Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of b-catenin, and enhanced tumor cell invasion

Commentator: 周 楠 樺 醫師              Time: PM 1:00- 2:00; 02/18/2004

Speaker: 張 心 玫                        Room: 601

Abstract:

Over-expression of EGF (epidermal growth factor) and its cognate receptor EGFR (epidermal growth factor receptor) has been shown to increase the metastasis, motility and invasion of a number of tumor cells¹.  Tumor metastasis is a complex process involving alternation in cell-extracellular matrix (ECM) and cell-cell junctions.  Down-regulation of an epithelial adherens junction protein, E-cadherin, also correlates with tumor development².  Whether there is a connection between EGFR and E-cadherin is currently not known, nor is the mechanism by which EGF affects the cell-cell junctions.  This paper demonstrated that EGF disrupted the cell-cell junctions and induced caveolin-dependent endocytosis of E-cadherin.  Prolonged treatment of EGF downregulats the expression of caveolin-1 and E-cadherin at transcription level.  Furthermore, EGF promotes the dissocation of b-catenin, another cell junction protein, from E-cadherin.  Subsequently, dissocated b-catenin translocated to the nucleus, and increased the TCF/LEF-1 transactivation through GSK-3b-independent pathway. Antisense RNA inhibition of caveolin-1in EGFR-overexpressing tumor cells recapitulates the above-mentioned EGF-induced effects and enhances tumor invasion.  Altogether, down-regulation of caveolin-1 represents a novel and important mechanism underlying the alternations of E-cadherin and b-catenin induced by EGF during tumor development³.

Reference:

1.       Price, J., Wilson, H., and Haites, N. 1996. Epidermal growth factor (EGF) increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A704.  Eur. J. Cancer. 32A: 1977–1982.

2.       Efstathiou, J., Liu, D., Wheeler, J., Kim, H., Beck, N., Ilyas, M. Karayiannakis, A., Mortensen, N., Kmiot, W., Playford, R. 1999. Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells. PNAS 96: 2316–2321.

3.       Zhimin Lu. Sourav G. Zhiyong W, and Tony H. 2003. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of b-catenin, and enhanced tumor cell invasion. Cancer cell. 4: 499-515