{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:38:50Z","timestamp":1792809530687,"version":"4.5.0"},"reference-count":28,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cysteine\u2010rich angiogenic inducer 61 (CYR61), a matricellular protein, has been implicated in gastric cancer aggressiveness through activation of integrin\u2010mediated NF\u2010\u03baB signaling; however, effective pharmacological strategies targeting this axis remain limited. Cyclopiane, a bioactive small\u2010molecule compound, has shown potential anti\u2010tumor activity, but its role and underlying mechanisms in gastric cancer have not been fully elucidated. This study aimed to investigate whether Cyclopiane suppresses gastric cancer invasion and angiogenesis via modulation of the CYR61\/\u03b1v\u03b23 integrin\/NF\u2010\u03baB signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human gastric cancer cell lines AGS and MKN45 were treated with increasing concentrations of Cyclopiane. Cell viability was assessed using MTT assays, while invasive capacity was evaluated using Matrigel\u2010coated Transwell assays. TUNEL staining was used to assess changes in apoptosis in tumor cells. The expression of invasion\u2010, angiogenesis\u2010, and inflammation\u2010related proteins was analyzed by Western blot (WB) and enzyme\u2010linked immunosorbent assay (ELISA). Transcriptomic profiling of AGS cells treated with Cyclopiane versus vehicle control was performed to identify differentially expressed genes and enriched signaling pathways. CYR61 overexpression was achieved via adeno\u2010associated virus (AAV\u2010CYR61), with its pathway involvement further validated using integrin \u03b1v\u03b23 antagonists. The conventional anticancer drug 5\u2010fluorouracil (5\u2010FU) was employed to compare Cyclopiane's therapeutic effects. In\u00a0vivo experiments utilized a nude mouse xenograft model to evaluate changes in tumor growth, angiogenesis, and inflammatory responses following Cyclopiane treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that Cyclopiane significantly reduced cell viability, invasive capacity of AGS and MKN45 cells and promoted apoptosis in a dose\u2010dependent manner, with its high\u2010dose effects comparable to those of 5\u2010FU. Transcriptomic analysis revealed that Cyclopiane downregulated CCN1\/CYR61, ITGAV and ITGB3 expression, with pathway enrichment identifying integrin signaling, ECM\u2010receptor interaction, focal adhesion and NF\u2010\u03baB pathways as the top modulated terms. In\u00a0vivo experiments demonstrated that Cyclopiane significantly inhibited tumor growth and progression. Both in\u00a0vivo and in\u00a0vitro studies showed Cyclopiane significantly downregulated vascular endothelial growth factor (VEGF), matrix metalloproteinase\u20102 (MMP\u20102), and MMP\u20109 expression while inhibiting integrin \u03b1v\u03b23 expression and NF\u2010\u03baB activation, as evidenced by reduced phosphorylation levels of p65 and I\u03baB\u03b1. Overexpression of CYR61 partially reversed the inhibition of invasion, angiogenic factor production, and NF\u2010\u03baB signaling mediated by Cyclopiane. The \u03b1v\u03b23\/\u03b1v\u03b25 integrin antagonist Cilengitide also exhibited tumor\u2010suppressive effects, and the co\u2010treatment of Cyclopiane with Cilengitide achieved the strongest tumor\u2010suppressive effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that modulation of the CYR61\/integrin\/NF\u2010\u03baB signaling axis contributes, at least in part, to the anti\u2010invasive and anti\u2010angiogenic effects of Cyclopiane in preclinical gastric cancer models. Further studies are required to establish its molecular target specificity, safety, selectivity, and translational potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72352","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:12:54Z","timestamp":1792563174000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclopiane Suppresses Gastric Cancer Invasion and Angiogenesis via the\n                    <scp>CYR61<\/scp>\n                    \/\u03b1v\u03b23 Integrin\/\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Pathway"],"prefix":"10.1002","volume":"15","author":[{"given":"Yingfeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Anhui Medical University  Hefei China"},{"name":"Anhui Public Health Clinical Center  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runben","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7395-1460","authenticated-orcid":false,"given":"Wenbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16172948"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201004\u20102639"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000509530"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113613"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2024.1222"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002780R"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/10732748221134398"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23020209"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706600200"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8845"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1481"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2017.11.008"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.3779\/j.issn.1009\u20103419.2014.12.06"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2013.08.026"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M402305200"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/md21110584"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103129"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201055189\u20108"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgz143"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010021\u201002108\u20100"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006832\u20101"},{"issue":"15","key":"e_1_2_12_23_1","first-page":"4263","article-title":"Cilengitide Targeting of Alpha(v)beta(3) Integrin Receptor Synergizes With Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts","volume":"62","author":"Burke P. A.","year":"2002","journal-title":"Cancer Research"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14110761"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010019\u20101776\u2010x"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn284"},{"issue":"9","key":"e_1_2_12_27_1","first-page":"3197","article-title":"Cyr61 Overexpression Induced by Interleukin 8 via NF\u2010kB Signaling Pathway and Its Role in Tumorigenesis of Gastric Carcinoma in Vitro","volume":"12","author":"Su R. L.","year":"2019","journal-title":"International Journal of Clinical and Experimental Pathology"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.4103\/tjo.TJO\u2010D\u201024\u201000086"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878\u20100261.12998"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72352","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.72352","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72352","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:09:24Z","timestamp":1792807764000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.72352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":28,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cam4.72352"],"URL":"https:\/\/doi.org\/10.1002\/cam4.72352","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72352"}}