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This study investigates the functional impact of CXCL14 on colon cancer by exploring its effects on tumor cell behavior and the immune microenvironment. We generated stable cell lines overexpressing CXCL14 in mouse MC38 and CT26 cells and human HCT15 colon cancer cells, and used these models to assess tumor growth, invasion, and immune cell infiltration. Our results demonstrate that CXCL14 suppresses colon cancer cell proliferation, migration, and metastasis. In vitro, CXCL14 inhibited the expression of matrix metalloproteinases (MMPs), key regulators of epithelial\u2013mesenchymal transition (EMT), suggesting a role in promoting mesenchymal\u2013epithelial transition (MET). Additionally, in vivo studies using a subcutaneous tumor model showed that CXCL14 not only suppressed tumor growth but also enhanced the infiltration of immune cells, including NK cells, dendritic cells (DCs), and T cells, converting the tumor microenvironment from a \u201ccold\u201d to a \u201chot\u201d phenotype. RNA sequencing and pathway analyses revealed that CXCL14 regulates the expression of genes associated with angiogenesis, immune response, and cell signaling, particularly through the MAPK pathway. Furthermore, CXCL14\u2019s influence on tumor progression was confirmed in a spleen-to-liver metastasis model, where its overexpression reduced metastatic spread. In conclusion, CXCL14 inhibits colon cancer progression by modulating both tumor cell behavior and the immune landscape, making it a promising candidate for targeted immunotherapy. Our findings highlight CXCL14\u2019s potential to enhance anti-tumor immunity and provide new insights into its therapeutic applications in colon cancer.<\/jats:p>","DOI":"10.3390\/cells15100860","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T21:07:16Z","timestamp":1778274436000},"page":"860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CXCL14 Inhibits Colon Cancer Progression by Modulating Tumor Cell Invasion and Immune Microenvironment"],"prefix":"10.3390","volume":"15","author":[{"given":"Yinjie","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1483-5787","authenticated-orcid":false,"given":"Siyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Niu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6826-1635","authenticated-orcid":false,"given":"Yanjing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7383-719X","authenticated-orcid":false,"given":"Buyong","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0661-5642","authenticated-orcid":false,"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8262","DOI":"10.1158\/0008-5472.CAN-04-2056","article-title":"BRAK\/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells","volume":"64","author":"Shellenberger","year":"2004","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2116027119","DOI":"10.1073\/pnas.2116027119","article-title":"Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity","volume":"119","author":"Tsujihana","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1084\/jem.194.6.855","article-title":"Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development","volume":"194","author":"Kurth","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.exphem.2006.05.015","article-title":"The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: Implications for the downregulation of CXCL14 in malignancy","volume":"34","author":"Starnes","year":"2006","journal-title":"Exp. Hematol."},{"key":"ref_5","first-page":"137","article-title":"Epigenetic silencing of CXCL14 induced colorectal cancer migration and invasion","volume":"16","author":"Cao","year":"2013","journal-title":"Discov. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.3892\/mmr.2014.2343","article-title":"Expression and effect of CXCL14 in colorectal carcinoma","volume":"10","author":"Lin","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/jcp.21877","article-title":"CXCL14 inhibits trophoblast outgrowth via a paracrine\/autocrine manner during early pregnancy in mice","volume":"221","author":"Kuang","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S1471-4906(03)00120-0","article-title":"Molecular evolution of CXC chemokines: Extant CXC chemokines originate from the CNS","volume":"24","author":"Huising","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13287-015-0088-z","article-title":"CXCL14 and MCP1 are potent trophic factors associated with cell migration and angiogenesis leading to higher regenerative potential of dental pulp side population cells","volume":"6","author":"Hayashi","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1080\/13813455.2020.1769677","article-title":"Effect of chemokine CXCL14 on in vitro angiogenesis of human hepatocellular carcinoma cells","volume":"128","author":"Liu","year":"2022","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.7150\/thno.17558","article-title":"A Crucial Role of CXCL14 for Promoting Regulatory T Cells Activation in Stroke","volume":"7","author":"Lee","year":"2017","journal-title":"Theranostics"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, Y., Wang, S., Niu, Y., Ma, B., and Li, J. (2023). Data Mining Suggests That CXCL14 Gene Silencing in Colon Cancer Is Due to Promoter Methylation. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202310.0147.v1"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chen, B., Huan, L., Lu, J., and Yuan, J. (2025). Shapley additive explanations based feature selection reveals CXCL14 as a key immune-related gene in predicting idiopathic pulmonary fibrosis. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1608078"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100263","DOI":"10.1016\/j.mocell.2025.100263","article-title":"Identification of a Unique Subpopulation of Mucosal Fibroblasts in Colorectal Cancer with Tumor-Restraining Characteristics","volume":"48","author":"Ku","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1093\/jimmun\/vkaf080","article-title":"CXCL14 is an essential modulator of TLR9 agonist-induced antitumor immune responses","volume":"214","author":"Tanegashima","year":"2025","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.1038\/s41388-022-02437-0","article-title":"Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer","volume":"41","author":"Wang","year":"2022","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e136687","DOI":"10.1172\/jci.insight.136687","article-title":"Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia","volume":"5","author":"Huot","year":"2020","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Khokhlova, O.N., Borozdina, N.A., Sadovnikova, E.S., Pakhomova, I.A., Rudenko, P.A., Korolkova, Y.V., Kozlov, S.A., and Dyachenko, I.A. (2022). Comparative Study of the Aftereffect of CO2 Inhalation or Tiletamine-Zolazepam-Xylazine Anesthesia on Laboratory Outbred Rats and Mice. