Marra et al. BMC Cancer 2010, 10:129 http://www.biomedcentral.com/1471-2407/10/129 R E S E A R C H A R T I C L E Open Access Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways Emanuele Marra1, Paolo Uva1, Valentina Viti1, Valeria Simonelli3, Eugenia Dogliotti3, Emanuele De Rinaldis4, Armin Lahm1, Nicola La Monica1, Alfredo Nicosia2, Gennaro Ciliberto1, Fabio Palombo1* Abstract Background: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. Methods: A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Results: Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNa/b receptor. Conclusions: These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response. Background PSCA has been discovered a decade ago and has been classified as a member of the Ly-6 family of GPI- anchored cell surface proteins [1]. It is expressed in most prostate cancer specimens, including high-grade prostatic intraepithelial neoplasia, primary androgen- dependent tumors, and hormone-refractory metastases. PSCA levels are positively correlated with Gleason grade, tumor stage, and biochemical recurrence. Its expression is also particularly elevated in bone metasta- sis. Finally, PSCA is strongly expressed in other malig- nancies, including bladder and pancreatic cancers [2-6]. * Correspondence: fabiopalombo@libero.it 1Istituto di Ricerche Biologia Molecolare P. Angeletti (IRBM), Via Pontina Km 30,600 00040 Pomezia (Rome) Italy Different immunotherapy approaches targeting PSCA have been tested in preclinical models including cancer vaccine, therapeutic monoclonal antibodies and antibody conjugated to toxic drugs [7-10]. More recently, a human monoclonal antibody targeting PSCA has been evaluated in a phase I clinical trial in prostate cancer patients (AACR 2006). Little information is available regarding the biological role of PSCA. Proteins belonging to the Ly6 family are involved in cell signaling events associated with thymic lymphocyte differentiation, maturation and activation. CD59, a member of this protein family, was shown to play a role in the protection against complement mediated lysis. In addition, it was found to be expressed in tumor cells where it may play a role in evading anti © 2010 Marra et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.