Expression of urokinase plasminogen activator and receptor in conjunction with the ets family and AP-1 complex transcription factors in high grade prostate cancers

Abstract

Expression of the urokinase plasminogen activator (uPA) and its receptor (uPAR) correlates with tumour cell invasiveness and helps to determine the prognosis of prostate and other cancers. The purpose of this study was to establish in prostate cancer, the ets family and AP-1 complex transcription factors that might activate the inducible AP-1 and AP-1/PEA3 elements of the uPA enhancer. uPA and uPAR were expressed preferentially in adenocarcinoma cells, but not the stroma of high grade prostate cancers. The ets family paralogues Fli-1 and Elf-1 were also highly expressed in adenocarcinoma cells of the majority of cancers, while Erg 1,2 and Ets-2 were expressed in a minority of cancers and Elk-1, PEA3 and PU.1 were minimally expressed. A minority of cancers expressed high levels of cytoplasmic and/or nuclear c-Jun and c-Fos transcription factors. We speculate as to the molecular basis for such expression.

Introduction

The expression of the urokinase plasminogen activator (uPA) and its receptor (uPAR) are prognostic indicators for the clinical outcome of many cancers 1, 2, including adenocarcinoma of the prostate [3]. uPA activates numerous matrix metalloproteinases and concomitantly promotes proteolysis of the extracellular matrix, tumour cell migration, intra- and extravasation, and also activation of mitogens and effectors of angiogenesis and of the osteoblastic reaction important for bone metastases 2, 4, 5. Tumour cell invasiveness and metastatic capacity are highly correlated with the expression of uPA and uPAR and are blocked by their inhibitors.

Expression of uPA is controlled by an inducible enhancer region bound by AP-1 complex proteins (Jun, Fos and activating transcription factor (ATF) family members and partners), ets family proteins, homeodomain proteins, the nuclear factor (NF)κB transcription factor [6]; also, the turnover of uPA mRNA is regulated [7]. The levels and activities of these transcription factors and the proteins determining uPA mRNA stability are modulated by, among others, the mitogen- and stress-activated protein kinase pathways [8]. In particular, prostate cancer progression correlates with activation of the mitogen-activated protein kinase (MAPK) pathway [9].

While AP-1 complex and NFκB proteins are expressed in many tissues, ets family proteins can be specific to particular types of tissues and cells and to cancers derived from them [10]. The over two dozen paralogous members of this ancient family of transcription factors can be organised into five subfamilies and 13 groups, based upon sequence conservation of their DNA binding domains [11]. Activation of the uPA enhancer also requires homeodomain proteins [12], which like ets proteins, can be specific to the development and maintenance of epithelial cells and the cancers derived from them. As the requirement for such tissue-specific proteins for expression of uPA may provide targets to selectively block tumour cell invasion, we seek to identify those particular ets family, AP-1 complex and homeodomain proteins that are highly expressed in prostate cancer, and then plan to analyse whether they are involved in uPA expression.