Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
Board

We have demonstrated that epidermal growth factor (EGF) in urine play a major role in bladder carcinogenesis by an animal model, the HTB system (Momose et al., 1991; Kawai et al., 1995; Fujimoto et al., 1996) as well as by an in vitro cell culture model (Kawamata et al., 1992, 1993, 1994). EGF is well known to be a potent mitogen, and activate the mitogen-activated protein (MAP) kinases in several cell types (Marshall, 1995). Recently, EGF is reported to activate the signal transducers and activators of transcription (STAT) proteins, and subsequently induce the expression of a cyclin-dependent kinase inhibitor, p21waf1 and inhibit the cell growth in several cancer cells (Chin et al., 1996; Jakus et al., 1996; Fan et al., 1995). On the other hand, several investigators examined the expression and distribution of EGF-receptor in normal and malignant urothelium by immuno-histochemical study (Messing et al., 1987, 1990). EGFR expression in normal bladder was found to be confined to the basal cell layer, whereas, bladder tumors expressed EGFR in all cell layers (Messing et al., 1987). Neal et al. (1985, 1990) and Berger et al. (1987) reported that the expression of EGFR was more abundant in malignant bladder tumor that in benign tumors, and the expression of EGFR was enhanced in high-grade and high-stage bladder tumors when compared to that in low-grade and low-stage tumors. However, at present, there is no detail report describing a functional implication of the EGF-EGFR signal transduction system with the growth of bladder cancer cells as well as bladder cancer progression.

In this study, we examined the response to exogenous EGF in human bladder cancer cell lines and immortalized human urothelial cells, and the activation of MAP kinase and STAT after EGF treatment in the bladder cells. Futhermore, we examined that whether the activated-STAT could bind to the sis-inducing element (SIE) in p21waf1 promoter, and whether EGF could directly induce the expression of p21waf1 mRNA in the bladder cells. Then we attempt to find the correlation between the mitogeneic effect and the level of activated MAP kinase and STAT-induced p21waf1 in human bladder cells after EGF treatment.

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