Anticarcinogenic Activity Of NSAID Mediated By TGFB GENE

TGFB基因介导的NSAID的抗癌活性

• 批准号: 6501215
• 负责人: Thomas Eling
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6501215
• 关键词: antineoplastics; apoptosis; cell line; chemoprevention; colorectal neoplasms; drug screening /evaluation; enzyme activity; enzyme inhibitors; gene expression; genetic promoter element; microarray technology; nonsteroidal antiinflammatory agent; peroxisome proliferator activated receptor; polymerase chain reaction; prostaglandin endoperoxide synthase; tissue /cell culture; transforming growth factors

Non-steroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of inflammatory diseases. Recently, NSAIDs have been reported to have a chemopreventive effect on the development of human colorectal cancer. NSAIDs can inhibit COX-1 and/or COX-2 activity and thus inhibit prostaglandin synthesis. However, some reports indicate that the chemopreventive effect on colon cancer may, in part, be independent of prostaglandin inhibition could dependent on gene expression. Our goal is to identify and characterize genes that are regulated by Cox inhibitors including selective Cox inhibitors. Our first attempt to identify Cox regulated genes we used a PCR base method. Treatment of human colon cancer cells as well as breast and lung cancer cells causes the up-regulation of novel gene (NAG-1, "NSAIDs activated gene") which we have characterized as member of the TGF-b superfamily gene. The project will be performed with three main aims; 1) to further characterize the expression of NAG-1 by NSAIDs and to explore the potential down regulation by pro-inflammatory agents, 2) to investigate the transacting elements in the NAG-1 gene promoter, 3) to identify of biological function(s) of NAG-1 protein in apoptosis and inflammation using cell culture and animal models. We have also use Micro-Array technology to identify gene induced by selective Cox inhibitors and have found a number of genes induced and suppressed by Cox inhibitor. The study may provide new insights and mechanisms for the attenuation of colon cancer and anti-inflammatory activity of NSAIDs.

非甾体抗炎药（NSAID）用于治疗炎症性疾病。最近，NSAIDs已被报道对人类结直肠癌的发展具有化学预防作用。NSAID可抑制考克斯-1和/或考克斯-2活性，从而抑制前列腺素合成。然而，一些报告表明，对结肠癌的化学预防作用可能部分不依赖于前列腺素抑制，可能依赖于基因表达。我们的目标是鉴定和表征受包括选择性考克斯抑制剂在内的考克斯抑制剂调控的基因。我们第一次尝试鉴定考克斯调控基因，我们使用PCR基础方法。人结肠癌细胞以及乳腺癌和肺癌细胞的治疗引起新基因（NAG-1，“NSAID激活基因”）的上调，我们将其表征为TGF-β超家族基因的成员。该项目将进行三个主要目的：1）进一步表征NAG-1通过NSAID的表达，并探索潜在的下调促炎剂，2）调查NAG-1基因启动子中的反式作用元件，3）使用细胞培养和动物模型鉴定NAG-1蛋白在细胞凋亡和炎症中的生物学功能。我们还利用基因芯片技术对选择性考克斯抑制剂诱导表达的基因进行了鉴定，发现了一系列被考克斯抑制剂诱导和抑制的基因。该研究可能为NSAID的结肠癌减毒和抗炎活性提供新的见解和机制。