Background. Dysregulation of STAT factors along with the negative feedback regulators of the Janus-activated kinase (JAK)-STAT pathway, such as members of the SOCS family have been implicated in prostate cancer (PCa) cell growth and survival. Although STAT3 involvement in PCa has been extensively studied, little is known about the role of STAT1. In this study, we aim to determine the clinical significance and functional role of STAT1 expression in PCa.

Material and Methods. STAT1 cytoplasmic, nuclear and membrane expression in PCa epithelial cells, was measured by immunohistochemistry (IHC) on 78 patients with hormone naïve prostate adenocarcinoma recruited at a referral centre between 1992 -2002. Biochemical relapse, survival from biochemical relapse and disease-specific survival according to high/low protein expression were analysed using Kaplan-Meier methods. Significant findings were included in a cox-regression model. Chi square test was used to assess associations with clinical parameters and Pearson's rank correlation coefficients (c.c) to assess association between protein expression. In in vitro studies we assessed the role of STAT1 in PCa epithelial cell (LNCaP and PC3) proliferation by wst-1 incorporation and real time tracking of growth of cells using XCELLigence (Roche, UK), apoptosis by DNA fragmentation and clonogenic capacity following transient silencing of STAT1 with siRNA (SmartPool, Dharmacon, UK).

Results. At diagnosis PCa patients with low membrane expression of STAT1 had significantly shorter time to biochemical relapse (3.8 vs 7.3 years, p=0.021) and overall survival (6.62 vs 9.34 years, p=0.056). To test whether these results stemmed from the functional role of STAT1 in regulating the proliferation of prostate epithelial cells, we silenced STAT1 in PCa cell lines. STAT1 silencing resulted in a moderate increase in LNCaP cells (72h, control: 100 ± 18 %; siRNA STAT1 treated: 114 ± 4.5 %, n=3), however a very pronounced increase was observed in the proliferation of PC3 cells (72h, control: 100 ± 12.1 %; siRNA STAT1 treated: 177.4 ± 38 %, n=4, p<0.001). These results were in accordance with data collected from XCELLigence showing increased PC3 cell numbers in STAT1 silenced cells over 10 days. In clonogenic assay an increased surviving fraction of cells was recorded after 10 days of silecing the cells with STAT1 compared to control. Furthermore, there was no significant change in apoptosis recorded in siRNA STAT1 treated cells.

Conclusion. Our results enable us to conclude that loss of STAT1 favors tumor formation in hormone naive PCa cells by leading to increased proliferation of PCa cells. We are currently investigating downstream transcription factors that STAT1 might employ in order to control the proliferation of PCa cells.

Citation Format: Sophia Hatziieremia, Pamela McCall, Jennifer Willder, Clare Orange, Morag Seywright, Mark A. Underwood, Joanne Edwards. Loss of STAT1 predicts outcome in prostate cancer patients at diagnosis by regulating the proliferation of prostate epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1. doi:10.1158/1538-7445.AM2013-1