Anti-carcinogenic Activity--Nsaids Mediated By New Tgf-b

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。在我们首次尝试鉴定考克斯调控基因时，我们使用了基于PCR的方法。用NSAIDs治疗人结肠癌细胞以及乳腺癌和肺癌细胞引起新基因（NAG-1，“NSAIDs激活基因”）的上调，我们将其表征为TGF-β超家族基因的成员。该项目有三个主要目的：1）进一步表征NSAID对NAG-1的表达，并探索促炎剂的潜在下调，2）研究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考克斯抑制剂调控的基因，并发现了许多被诱导和抑制的基因。例如，考克斯抑制剂改变了ATF 3、TSP-1和层粘连蛋白的表达，并且这些蛋白质具有与NSAID的生物活性相关的生物活性。这些研究可能为NSAID的结肠癌减毒和抗炎活性提供新的见解和机制。

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 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. For example the expression ATF3, TSP-1 and laminin are altered by Cox inhibitor and these proteins have biological activities associated with the biological activity of NSAIDs. These studies may provide new insights and mechanisms for the attenuation of colon cancer and anti-inflammatory activity of NSAIDs.