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 chemo-resistance is essential. A promising colon cancer chemopreventive agent, phospho-sulindac (P-S), inhibits colon cancer cell growth more potently than sulindac 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. Our hypothesis, based on preliminary results, is that miRNA expression/regulation differs between AA and Caucasians and this difference may account, at least in part, a) for the differential response to chemoprevention and b) for the differential incidence of colorectal cancer. To test these hypotheses, we propose the following three specific aims: 1) To study the effect of P-S on p53, NF-kB, 2-catenin, and cell kinetics in human colon cancer cell lines originating from Caucasians and AA;2) To assess the effect of P- S on the miRNA profile in a p53 null murine model of colon cancer;and, 3) Determine the miRNA profile in human colon cancer samples from AA and Caucasian patients. The results from these findings will lead to the understanding of a worldwide issue and provide details for the development of chemopreventive agents that will span diverse populations.
We will define the mechanisms by which P-S exert its inhibitory effect on the growth of colon cancer cells and address racial disparities as a result of genetic mutations. We will evaluate in cell culture, using cell lines derived from Caucasians and AA colon cancer tissues, changes (by microarray analysis) in the expression of transcription factors and miRNAs. In addition, we will test whether our in vitro findings are relevant to a preclinical model of colon cancer. This study will evaluate directly in a p53 null and C57BL/6 (parent background) mice model the effect of P-S on the expressions of transcription factors and miRNAs. Thereby, we will test the key mechanistic findings from the in vitro study. Lastly, we will compare and contrast prospective and retrospective colon cancer tissue of Caucasians and AA at the protein, RNA, and DNA levels. Being able to demonstrate that P-S induces a potentially important molecular change in the malignant colonocytes that may be relevant to its pharmacological actions in cancer would indicate an important breakthrough in the prevention of colon cancer. Also, being able to attribute a genetic causative effect to resistance to chemotherapeutic agents will address the issue of racial disparity.
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