engleski

Expression of urokinase plasminogen activator during epithelial-mesenchimal transition

In normal epithelium E-cadherin mediated cell-cell adhesion connect epithelial cells, gives them typical epithelial organisation and limit the ability of epithelial cells to migrate. The down regulation of E-cadherin gene expression has been observed in many carcinomas during their progression leading to dedifferentiated mesenchymal phenotype (epithelial mesenchymal transition, EMT), and increased migratory behaviour. Changes in cell morphology during EMT are necessarily associated with the cytoskeletal reorganisation which, in turn induce expression of the various genes, among them urokinase plasminogen activator (uPA). uPA is a serine protease, which promotes the formation of plasmin from plasminogen, the key protease in fibrinolysis and degradation of extracellular matrix, a key step in invasion and metastasis of tumor cells. Aim of this study was to investigate the level of uPA gene expression and to elucidate the mechanism of uPA gene regulation during epithelial mesenchymal transition. We have shown that uPA expression correlates with the loss of E-cadherin expression, cytoskeletal rearrangement, fibroblastic phenotype, and expression of other mesenchymal markers such as N-cadherin and isoform of catenin p120 of 120 kDa. uPA gene transcription was up to 20 fold higher in fibroblastic cell lines (SW800 and J82), with regard to epithelial cell lines (RT112, SCaBER, 575A). ERK1, 2 MAP kinase activity was crucial for uPA activity and expression in human bladder carcinoma cells. PD 98059, an ERK1, 2 MAP kinase inhibitor, decreased uPA expression in all cell lines tested, regardless of their morphology. Curcumin, an JNK MAP kinase inhibitor, decreased uPA activity, not affecting its expression. In fibroblastic cell lines SW800 and J82, we detected eight fold higher activity of c-Jun transcription factor, implicating higher JNK activity. In conclusion, during epithelial mesenchymal transition of human bladder carcinoma cells, uPA expression correlates with E-cadherin function. Activity of ERK MAP kinases is essential for uPA expression.

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