Abstract Title:

Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat.

Abstract Source:

Gastroenterology. 2008 Nov 24. PMID: 19111725

Abstract Author(s):

Cristian Taccioli, Shao-Gui Wan, Chang-Gong Liu, Hansjuerg Alder, Stefano Volinia, John L Farber, Carlo M Croce, Louise Y Y Fong


BACKGROUND & AIMS: 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 the Affymetrix Rat Genome GeneChip (Santa Clara, CA). 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 S100 calcium binding protein A9 (S100A9) up-regulated 57-fold and 5-fold, respectively. Response to external stimulus comprising S100A8 was the only significantly overrepresented biological pathway among the up-regulated genes. 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, 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 by a COX-2 inhibitor, reduced the overexpression of these 4 proteins. In addition, 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-receptor for advanced glycation end products 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.

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