Hexavalent chromium [Cr(VI)] long-term exposure is associated with human lung cancer. Although there is emerging interest in the mechanism underlying Cr(VI)-induced carcinogenesis, the mechanism and role of Cr(VI) in inducing carcinogenesis still remains to be elucidated. In preliminary studies, we used human peripheral blood mononuclear cells (PBMC cells) from Cr(VI) exposed and control subjects to perform whole genome expression array analysis, and found that IL-8 and CXCL5 are the two most up-regulated genes detected in the exposure group compared with non-exposure subjects. We validated our findings by RT-qPCR and ELISA assay. Additionally, we found that miR-199a suppression and ?-catenin upregulation are important for IL-8 and CXCL5 induction. Forced expression of miR-199a and knockdown of IL-8 or CXCL5 inhibited both cell transformation and angiogenesis. These findings are consistent with our results obtained from Cr(VI)- transformed cells and from in vitro studies. Furthermore, we found that ?-catenin directly activated IL-8 expression at transcriptional level, while miR-199a directly targets hypoxia-inducible factor 1? (HIF-1?) for inhibiting HIF-1? expression. We hypothesize that miR-199a suppression and ?-catenin upregulation are important in Cr(VI)-induced tumorigenesis and angiogenesis through induction of IL- 8 and CXCL5 expression. Tumor cell growth and angiogenesis are the important characteristics of carcinogenesis, transformation from normal cells to cancer cells. In order to test this hypothesis, we will perform three specific aims:
Aim 1) To determine role of miR-199a suppression and ?-catenin upregulation in Cr(VI)-induced cell transformation, and identify the mechanism of IL-8 and CXCL5 elevation.
Aim 2) To determine roles of miR-199a, ?-catenin, IL-8, and CXCL5 in Cr(VI) transformed cell-induced tumor growth.
Aim 3) To determine whether Cr-T cells induce tumor angiogenesis through IL-8 receptors using chimeric tumor model and determine expression levels of IL-8, CXCL5, ?-catenin, and miR-199a in peripheral blood mononuclear cells (PBMCs) and plasma, and the possible correlations with Cr(VI) internal exposure doses in workers with occupational Cr(VI) exposure. We will use a combination of molecular approaches, a n animal model, and blood and tissue samples from human subjects to define roles and mechanisms of miR-199a, ?- catenin, IL-8, and CXCL5 in Cr(VI)-induced cell transformation, tumor growth, and angiogenesis. These studies will not only help us understand the underlying mechanisms of Cr(VI) in inducing carcinogenesis, but also identify potential new biomarkers for early detection of Cr(VI) exposure of workers in electroplating factories in the future.
Long-term human exposure to chromate compounds is known to induce lung cancer. This proposed study will identify new mecahism(s) of chromium in inducing tumorigenesis and angiogenesis. The results will be important to understand new mechanism of chromium for inducing carcinogenesis and for finding potential new biomarkers for detecting chromium exposure in the future.