title: Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression.
abstract: Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2(-/-) mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2(-/-) and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2(-/-) mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2(-/-) vs. ZS:Cox-2(-/-) forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2(-/-) forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2(-/-) mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Shao-Gui
authors.initials: SG
authors.lastname: Wan
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Yubao
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hongping
authors.initials: H
authors.lastname: Chen
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Smalley
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Liu
authors.forename: John L
authors.initials: JL
authors.lastname: Farber
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Louise Y Y
authors.initials: LY
authors.lastname: Fong
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D002273:Carcinogens; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D015032:Zinc / Q000172:deficiency*
chemical_list: D040501:Calgranulin A; D002273:Carcinogens; C086145:S100a8 protein, mouse; D015112:4-Nitroquinoline-1-oxide; C030132:N-methyl-N-nitroso-(4-methylphenyl)methylamine; D051546:Cyclooxygenase 2; D015032:Zinc; D004128:Dimethylnitrosamine