Pan Mei-Ren, Chang Hui-Chiu, Chuang Lea-Yea, Hung Wen-Chun
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Exp Biol Med (Maywood). 2008 Apr;233(4):456-62. doi: 10.3181/0709-RM-257.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to exhibit potent anticancer effects in vitro and in vivo. One of the mechanisms by which NSAIDs suppress tumorigenesis is inhibition of angiogenesis and metastasis. In this study, we used a microarray system to study the change of expression profile of metastasis-related genes regulated by NS398, a NSAID and a cyclooxygenase-2 (COX-2) inhibitor. We found that several negative regulators of cell invasion, including secreted protein acidic and rich in cysteine (SPARC), thrombospondin 1 (TSP-1), thrombospondin 3 (TSP-3), and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) are upregulated by NS398. In addition, we demonstrated that upregulation of SPARC expression by NS398 in human lung cancer cells is mediated by promoter demethylation and associated with a decrease in DNA methyltransferase (DNMT) expression. This is the first report to show that NS398 can inhibit the expression of DNMT1 and 3b. Functional assay indicated that SPARC is a critical mediator for NS398 to inhibit cell invasion. Our results provide new insights for the understanding of the anticancer actions of NSAIDs.
非甾体抗炎药（NSAIDs）已被证明在体外和体内均具有强大的抗癌作用。NSAIDs抑制肿瘤发生的机制之一是抑制血管生成和转移。在本研究中，我们使用微阵列系统来研究NS398（一种NSAID和环氧化酶-2（COX-2）抑制剂）调节的转移相关基因表达谱的变化。我们发现，几种细胞侵袭的负调节因子，包括富含半胱氨酸的酸性分泌蛋白（SPARC）、血小板反应蛋白1（TSP-1）、血小板反应蛋白3（TSP-3）和基质金属蛋白酶-2组织抑制剂（TIMP-2），被NS398上调。此外，我们证明NS398在人肺癌细胞中上调SPARC表达是由启动子去甲基化介导的，并且与DNA甲基转移酶（DNMT）表达的降低有关。这是首次报道NS398可抑制DNMT1和3b的表达。功能分析表明，SPARC是NS398抑制细胞侵袭的关键介质。我们的结果为理解NSAIDs的抗癌作用提供了新的见解。
