Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability (Nature, 2005, 436:123-127)

報告日期: 2006/04/14
報告時間: 16:00/16:50
報告學生: 李美逸
講評老師: 黃溫雅


Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability

Derek C. Radisky et al. Nature 436(7), 123-127 (2005)


Speaker: Mei-Yi Lee              Time: 4/14/2006 16:00-17:00

Commentator: Wen-Ya Huang                Place: Room 602



        MMP-3/stromelysin, which is a stromal enzyme upregulated in many types of breast tumors, induces transformation in normal mammary epithelial cells and mammary carcinoma in transgenic mice. MMP-3 can induce epithelial-mesenchymal transition (EMT) in culture and in vivo. Targeted expression of MMP-3 in the mammary glands of transgenic mice also induces genomic changes. It is still unclear about the mechanism how MMP-3 induces the phenotypic and genotypic changes of normal mammary epithelial cells. Here, the authors delineate the molecular pathways under MMP-3-induced EMT and genomic instability. The process of EMT requires changes in the actin cytoskeleton. The activities of RhoA and Cdc42 were not affected when SCp2 cells were treated with MMP-3. The authors found that Rac1b, an alternatively spliced isoform of Rac1, was upregulated and necessary for MMP-3-induced motility. MMP-3 or Rac1b activates the mitochondrial production of reactive oxygen species (ROS), which subsequently stimulate the expression of Snail1, a transcription repressor of E-cadherin, and lead to EMT. Besides, MMP-3-induced ROS production also causes cellular damage and genomic instability. This paper provides an important notion that how the microenvironmental enzyme can not only directly impair the genetic integrity of normal cells and drive the onset of cancer, but also foster the tumor progression toward malignancy.



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