MicroRNA and colorectal cancer chemoprevention

描述（由申请人提供）：根据美国癌症协会最新的癌症统计报告，结直肠癌仍然是美国癌症死亡的主要原因。因此，开发更安全、更有效的治疗和预防结直肠癌的药物仍然是一个未满足的需求。大量研究报道，非甾体抗炎药（NSAID）舒林酸对家族性腺瘤性息肉病患者的癌前腺瘤治疗非常有效，并在临床前动物模型中显示出良好的抗癌活性；然而，环氧化酶（COX）抑制的不良副作用限制了舒林酸用于化学预防的长期使用。我们前期的研究报道了两种非COX抑制衍生物sulindac sulfide amide （SSA）和sulindac benzylamine （SBA）与sulindac sulfide （SS）相比，具有更好的抑制结直肠肿瘤细胞生长的效力和疗效。这些结果表明，舒林酸的抗癌活性可能归因于不同于COX抑制的其他潜在机制。在本应用中，我们将针对其抗癌活性

DESCRIPTION (provided by applicant): According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains a leading cause of death from cancer in the United States. Therefore, there is still an unmet need to develop safer and more efficacious agents for treatment and prevention of colorectal cancer. Numerous studies report that the nonsteroidal anti-inflammatory drug (NSAID), sulindac is highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and shows promising anticancer activity in preclinical animal models; however, the adverse side effects resulting from cyclooxygenase (COX) inhibition limit the long-term use of sulindac for chemoprevention. Our previous studies reported that two non- COX inhibitory derivatives, sulindac sulfide amide (SSA) and sulindac benzylamine (SBA), can inhibit colorectal tumor cell growth with better potency and improved efficacy when compared to sulindac sulfide (SS).These results imply that anticancer activity of sulindac might attribute to other underlying mechanisms distinct from COX inhibition. In this application, we will aim at anticancer activity of SSA and SBA in prevention of colorectal tumor progression and metastasis, and focus on mechanism of action. Our recent results show that SS at sub-cytotoxic concentrations can efficiently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism of action appears to involve microRNAs (miRNAs), which are a set of small non-coding RNA molecules acting as master regulators of gene expression. A tumor suppressor miRNA, miR-200, was found to be up-regulated by SS and its non-COX inhibitory derivatives through the signaling pathway mediated by the transcriptional repressor snail. Given the documented tumor suppressive roles in promotion of apoptosis and inhibition of metastasis, we hypothesize that miR-200 is a key factor to mediate the non-COX anticancer activity of SSA and SBA for prevention of colorectal cancer. Three specific aims are proposed to address this hypothesis are: (1) to study the mechanistic basis of miR-200 in mediation of anticancer activities of SSA and SBA in vitro; (2) to study the role of miR-200 in mediating anticancer activities of sulindac in vivo; (3) to assess the clinical relevance of snail/miR-200/E-cadherin to human colorectal cancer progression. This application is being submitted in response to PA-12-213 and will address two research objectives: "determine the molecular pathways targeted by non-coding RNAs (ncRNAs) that predispose to cancer initiation or progression" and "determine whether interfering with oncogenic ncRNAs processing, target selection, or associated pathways prevent cancer progression". The proposed studies have the potential to impact human health by: 1) providing a mechanistic rationale in support of an ongoing national clinical trial studying prevention of colorectal cancer metastasis by sulindac; 2) evaluating novel non-COX inhibitory directives of sulindac to accelerate their preclinical development; and 3) identifying new therapeutic targets and/or biomarkers for clinical trials.