Title page for etd-0823110-172725


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URN etd-0823110-172725
Author Chun-Wei Chuang
Author's Email Address No Public.
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Department Institute of Biomedical Sciences
Year 2009
Semester 2
Degree Master
Type of Document
Language zh-TW.Big5 Chinese
Title Study of the molecular mechanism by which COX-2 regulates CCR7 expression
Date of Defense 2010-07-29
Page Count 108
Keyword
  • Sp1
  • CCR7
  • AKT
  • COX-2
  • Abstract The metastatic spread of tumor cells is the major lethal aspect of cancer, and lymphatic metastasis is one of the most important routes. Recent studies indicated that cyclooxygenase-2 (COX-2) expression is frequently associated with lymph node metastasis and over-expression of COX-2 can enhance lymphatic invasion of cancer cells. The interaction of chemokines and their cognate receptors also plays a critical role in cancer metastasis. Previous results of our laboratory demonstrated that CCR7 is a downstream target for COX-2 and COX-2 up-regulated CCR7 expression via the EP2 and EP4 receptor. We also found that protein kinase A (PKA) and AKT kinase are involved in COX-2-induced CCR7. In this study, we provided further evidences that COX-2 directly stimulates CCR7 expression via promoter activation. Promoter deletion and mutation assay indicated that COX-2 stimulated CCR7 promoter via the Sp1 binding site located at the -61/-52 bp region upstream of the transcription start site. Increase of Sp1 binding to CCR7 promoter by COX-2 was confirmed by chromatin immunoprecipitation (ChIP) assay. Furthermore, knockdown of Sp1 expression resulted in inhibition of PGE2-induced CCR7, and over-expression of Sp1 potently up-regulated CCR7 in MCF-7 cells. In vitro kinase assay indicated that AKT could directly phosphorylate Sp1 at S42, T679 and S698 sites. And the phosphorylation of Sp1 by AKT led to enhanced protein stability and DNA binding affinity of Sp1. The results of immunohistochemistry indicated that CCR7 expression was significantly associated with Sp1 and phosphor-AKT. Taken together, COX-2 may act via the EP receptor/PKA/AKT/Sp1 signaling pathway to stimulate CCR7 expression in breast cancer cells to promote lymphatic spread.
    Advisory Committee
  • Long-Sen Chang - chair
  • Yow-Ling Shiue - co-chair
  • Wen-Chun Hung - advisor
  • Files
  • etd-0823110-172725.pdf
  • indicate in-campus access in a year and off_campus not accessible
    Date of Submission 2010-08-23

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