Role of Matrix Metalloproteinase-9 and Urokinase Plasminogen Activator in Both Models of Intact Amniotic Membrane-Expanded Limbal Epithelial Cells and Lung Cancer
| Autor: | Ching Yi Cheng, 鄭靜宜 |
|---|---|
| Rok vydání: | 2009 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 97 Matrix metalloproteases (MMPs)-mediated extracellular matrix (ECM) degradation potentially releases cryptic motility factors involved in somatic SC migration and epithelial outgrowth. We have previously demonstrated that MMP-9 plays an important role in LECs cultivated on AM. Here, we further investigated that MMP-9 activity was up-regulated by PA/plasmin which processed Ln5 r2-chain to facilitate limbal outgrowth on intact AM. Furthermore, the mechanisms underlying cell-ECM interaction-induced MMP-9 expression and cell outgrowth were investigated. The results suggested that both MAPKs and PI3-K/Akt are required for limbal epithelial outgrowth on intact AM, only the PI3-K/Akt/JNK is essential for MMP-9 expression mediated through activation of NF-κB in this model. In addition, we established the roles of uPAR/EGFR/β1 or β4 integrin clustering-related FAK, Src and Ca2+-dependent PKC activation signals are involved in the outgrowth of intact AM-expanded LECs. Taken together, this study, at least in part, disclosed the signaling pathways underlying ex vivo expansion of human limbal explants cultivated on intact AM. ECM breakdown is accomplished by the concerted action of several proteases, including the uPA-system and MMPs, which is crucial for cancer invasion and metastasis. Several reports have shown that the levels of IL-1β, PA/plasmin system and MMP-9 in plasma of the patients with lung cancer are significantly elevated and link to the invasion of tumor cells. Therefore, we investigated whether IL-1β-induced expression of uPA and MMP-9 participated in lung cancer progression. In this part of thesis, IL-1β significantly induced uPA expression association with tumor cell migration via PKCα-dependent JNK1/2 and NIK cascades, linking to IκB kinase (IKK)α/β activation, p65 translocation and transcription activity. In addition to uPA, IL-1β-induced MMP-9 expression has been shown to be regulated by MAPKs, NF-κB and AP-1 in previous study. In addition to these pathways, transactivation of non-receptor tyrosine kinases (Src), EGF receptor (EGFR), PDGF Receptor (PDGFR), and phosphatidylinositol 3-kinase (PI3K)/Akt has been shown to be implicated in the expression of inflammatory proteins associated with cell migration. Here, we investigated whether these different mechanisms participating in IL-1β-induced MMP-9 expression in lung A549 cells. The results suggested that in A549 cells, Akt phosphorylation-mediated through transactivation of Src-dependent EGFR/PDGFR promotes the transcriptional NF-kB activity and leads to MMP-9 expression associated with cell migration induced by IL-1β. Increased understanding of signal transduction mechanisms underlying regulation of uPA and MMP-9 expression will create opportunities for the development of therapeutic interventions against progression of lung cancer. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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