Phosphosulindac, miRNAs and cancer racial disparity

描述（由申请人提供）：流行病学数据表明，高加索人和非洲裔美国人（AA）之间结肠癌的发病率和死亡率不成比例。虽然社会经济和饮食差异导致了这种差异，但必须涉及其他潜在因素。例如，这两个群体对化学预防剂的反应是不同的。由于化学预防剂通过分子靶点发挥作用，这种差异表明遗传水平上的差异。因此，产生和评价化学预防剂，解决化学抗性的问题是至关重要的。磷酸-舒林酸（phospho-sulindac，P-S）是一种很有前途的结肠癌化学预防剂，其通过抑制细胞增殖和增强细胞杀伤而比舒林酸更有效地抑制结肠癌细胞生长。然而，对癌细胞中负责这种效应的分子靶点知之甚少。基于初步结果，我们的假设是AA和高加索人之间的miRNA表达/调节不同，这种差异可能至少部分解释了a）对化学预防的不同反应和B）结直肠癌的不同发病率。为了验证这些假设，我们提出了以下三个具体目标：1）研究P-S对源自高加索人和AA的人结肠癌细胞系中的p53、NF-κ B、2-catenin和细胞动力学的影响; 2）评估P-S对结肠癌p53缺失小鼠模型中的miRNA谱的影响;和，3）确定来自AA和高加索人患者的人结肠癌样品中的miRNA谱。这些发现的结果将导致对一个全球性问题的理解，并为开发跨越不同人群的化学预防剂提供详细信息。

DESCRIPTION (provided by applicant): 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.