972","author":"Khan","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1007\/s10528-024-10796-4","article-title":"Impact of Doxorubicin and Docetaxel on Immune Checkpoint Expression in Colorectal Cancer: Insights into Chemotherapy Resistance Mechanisms","volume":"63","author":"Nasiri","year":"2025","journal-title":"Biochem. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1007\/s12029-023-00927-2","article-title":"Immune Checkpoint Inhibitors in pMMR\/MSS Colorectal Cancer","volume":"54","author":"Reddy","year":"2023","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.jcmgh.2021.05.018","article-title":"Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance","volume":"12","author":"Zhang","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wu, M., Wu, X., Wang, X., Hong, X., Liu, Y., Lv, G., Li, C., Pan, Z., Zhang, R., and Chen, G. (2023). IDO1\/COX2 Expression Is Associated with Poor Prognosis in Colorectal Cancer Liver Oligometastases. J. Pers. Med., 13.","DOI":"10.3390\/jpm13030496"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2387192","DOI":"10.1155\/2022\/2387192","article-title":"CCL3 Promotes Proliferation of Colorectal Cancer Related with TRAF6\/NF- \u03ba B Molecular Pathway","volume":"2022","author":"Ma","year":"2022","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e008722","DOI":"10.1136\/jitc-2023-008722","article-title":"CCR5 and CCL5 in Metastatic Colorectal Cancer","volume":"12","author":"Schlechter","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.canlet.2015.02.021","article-title":"CXCL8, Overexpressed in Colorectal Cancer, Enhances the Resistance of Colorectal Cancer Cells to Anoikis","volume":"361","author":"Xiao","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"216263","DOI":"10.1016\/j.canlet.2023.216263","article-title":"CXCL10 Mediates CD8+ T Cells to Facilitate Vessel Normalization and Improve the Efficacy of Cetuximab Combined with PD-1 Checkpoint Inhibitors in Colorectal Cancer","volume":"567","author":"Yan","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nersisyan, S., Novosad, V., Engibaryan, N., Ushkaryov, Y., Nikulin, S., and Tonevitsky, A. (2021). ECM\u2013Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.782699"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev-med-062913-051343","article-title":"The PI3K\/AKT Pathway as a Target for Cancer Treatment","volume":"67","author":"Mayer","year":"2016","journal-title":"Annu. Rev. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116690","DOI":"10.1016\/j.bcp.2024.116690","article-title":"Curcumin Alleviates the Aggressiveness of Breast Cancer through Inhibiting Cell Adhesion Mediated by TEAD4-Fibronectin Axis","volume":"232","author":"Li","year":"2025","journal-title":"Biochem. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dong, L., Fu, L., Zhu, T., Wu, Y., Li, Z., Ding, J., Zhang, J., Wang, X., Zhao, J., and Yu, G. (2023). A Five-Collagen-Based Risk Model in Lung Adenocarcinoma: Prognostic Significance and Immune Landscape. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1180723"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Malerba, S., Vladimirov, M., Goyal, A., Dulskas, A., Bau\u0161ys, A., Cwalinski, T., Girnyi, S., Skokowski, J., Duka, R., and Molchanov, R. (2026). Artificial Intelligence Applications in Gastric Cancer Surgery: Bridging Early Diagnosis and Responsible Precision Medicine. J. Clin. Med., 15.","DOI":"10.3390\/jcm15062208"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7","DOI":"10.56782\/pps.229","article-title":"Review of the Effects of Sodium Butyrate on Obesity, Inflammatory Bowel Disease, Pregnancy and Colorectal Cancer","volume":"22","author":"Flegiel","year":"2024","journal-title":"Prosp. Pharm. Sc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101","DOI":"10.56782\/pps.344","article-title":"Nifedipine\u2019s Synergistic Therapeutic Potential: Overcoming Challenges and Embracing Novel Applications in Pharmacotherapy","volume":"23","author":"Hussain","year":"2025","journal-title":"Prospect. Pharm. Sci."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/977\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:59:53Z","timestamp":1787219993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080977"],"URL":"https:\/\/doi.org\/10.3390\/genes17080977","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}