{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T18:45:44Z","timestamp":1774118744939,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2010,11,9]],"date-time":"2010-11-09T00:00:00Z","timestamp":1289260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2011,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Zinc (Zn)\u2010deficiency (ZD) is implicated in the pathogenesis of human oral\u2010esophageal cancers. Previously, we showed that in ZD mice genetic deletion of <jats:italic>cyclooxygenase\u20102<\/jats:italic> (<jats:italic>Cox\u20102<\/jats:italic>) enhances <jats:italic>N<\/jats:italic>\u2010nitrosomethylbenzylamine\u2010induced forestomach carcinogenesis. By contrast, <jats:italic>Cox\u20102<\/jats:italic> deletion offers protection in Zn\u2010sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX\u20102 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a <jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse tongue cancer model that mimics pharmacologic blockade of COX\u20102 by firstly examining transcriptome profiles of forestomach mucosa from <jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and wild\u2010type mice on a ZD <jats:italic>vs<\/jats:italic>. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach\/tongue preneoplasia and carcinomas. In <jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exposed to the tongue carcinogen 4\u2010nitroquinoline 1\u2010oxide, dietary ZD elicited tongue\/esophagus\/forestomach carcinomas that were prevented by ZS. The precancerous ZD:<jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>vs<\/jats:italic>. ZS:<jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> forestomach had an inflammatory signature with upregulation of the proinflammation genes <jats:italic>S100a8<\/jats:italic> and <jats:italic>S100a9<\/jats:italic>. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising <jats:italic>S100a8<\/jats:italic>\/<jats:italic>a9<\/jats:italic> and an nuclear factor (NF)\u2010\u03baB network with connectivity to S100A8. Immunohistochemistry revealed co\u2010overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end\u2010products (RAGE), NF\u2010\u03baB p65, and cyclin D1, in ZD:<jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> forestomach\/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE\u2010S100A8\/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn\u2010replenishment in ZD:<jats:italic>Cox\u20102<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation\u2010associated cancer pathways that fuel tumor progression and bypass the antitumor effect of <jats:italic>Cox\u20102<\/jats:italic> ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy.<\/jats:p>","DOI":"10.1002\/ijc.25688","type":"journal-article","created":{"date-parts":[[2010,9,20]],"date-time":"2010-09-20T17:21:48Z","timestamp":1285003308000},"page":"331-345","source":"Crossref","is-referenced-by-count":32,"title":["Zinc deficiency activates S100A8 inflammation in the absence of COX\u20102 and promotes murine oral\u2010esophageal tumor progression"],"prefix":"10.1002","volume":"129","author":[{"given":"Shao\u2010Gui","family":"Wan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Taccioli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yubao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl J.","family":"Smalley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu\u2010Ping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Farber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise Y. 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