Abstract A54: miRNA profiling: prognostic markers in chemoprevention

Abstract

Abstract Epidemiological data has demonstrated that colon cancer is disproportional in incidence and mortality between Caucasians and African Americans (AA). Whereas socioeconomic and dietary differences contribute to this disparity other underlying factors must be involved. For instance, the response to chemopreventive agents is different between these two populations. Since chemopreventive agents exert their effect through a molecular target, this disparity would suggest differences at the genetic level. Therefore, the generation and evaluation of chemopreventive agents that address the issue of chemoresistance is essential. As such, we have demonstrated that promising colon cancer chemopreventive agents, derivatives of nonsteroidal anti-inflammatory drugs (NSAIDs), inhibits colon cancer cell growth by inhibiting cell proliferation and enhancing cell killing. However, very little is known about the molecular targets in the cancer cell that are responsible for this effect. microRNAs (miRNAs), small (17-22 nt) regulatory RNAs, are known to control gene expression and translational repression or degradation, via specific sites at the 3’-UTR of its target mRNAs. The deletion or mutation of one particular miRNA could potentially lead to the progression of disease; specifically, cancer. Therefore, using total RNA isolated from tumors of xenographic mouse and colorectal cancer cells treated with NSAID derivatives, miRNA distribution patterns were determined. Protein lysates of the tumors and tissue culture cells were also examined for levels of transcriptional activating factors (i.e., NF-kB and p53). We demonstrate that derivatives of NSAIDs altered the synthesis or activity of multiple miRNA and transcriptional DNA-binding factors In vivo and In vitro. Of interest, our chemopreventive agents induced expression Levels of, among others, the tumor suppressor Let-7 miRNA family. In addition, this increase was directly related to the presence of a functional p53 gene product. Thus, a correlation of altered level of miRNA and the expression and/or activation of its target genes may assist us with ascertaining the association of miRNAs with poor clinical outcome. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A54.