Abstract #LB-289: Dietary zinc deficiency induces a proinflammatory gene signature in forestomach mucosa and predisposes COX-2 null mice to carcinogenesis
Authors: Shao-Gui Wan, Cristian Taccioli, Xiu-Ping Liu, Carlo Croce, John Farber, Louise Fong
Journal: Cancer Research (2009)

Background & Aims: Dietary zinc-deficiency (ZD) in humans is associated with an increased risk of esophageal cancer. In rodents, ZD predisposes to carcinogenesis by causing cellular proliferation and alterations in gene expression. In ZD mice, targeted disruption of the cyclooxygenase-2 (COX-2) pathway by genetic deletion did not prevent chemically induced forestomach tumorigenesis as it did in mice on a zinc-sufficient (ZS) diet (Int J Cancer 2008; 122:978-89). ZD caused hyperplasia in COX-2-/- mouse forestomach and enhanced chemically induced forestomach carcinogenesis in COX-2-/- versus wild-type (Wt) mice. To test the hypothesis that under ZD conditions alternative cancer pathways are induced in COX-2-/- forestomach that abolish the beneficial effects of blocking the COX-2 pathway, we evaluated expression profiles of forestomach mucosa from COX-2-/- and Wt mice on a ZD versus ZS diet. Methods: Expression analysis were performed on ZD:COX-2-/-, ZS:COX-2-/-, ZD:Wt, and ZS:Wt forestomach mucosa (n = 4/group), using GeneChip® Mouse Genome 430 2.0 Array (Affymetrix). The role of a top up-regulated gene S100 calcium binding protein A8 (S100A8) in COX-2-/- mouse forestomach preneoplasia is characterized by immunohistochemistry and real-time quantitative polymerase chain reaction. Results: ZD induced a protumorigenic gene signature in ZD:COX-2-/- vs ZD:Wt mouse forestomach. Upregulation of the inflammation-associated genes S100A8/A9, mast cell protease 1 and 2 (MCPT1/2); keratin tumor markers (KRT6, KRT8, KRT16, KRT18, KRT19); and deleted in malignant brains tumors 1 (DMBT1) was found in ZD:COX-2-/- vs ZD:Wt forestomach but not in ZS:COX-2-/- vs ZS:Wt forestomach. Instead, ZS:COX-2-/- showed upregulation of gastrokine 1 and 2 (GKN1/2 ), trefoil factor 1 (TFF1), and mucin 5, subtypes A and C, tracheobronchial (MUC5AC). Independent of genotype, ZD induced a similar protumorigenic gene signature in ZD:COX-2-/- vs ZS:COX-2-/- and in ZD:Wt vs ZS:Wt mouse forestomach. The finding that ZD induces S100A8/A9 overexpression in COX-2-/- and Wt mouse forestomach is consistent with our recent report that in rat esophagus zinc regulates S100A8 expression and modulates the link between S100A8-RAGE interaction and downstream NF-\#954;\#914;/COX-2 signaling, an inflammation pathway in carcinogenesis (Gastroenterology 2008 Nov 24). Conclusions: The data show that alternative protumorigenic pathway(s), for example, the inflammation-associated S100A8 signaling, is up-regulated in the forestomach of ZD:COX-2-/- mice, thereby setting the stage for the inefficacy of cancer prevention in these mice by targeting the COX-2 pathway. More broadly, our data suggest zinc supplementation should be explored in human targeted cancer therapies for esophageal cancer, especially in ZD patients. Supported by NIH grant #CA118560.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-289.