Functional roles of COX-2 induced CCR7 and other metastasis-related genes in cancer progression and suppression by anti-cancer drugs

• Main Authors: Mei-Ren Pan, 潘美仁
• Other Authors: Wen-Chun Hung
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/96688852419262678011

博士 === 高雄醫學大學 === 醫學研究所 === 96 === My thesis focuses on cyclooxygenase-2 (COX-2) - mediated tumor metastasis and anti-metastatic mechanism of non-steroidal anti-inflammatory drugs (NSAIDs). It is divided into two major parts. In part I, I aimed to study the mechanism by which COX-2 enhances lymphangiogenesis and lymph node metastasis. I provided evidences that CCR7 is a downstream target for COX-2 to enhance the migration of breast cancer cells toward lymphatic endothelial cells (LECs) and to promote lymphatic invasion. I also studied the effect of a bioactive withanolide Tubocapsanolide A (Tubo A) isolated from Tubocapsium anomalum on CCR7 expression and lymphatic invasion of breast cancer cells. I concluded that Tubo A inhibited CCR7 expression in breast cancers by down-regulating IKK and MSK1 signaling to repress NF-κB-mediated CCR7 gene expression. In part Π, by using microarray system, I identified several metastasis–associated genes which are regulated by NSAIDs. In previous study, I found NSAIDs inhibited cancer cell invasion via negative regulation of the expression and activity of MMP-2. In the work, I found that several negative regulators of cell invasion including secreted protein acidic and rich in cycteine (SPARC), thrombospondin 1 (TSP1), thrombospondin 3 (TSP3) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) were up-regulated by NS398. We focus on the study of TSP 1 and SPARC. Both of them belong to tumor suppressors in many cancer cell types. I used specific anti-body to block the activity of these two proteins, and found that the invasion ability was increased. I confirmed that they played critical roles in the inhibition of the A549 lung cancer cells by NSAIDs. I also found they were up-regulated by NSAIDs via different molecular mechanisms. I demonstrated NSAIDs increased SPARC exprsssion via regulation of promoter demethylation and induced TSP 1 expression via elevation of transcription and RNA stability. In this study, I not only elucidates how COX-2 to enhance the lymphatic ability of tumor cell, but also identifies more novel genes regulated by NSAIDs. Moreover, I identifies another novel anti-cancer drug to decrease the migration of breast cancer cells toward LECs via inhibition of expression of CCR7.