title: Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat.
abstract: OBJECTIVE
  Zinc deficiency is implicated in the pathogenesis of human esophageal cancer. In the rat esophagus, it induces cell proliferation, modulates genetic expression, and enhances carcinogenesis. Zinc-replenishment reverses proliferation and inhibits carcinogenesis. The zinc-deficient rat model allows the identification of biological differences affected by zinc during early esophageal carcinogenesis.
  
  
  METHODS
  We evaluated gene expression profiles of esophageal epithelia from zinc-deficient and replenished rats vs zinc-sufficient rats using microarray analysis. We characterized the role of the top-up-regulated gene S100A8 in esophageal hyperplasia/reversal and in chemically induced esophageal carcinogenesis in zinc-modulated animals by immunohistochemistry and real-time quantitative polymerase chain reaction.
  
  
  RESULTS
  The hyperplastic-deficient esophagus has a distinct expression signature with the proinflammation genes S100 calcium binding protein A8 (S100A8) and A9 (S100A9) up-regulated 57-fold and 5-fold, respectively. Zinc replenishment rapidly restored to control levels the expression of S100A8/A9 and 27 other genes and reversed the hyperplastic phenotype. With its receptor for advanced glycation end products (RAGE), colocalization and overexpression of S100A8 protein occurred in the deficient esophagus that overexpressed nuclear factor kappaBeta p65 and cyclooxygenase-2 (COX-2) protein. Zinc replenishment, but not a COX-2 inhibitor, reduced the overexpression of these 4 proteins. Additionally, esophageal S100A8/A9 messenger RNA levels were associated directly with the diverse tumorigenic outcome in zinc-deficient and zinc-replenished rats.
  
  
  CONCLUSIONS
  In vivo zinc regulates S100A8 expression and modulates the link between S100A8-RAGE interaction and downstream nuclear factor kappaBeta/COX-2 signaling. The finding that zinc regulates an inflammatory pathway in esophageal carcinogenesis may lead to prevention and therapy for this cancer.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Shao-Gui
authors.initials: SG
authors.lastname: Wan
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
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: D000818:Animals; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004947:Esophagus / Q000473:pathology / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D008297:Male; D010641:Phenotype; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D015032:Zinc / Q000172:deficiency* / Q000494:pharmacology*
chemical_list: D040501:Calgranulin A; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; D015032:Zinc