421회 Roles of Ras and Matrix Metalloproteinases in Human Breast Cell I…

421회 (2008. 11. 20.)

연사: 문 애 리, 덕성여자대학교

제목: Roles of Ras and Matrix Metalloproteinases in Human Breast Cell Invasion

Abstract 

Human tumors frequently exhibit constitutively activated Ras signaling which contributes to the malignant phenotype.  To dissect distinct Ras isoform-specific functions in malignant phenotypic changes, H-Ras- and N-Ras-activated MCF10A human breast epithelial cell lines were established.  H-Ras, but not N-Ras, induces MCF10A cell invasion and migration, while both H-Ras and N-Ras induce cell proliferation and phenotypic transformation.  H-Ras-mediated MCF10A cell invasion involves activation of ERKs and p38 MAPK leading to increased expression of matrix metalloproteinase (MMP)-2 and -9.  Activating transcription factor (ATF)2 was a transcription factor responsible for p38 MAPK-upregulated MMP-2 gene expression through binding to the functional AP-1 site.  Activation of ATF2 was crucial for MMP-2 promoter activity as well as induction of invasive and migratory phenotypes in MCF10A cells, providing an evidence for a direct role of ATF2 activation in malignant phenotypic changes of human breast epithelial cells.  We investigated the gene expression profile specific to the biological processes of human breast epithelial cell invasion and migration using an MCF10A model in which the H-Ras or N-Ras signaling pathway is constitutively activated.  These cell lines provide an experimental system to separate the gene expression profile associated with cell invasion apart from cell proliferation/transformation.  Analysis of whole human genome microarray revealed that 412 genes were differentially expressed among MCF10A, N-Ras MCF10A and H- Ras MCF10A cells.  Two calcium-binding proteins, S100A8 (myeloid-related protein-8, MRP8, or calgranulin A) and S100A9 (MRP14 or calgranulin B), were prominently upregulated in an H-Ras-specific manner.  Importantly, siRNA-mediated knockdown of S100A8 or S100A9 expression significantly reduced H-Ras-mediated MCF10A cell invasion and migration.  Our gene profile data provide invaluable information which might be useful for identification of additional potential targets for prognosis and/or therapy of metastatic breast cancer.