Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways.
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 IFNalpha/beta 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.
Marra
Emanuele
E
Istituto di Ricerche Biologia Molecolare P, Angeletti, Via Pontina Km 30,600 00040 Pomezia (Rome) Italy.
Uva
Paolo
P
Viti
Valentina
V
Simonelli
Valeria
V
Dogliotti
Eugenia
E
De Rinaldis
Emanuele
E
Lahm
Armin
A
La Monica
Nicola
N
Nicosia
Alfredo
A
Ciliberto
Gennaro
G
Palombo
Fabio
F
D000818:Animals; D000951:Antigens, Neoplasm; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002999:Clone Cells; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D004318:Doxycycline