BACKGROUND: Stromal-epithelial interactions play a critical role in development of benign prostatic hyperplasia (BPH). We have previously shown that stromal cells associated with prostatic carcinoma can potentiate proliferation and reduce cell death of prostatic epithelial cells. Here we examine the effect of expression of a specific stromally expressed gene, c-Jun, on prostate epithelial proliferation.
METHODS: Microarray analysis of BPH stromal and epithelial cells revealed seven-fold increased expression of the Jun-family of genes in the stroma. Histologic analysis of 15 BPH samples revealed increased immunoreactivity of c-Jun protein in the stromal compartment as compared to the epithelial cells. To test whether stromal expression of c-Jun can affect prostate epithelial proliferation, c-jun +/+ and c-jun -/- fibroblasts were co-cultured with prostate epithelial cells, BPH-1. Cells were assayed for proliferation and expression of proteins using Western Blot and ELISA assays.
RESULTS: c-jun+/+ fibroblasts secret higher level of IGF-1 and stimulate BPH-1 cellular proliferation. In addition, stromally secreted IGF-1 up-regulates epithelial MAP kinase, Akt and cyclinD protein levels, while down-regulating CDK inhibitor p27 protein levels.
CONCLUSIONS: These data suggest that stromally expressed c-Jun promotes prostatic epithelial proliferation through IGF-1 as a paracrine signal which in turn can promote prostate epithelial proliferation. Identification of the signal transduction pathways between prostate epithelial cells and the surrounding stromal cells will improve our understanding of the normal and abnormal biology in prostatic diseases.