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020512"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1038\/s41388-020-1217-4","article-title":"MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness","volume":"39","author":"Li","year":"2020","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/s41591-023-02324-5","article-title":"An integrated tumor, immune and microbiome atlas of colon cancer","volume":"29","author":"Roelands","year":"2023","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.cell.2019.03.030","article-title":"Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities","volume":"177","author":"Vasaikar","year":"2019","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/pro.4218","article-title":"PANTHER: Making genome-scale phylogenetics accessible to all","volume":"31","author":"Thomas","year":"2022","journal-title":"Protein Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.humpath.2018.03.030","article-title":"MMP14 predicts a poor prognosis in patients with colorectal cancer","volume":"83","author":"Cui","year":"2019","journal-title":"Hum. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1038\/s41591-022-01930-z","article-title":"Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer","volume":"28","author":"Chatila","year":"2022","journal-title":"Nat. Med."},{"key":"ref_26","first-page":"100625","article-title":"Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors","volume":"5","author":"Gyorffy","year":"2024","journal-title":"Innovation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.addr.2008.12.016","article-title":"In vivo gene regulation using tetracycline-regulatable systems","volume":"61","author":"Stieger","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"494","DOI":"10.7150\/jca.21562","article-title":"Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients","volume":"9","author":"Ning","year":"2018","journal-title":"J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1016\/j.febslet.2014.11.009","article-title":"CXCL14 is no direct modulator of CXCR4","volume":"588","author":"Otte","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.febslet.2013.04.046","article-title":"CXCL14 is a natural inhibitor of the CXCL12-CXCR4 signaling axis","volume":"587","author":"Tanegashima","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1515\/bmc-2014-0007","article-title":"CXCL14 antagonizes the CXCL12-CXCR4 signaling axis","volume":"5","author":"Hara","year":"2014","journal-title":"Biomol. Concepts"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1097\/PGP.0000000000000362","article-title":"CXCL14-CXCR4 and CXCL12-CXCR4 Axes May Play Important Roles in the Unique Invasion Process of Endometrioid Carcinoma With MELF-Pattern Myoinvasion","volume":"36","author":"Yasuda","year":"2017","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kouzeli, A., Collins, P.J., Metzemaekers, M., Meyrath, M., Szpakowska, M., Artinger, M., Struyf, S., Proost, P., Chevigne, A., and Legler, D.F. (2020). CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.561404"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107681","DOI":"10.1016\/j.intimp.2021.107681","article-title":"Chemokine CXCL14; a double-edged sword in cancer development","volume":"97","author":"Markov","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1002\/mc.23188","article-title":"The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses","volume":"59","author":"Westrich","year":"2020","journal-title":"Mol. Carcinog."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40364-020-00228-x","article-title":"Roles of IFN-gamma in tumor progression and regression: A review","volume":"8","author":"Jorgovanovic","year":"2020","journal-title":"Biomark. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Decock, J., Comito, G., and Zaravinos, A. (2023). Editorial: Tumor microenvironment, inflammation, and resistance to immunotherapies. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1215332"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1242\/dev.071209","article-title":"Epithelial-mesenchymal transitions: Insights from development","volume":"139","author":"Lim","year":"2012","journal-title":"Development"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tanegashima, K., Okamoto, S., Nakayama, Y., Taya, C., Shitara, H., Ishii, R., Yonekawa, H., Minokoshi, Y., and Hara, T. (2010). CXCL14 deficiency in mice attenuates obesity and inhibits feeding behavior in a novel environment. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010321"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Jin, Y., Li, J., Yan, Y., Wang, T., Wang, X., Li, Z., and Qin, X. (2024). CXCL14 as a Key Regulator of Neuronal Development: Insights from Its Receptor and Multi-Omics Analysis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031651"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5596","DOI":"10.1210\/en.2009-0570","article-title":"The cytokine gene CXCL14 restricts human trophoblast cell invasion by suppressing gelatinase activity","volume":"150","author":"Kuang","year":"2009","journal-title":"Endocrinology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9023","DOI":"10.1073\/pnas.0602681103","article-title":"GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis","volume":"103","author":"Xu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5558","DOI":"10.1158\/0008-5472.CAN-10-4543","article-title":"GPR56 Regulates VEGF production and angiogenesis during melanoma progression","volume":"71","author":"Yang","year":"2011","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5490","DOI":"10.4049\/jimmunol.174.9.5490","article-title":"Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo","volume":"174","author":"Shurin","year":"2005","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.bbrc.2013.04.106","article-title":"Genetic deletion of Cxcl14 in mice alters uterine NK cells","volume":"435","author":"Cao","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e001048","DOI":"10.1136\/jitc-2020-001048","article-title":"Malignant cell-specific CXCL14 promotes tumor lymphocyte infiltration in oral cavity squamous cell carcinoma","volume":"8","author":"Parikh","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kienzl, M., Maitz, K., Sarsembayeva, A., Valadez-Cosmes, P., Gruden, E., Ristic, D., Herceg, K., Kargl, J., and Schicho, R. (2024). Comparative Study of the Immune Microenvironment in Heterotopic Tumor Models. Cancers, 16.","DOI":"10.3390\/cancers16020295"},{"key":"ref_48","first-page":"418","article-title":"Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions","volume":"3","author":"Nei","year":"1986","journal-title":"Mol. Biol. Evol."},{"key":"ref_49","first-page":"725","article-title":"A codon-based model of nucleotide substitution for protein-coding DNA sequences","volume":"11","author":"Goldman","year":"1994","journal-title":"Mol. Biol. Evol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/860\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:19:10Z","timestamp":1779337150000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/860"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":49,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15100860"],"URL":"https:\/\/doi.org\/10.3390\/cells15100860","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}