Abstract 4174: Cxcl5 and Cxcl2 overexpression in esophageal carcinogenesis is associated with rapid tumor formation in zinc-deficient rats (2010)

Abstract Objectives: Zinc-deficiency (ZD) is implicated in the pathogenesis of human esophageal cancer. It induces cell proliferation, modulates genetic expression, and enhances carcinogenesis. Zinc-replenishment (ZR) reverses proliferation and inhibits carcinogenesis. Recently, we showed that a ZD diet induces overexpression of the proinflammation mediators S100a8/a9 in hyperplastic rat esophagus, providing evidence that zinc regulates an inflammatory pathway in early esophageal carcinogenesis (Gastroenterology, 136: 953-966, 2009). Here we determined the biological processes affected by zinc nutrition during rapid N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor development and its prevention. Methods: We evaluated gene expression profiles of esophageal mucosa from zinc-modulated rats at 5 weeks after an NMBA dose and at 15 weeks (endpoint) with 3 NMBA doses, using Affymetrix Rat Genome GeneChip. Here, ZD rats documented a significantly higher tumorigenic outcome than control zinc-sufficient (ZS) rats (tumor incidence, 100% vs 16.6%; multiplicity, 11 ± 3.8 vs 0.5 ± 0.3, P&amp;lt;0.001). Replenishing zinc after the first NMBA dose led to a low tumorigenic outcome in ZR vs ZD rats (incidence, 28.9% vs 100%; multiplicity, 0.6 ± 0.4 vs 11 ± 3.8, P&amp;lt;0.001). Results: The ZD esophagi have a distinct expression signature versus ZS esophagi at both time points. At 5 weeks, in addition to S100a8/a9 overexpression (up 2.5-fold), the dysplastic ZD esophagi showed up-regulation of several cancer-related inflammation genes, including CXC chemokines Cxcl5 and Cxcl2 (up &amp;gt;25-fold); Ptgs2 (up 26-fold); and Il17f (up 2.7 fold). At endpoint, the tumor-bearing ZD esophagus displayed a neoplastic gene signature, with increased up-regulation of Cxcl5 and Cxcl2 (up 84- and 38-fold), Cxcl3 (up 9-fold), Cxcl1 (up 7-fold), Ptgs2 (up 41-fold), Il1b (up 12-fold), Il17f (up 7.5-fold), and S100a8/a9 (up 2.1-fold). Replenishing zinc led to a global reversal of abnormal gene expression, resulting in an expression profile similar to that of ZS esophagi. In parallel to mRNA expression, CXCL5, CXCL2, COX-2, and S100A8/A9 protein expression was similarly modulated by ZD and ZR, as shown by ELISA, immunoblotting, and immunohistochemistry assays. Ingenuity Pathway Analysis predicted an Il1b-centric network, with direct connections to many up-regulated genes. Conclusions: ZD fuels inflammation and drives carcinogenesis by inducing overexpression of several cancer-related inflammation genes, including Cxcl5 and Cxcl2. ZR modulates inflammatory responses and inhibits tumor growth. The data provide a new understanding of the molecular role of zinc in esophageal carcinogenesis/prevention and suggest that zinc supplementation should be more thoroughly explored in human prevention clinical trials for upper aerodigestive tract cancer. Supported by NIH grant CA118560. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4174.