Mediation of Anti-carcinogenic Activity Of NSAIDS

非甾体抗炎药（NSAIDs）用于治疗炎症性疾病。最近，有报道称非甾体抗炎药对人类结直肠癌的发展具有化学预防作用。非甾体抗炎药可以抑制COX-1和/或COX-2活性，从而抑制前列腺素的合成。然而，一些报道表明，对结肠癌的化学预防作用可能部分独立于前列腺素抑制，可能依赖于基因表达。我们的目标是鉴定和表征受Cox抑制剂（包括选择性Cox抑制剂）调控的基因。在我们第一次尝试鉴定Cox调节基因时，我们使用了基于PCR的方法。用非甾体抗炎药治疗人类结肠癌细胞以及乳腺癌和肺癌细胞导致新基因(NAG-1, ？非甾体抗炎药激活基因？)，我们已经确定为TGF-b超家族基因的成员。该项目有三个主要目标；1)进一步表征nsaid对NAG-1的表达，并探讨促炎药对NAG-1的下调作用；2)研究NAG-1基因启动子中的交易元件；3)通过细胞培养和动物模型，确定NAG-1蛋白在细胞凋亡和炎症中的生物学功能。此外，我们还利用微阵列技术鉴定了受Cox抑制剂调控的基因，并发现了一些被诱导和抑制的基因。这些研究可能为非甾体抗炎药抑制结肠癌和抗炎活性提供新的见解和机制。

Non-steroidal anti-inflammatory drugs (NSAIDs) are used for the treatment of inflammatory diseases. Recently, NSAIDs have been reported to have chemopreventive effects 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. In our first attempt to identify Cox regulated genes we used a PCR based method. Treatment of human colon cancer cells as well as breast and lung cancer cells with NSAIDs caused the up-regulation of novel gene (NAG-1, ?NSAIDs activated gene?) that we have characterized as member of the TGF-b superfamily gene. The project has with three primary 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, and 3) to identify of biological function(s) of NAG-1 protein in apoptosis and inflammation using cell culture and animal models. In addition, we have also used Microarray technology to identify genes regulated by Cox inhibitors and have found a number of genes that are induced and suppressed. These studies may provide new insights and mechanisms for the attenuation of colon cancer and anti-inflammatory activity of NSAIDs.