{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T10:49:29Z","timestamp":1791802169630,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171178"],"award-info":[{"award-number":["32171178"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In colorectal cancer (CRC), metastasis drives fatalities, necessitating the discovery of therapeutic targets modulating its progression. Though the secreted protein\u2010coding gene leucine\u2010rich repeat neuronal 4 (\n                    <jats:italic>LRRN4<\/jats:italic>\n                    ) was shown to be highly overexpressed in CRC and linked to decreased survival in the analysis of TCGA\u2010CRC datasets, little is known about its function as well as mechanism in CRC metastasis. Thus, our work aimed to investigate\n                    <jats:italic>LRRN4<\/jats:italic>\n                    functions and its role in CRC metastasis. We first confirmed that CRC metastasis was related to raised\n                    <jats:italic>LRRN4<\/jats:italic>\n                    expression in CRC tissues.\n                    <jats:italic>LRRN4<\/jats:italic>\n                    depletion using siRNA\/shRNA inhibited CRC metastasis\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , decreasing vimentin and increasing E\u2010cadherin levels, whereas its overexpression yielded opposite effects. Mechanistically,\n                    <jats:italic>LRRN4<\/jats:italic>\n                    promoted CRC metastasis by upregulating\n                    <jats:italic>IL23A<\/jats:italic>\n                    expression and triggering\n                    <jats:italic>JAK2<\/jats:italic>\n                    \u2013\n                    <jats:italic>STAT3<\/jats:italic>\n                    signaling, as evidenced by\n                    <jats:italic>LRRN4<\/jats:italic>\n                    depletion\u2010reduced\n                    <jats:italic>IL23A<\/jats:italic>\n                    expression and downstream\n                    <jats:italic>JAK2<\/jats:italic>\n                    \u2013STAT3 activity; the\n                    <jats:italic>STAT3<\/jats:italic>\n                    inhibitor and recombinant human IL23 protein rescued the promotion and inhibition of cell migration induced by\n                    <jats:italic>LRRN4<\/jats:italic>\n                    overexpression and knockdown, respectively. Kaplan\u2013Meier analysis and the K\u2010independent samples nonparametric test revealed that the upregulated marker proportion was positively related to the likelihood of metastases, and people having raised\n                    <jats:italic>IL23A<\/jats:italic>\n                    and\n                    <jats:italic>LRRN4<\/jats:italic>\n                    levels had the lowest survival. Finally, elevated\n                    <jats:italic>LRRN4<\/jats:italic>\n                    expression in CRC tissues was correlated with promoter hypomethylation. Thus,\n                    <jats:italic>LRRN4<\/jats:italic>\n                    is upregulated by promoter DNA hypomethylation, and the\n                    <jats:italic>LRRN4<\/jats:italic>\n                    \u2013\n                    <jats:italic>IL23A<\/jats:italic>\n                    \u2013\n                    <jats:italic>JAK2<\/jats:italic>\n                    \u2013\n                    <jats:italic>STAT3<\/jats:italic>\n                    axis is a critical driver of CRC metastasis, representing a promising therapeutic target and prognostic biomarker.\n                  <\/jats:p>","DOI":"10.1002\/mc.70169","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T18:35:25Z","timestamp":1787250925000},"page":"1425-1441","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>LRRN4<\/i>\n                    Upregulates the\n                    <i>IL23A<\/i>\n                    \u2013\n                    <i>JAK2<\/i>\n                    \u2013\n                    <i>STAT3<\/i>\n                    Signaling Axis and Drives Colorectal Cancer Metastasis"],"prefix":"10.1002","volume":"65","author":[{"given":"Jiatian","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Minimally Invasive Intervention Peking University Shenzhen Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Min","sequence":"additional","affiliation":[{"name":"Basic Medical Science Department Zunyi Medical University\u2010Zhuhai Campus Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0975-4434","authenticated-orcid":false,"given":"Zesong","family":"Li","sequence":"additional","affiliation":[{"name":"Basic Medical Science Department Zunyi Medical University\u2010Zhuhai Campus Zhuhai China"},{"name":"Shenzhen Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital) Shenzhen China"},{"name":"Medical Research Center The Affiliated Yuebei People's Hospital of Shantou University Medical College Shaoguan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Wang","sequence":"additional","affiliation":[{"name":"Shenzhen Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital) Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center The Affiliated Yuebei People's Hospital of Shantou University Medical College Shaoguan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xigang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital) Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0193-090X","authenticated-orcid":false,"given":"Xina","family":"Xie","sequence":"additional","affiliation":[{"name":"Shenzhen Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital) Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21728"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw235"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6670"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2024.12.069"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241512133"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-022-01569-x"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2025.156908"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-025-01306-8"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.10.4166-4175.2005"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfda.2018.11.009"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14042"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5579"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.200"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025391"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-022-02579-x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-010-9305-4"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013091"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13027-025-00670-2"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07503-5"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1590\/1678-4685-gmb-2021-0138"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3758"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106210"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.03.014"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-051113-024537"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-3534-8"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1161-8"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010217"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1428-0"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-022-01319-4"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.08.004"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17228"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102184"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2019.02.018"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20143394"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology14040347"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-25059-8"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.4103\/aja202173"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15698"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0154"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11465"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2018.12.002"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2012.739"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgu017"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028530"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200502200"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32682"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20190037"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0296"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1080\/17501911.2025.2548755"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083557"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2021.112953"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70169","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mc.70169","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.70169","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T10:31:12Z","timestamp":1791801072000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.70169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":53,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/mc.70169"],"URL":"https:\/\/doi.org\/10.1002\/mc.70169","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"assertion":[{"value":"2025-12-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}