{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:41:19Z","timestamp":1785426079555,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370755"],"award-info":[{"award-number":["32370755"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32370755"],"award-info":[{"award-number":["32370755"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["20Y11908300"],"award-info":[{"award-number":["20Y11908300"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"award":["20Y11908300"],"award-info":[{"award-number":["20Y11908300"]}],"id":[{"id":"https:\/\/ror.org\/03kt66j61","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Research Fund Program of Anhui Medical University","award":["2022xkj044"],"award-info":[{"award-number":["2022xkj044"]}]},{"name":"Research Fund Program of Anhui Medical University","award":["2022xkj173"],"award-info":[{"award-number":["2022xkj173"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets\u2014GSE41258, GSE44076, GSE81558, and GSE117606\u2014along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein\/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial\u2013mesenchymal transition (EMT) and the PI3K\/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K\/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K\/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment.<\/jats:p>","DOI":"10.3390\/cancers18081311","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:42:45Z","timestamp":1776771765000},"page":"1311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MDK Activates the PI3K\/AKT Axis to Induce AP2A1 Expression and Epithelial\u2013Mesenchymal Transition in Colorectal Cancer"],"prefix":"10.3390","volume":"18","author":[{"given":"Tengfei","family":"Li","sequence":"first","affiliation":[{"name":"Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200082, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200082, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Guo","sequence":"additional","affiliation":[{"name":"General Surgery, Cancer Center, Department of Colorectal Surgery, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital, Hangzhou Medical College), Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200082, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiji","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200082, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunsheng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230601, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesavamoorthy","family":"Gandhervin","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Pudong Hospital Affiliated to Fudan University, Fudan University School of Medicine, Shanghai 201399, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moubin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Yangpu Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200082, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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