{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:25:05Z","timestamp":1772987105365,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Biochemistry &amp;amp; Function"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>This study uncovers a novel post\u2010translational regulatory mechanism through which MDM2 stabilizes IL\u201033 via K63\u2010linked ubiquitination, thus facilitating the progression of gastric cancer. Using MKN45 and AGS gastric cancer cells, we conducted MDM2 knockdown followed by qPCR and Western blot to evaluate IL\u201033 regulation. Co\u2010IP and cycloheximide chase assays verified MDM2\u2010IL\u201033 binding and stabilization. Ubiquitination assays using WT and mutant (K63R\/K48\u2010only) ubiquitin identified MDM2\u2010dependent K63\u2010linked polyubiquitination of IL\u201033. A subcutaneous xenograft tumor model in nude mice was established to validate the oncogenic role of the MDM2\u2010IL\u201033 axis in vivo. Functional assays (CCK\u20108, colony formation, Transwell, and wound healing) revealed MDM2's requirement for IL\u201033\u2010mediated oncogenic effects. Western blots showed MDM2\u2010IL\u201033 axis modulates apoptosis (Bcl\u20102\/Bax\/Caspase\u20103) and ERK signaling (p\u2010ERK\/p\u2010JNK). We have demonstrated that knocked down MDM2 significantly decreases IL\u201033 protein levels without influencing its mRNA expression, suggesting that the regulation occurred at the post\u2010translational stage. Co\u2010immunoprecipitation assays have confirmed the physical interaction between MDM2 and IL\u201033 in gastric cancer cell lines, namely MKN45 and AGS. Meanwhile, ubiquitination assays have revealed that MDM2 specifically mediated the K63\u2010linked polyubiquitination of IL\u201033, thereby enhancing its stability. Functionally, overexpressing IL\u201033 promoted malignant phenotypes in gastric cancer cells, such as increased cell viability, enhanced clonogenic growth, and augmented invasion and migration capabilities. Intriguingly, depleting MDM2 effectively abolished these promoting effects. Mechanistically, the MDM2\u2010IL\u201033 axis exerted its influence by suppressing apoptosis through modulating the expression of Bcl\u20102\/Bax\/Caspase\u20103, and by activating the oncogenic ERK\/JNK signaling pathway. Crucially, MDM2 overexpression promoted tumor growth, which was effectively reversed by transfection with si\u2010MDM2. These findings firmly established MDM2 as a crucial regulator of IL\u201033 stability and highlighted the significant therapeutic potential of targeting the MDM2\u2010IL\u201033 interaction to impede gastric cancer progression.<\/jats:p>","DOI":"10.1002\/cbf.70179","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T11:08:17Z","timestamp":1769857697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The MDM2\u2010IL\u201033 Axis Promotes Gastric Tumorigenesis via K63 Ubiquitination\u2010Dependent ERK\/JNK Activation"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0037-7727","authenticated-orcid":false,"given":"Ning","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong Province P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Zan","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong Province P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong Province P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong Province P. R. 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-024-04499-y"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.41.2.142"},{"issue":"3","key":"e_1_2_8_4_1","first-page":"499","article-title":"Characteristics of Gastric Cancer Invading to the Proper Muscle Layer\u2010\u2010With Special Reference to Mortality and Cause of Death","volume":"15","author":"Yoshikawa K.","year":"1985","journal-title":"Japanese Journal of Clinical Oncology"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202260"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b00201"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c03471"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2022.5322"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.454470"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112414"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53006-w"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7040064"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.04.005"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02432"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12552"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.12000"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.9b00099"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202400249"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9091944"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c03640"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.2c07904"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0135"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmt147"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0102-8650201400160004"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2014.09.007"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmp053"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2014.15.20.8539"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-7-271"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-021-00608-4"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2016.176"}],"container-title":["Cell Biochemistry and Function"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbf.70179","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbf.70179","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbf.70179","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:49:15Z","timestamp":1772966955000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/cbf.70179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/cbf.70179"],"URL":"https:\/\/doi.org\/10.1002\/cbf.70179","archive":["Portico"],"relation":{},"ISSN":["0263-6484","1099-0844"],"issn-type":[{"value":"0263-6484","type":"print"},{"value":"1099-0844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]},"assertion":[{"value":"2025-05-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70179"}}