MicroRNA, sulindac, and breast cancer chemoprevention

描述（申请人提供）：流行病学、临床和临床前研究表明，非甾体抗炎药（NSAID）具有显著的癌症化学预防活性。然而，与环氧合酶（考克斯）抑制和生理学上重要的甘草素的抑制相关的毒性限制了人类常规使用NSAID用于癌症化学预防。先前的研究已经证明，NSAID的抗肿瘤活性可以归因于诱导细胞凋亡的COX非依赖性机制。因此，有强有力的证据支持开发具有更安全和更有效的癌症化学预防潜力的新药。最近的初步观察促使我们假设特定的microRNAs（miRNAs）可以介导NSAID舒林酸硫化物（SS）的癌症化学预防活性。miRNA是一种小的非编码RNA分子，通过抑制其同源靶基因的翻译，在控制细胞生长、分化、凋亡和肿瘤发生中发挥重要作用。我们的初步结果表明，当使用2倍截止值时，SS治疗人乳腺癌细胞上调了58个miRNA，下调了59个miRNA。一种名为miR-200 b的miRNA在SS和一种活性更高的非COX抑制性SS衍生物舒林酸硫酰胺（SSA）治疗后表现出明显的诱导作用，我们最近发现SSA可抑制DMBA大鼠模型中的乳腺肿瘤发生。MiR-200 b可以降低cGMP特异性磷酸二酯酶PDE 5的表达，该磷酸二酯酶PDE 5先前已被报道在肿瘤细胞中过表达，并与SS的凋亡诱导活性密切相关。这些结果表明，miR-200 b参与介导舒林酸的癌症化学预防活性的关键分子事件。此外，我们发现miRNAs可以通过NF-：B转录调节机制介导SS对乳腺癌细胞侵袭的抑制。解决该假设的具体目的如下：1）确定miR-200 B是否通过抑制PDE 5介导乳腺肿瘤细胞对SS和SSA的敏感性，和2）确定SS和SSA对肿瘤细胞侵袭的抑制作用是否由miRNA和NF-：B抑制介导。预计拟议的研究将为特定的miRNAs如何介导舒林酸的乳腺癌化学预防活性提供有价值的见解，这些研究将探索涉及抑制肿瘤细胞侵袭的新活性。

DESCRIPTION (provided by applicant): Epidemiological, clinical and preclinical studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) possess striking cancer chemopreventive activities. However, toxicities related to cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limit the regular use of NSAIDs by humans for cancer chemoprevention. Previous studies have demonstrated that the antineoplastic activities of NSAIDs can be attributed to a COX-independent mechanism that induces apoptosis. Thus, there is strong evidence to support the development of new drugs that have the potential to be safer and more efficacious for cancer chemoprevention. Recent preliminary observations have prompted us to hypothesize that specific microRNAs (miRNAs) can mediate the cancer chemopreventive activity of the NSAID sulindac sulfide (SS). MiRNAs are small, non-coding RNA molecules that play important roles in controlling cell growth, differentiation, apoptosis, and tumorigenesis through the translational repression of their cognate target genes. Our pilot results showed that SS treatment of human breast cancer cells up-regulated 58 and down-regulated 59 miRNAs when a 2-fold cutoff was used. One miRNA, termed miR-200b, exhibited a pronounced induction in response to treatment with SS and a more active, non-COX-inhibitory SS derivative, sulindac sulfide amide (SSA), which we recently found to inhibit mammary tumorigenesis in the DMBA rat model. MiR-200b can reduce the expression of the cGMP-specific phosphodiesterase PDE5, which has been previously reported to be overexpressed in tumor cells and closely associated with the apoptosis-inducing activity of SS. These results suggest that miR-200b is involved in a key molecular event that mediates the cancer chemopreventive activity of sulindac. Moreover, we found that miRNAs could mediate the suppression of breast cancer cell invasion by SS through a mechanism involving NF-:B transcriptional regulation. The specific aims to address this hypothesis are as follows: 1) determine if miR-200b mediates the sensitivity of breast tumor cells to SS and SSA by suppressing PDE5 and 2) determine if the inhibitory effects of SS and SSA on tumor cell invasion are mediated by miRNA and NF-:B inhibition. The proposed studies are anticipated to provide valuable insights into how specific miRNAs mediate the breast cancer chemopreventive activity of sulindac, and these studies will explore new activities involving the suppression of tumor cell invasion.