| Summary: | 碩士 === 國立暨南國際大學 === 生物醫學科技研究所 === 98 === TGF-β1 is a potent inducer of epithelial-mesenchymal transition（EMT）which plays an important role in lung cancer metastasis. During metastatic process, lung cancer cells within the primary tumor employ EMT to gain migratory and invasive properties. EMT is characterized by cytoskeletal reorganization, loss of cell adhesion, increased cell mobility and especially repression of E-cadherin expression which localizes in the epithelial cell-cell junctions. Luteolin is a natural flavonoid which possesses a variety of pharmacological activities, including anti-inflammatory and anti-cancer. Our previous study shows that luteolin can suppress TGF-β1-mediated lung fibroblast migration and repressed mesenchymal cell morphology. To examine whether lutoelin might suppressed cancer cell invasion and EMT events induced by TGF-β1, human lung adenocarcinoma A549 cell line was used. Our results showed that luteolin significantly attenuated TGF-β1-induced A549 cell migration/invasion. This event was accompanied by modulation of E-cadherin expression. Pretreatment with luteolin effectively reversed TGF-β1-mediated E-cadherin gene downregulation. In addition, incubation of A549 cells with TGF-β1 resulted in activation of phosphatidylinositol 3-kinase（PI3K）and Akt as evidenced by increased PI3K（p85）, Akt-Ser473 and mTOR phosphorylation, this event was significantly inhibited by luteolin. Moreover, luteolin blocked TGF-β1-mediated IκB degradation and NFκB p65 translocation. Furthermore, luteolin decreased TGF-β1-induced Snail upregulation which was thought to negatively regulate the expression of E-cadherin. Interestingly, TGF-β1-stimulated E-cadherin downregulation and Snail upregulation were blocked with inhibitors of PI3K/Akt and NFκB. The data implied that the activation of PI3K/Akt and NFκB pathway was necessary for TGF-β1-stimulated downregulation of E-cadherin and upregulation of Snail, which in turn was necessary for TGF-β1-induced EMT. Overall, our findings indicate that TGF-β1 may activate NFκB by Akt that upregulates Snail expression and downregulates E-cadherin expression, and consequently induced EMT. However, luteolin can reverse TGF-β1-stimulated E-cadherin downregulation through repression of Snail by PI3K/Akt－NFκB signaling pathway.
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