Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

Abstract

BackgroundProstate 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.MethodsA 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 qPCRResultsDown 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 IFNα/β receptor.ConclusionsThese 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.

PSCA promotes prostate cancer proliferation and cell‐cycle progression by up‐regulating c‐Myc

“…This is consistent with the findings of Kawaguchi and colleagues in lung cancer cells . Marra et al also found that knockdown of the PSCA was associated with reduced bladder cancer cell proliferation in vitro and in vivo. However, Ono et al observed the cell growth‐inhibitory activity of PSCA expression in gallbladder cancer.…”

Genetic Variation in the Prostate Stem Cell Antigen Gene and Upper Gastrointestinal Cancer in White Individuals

“…In vitro studies have shown that PSCA influences survival in gastric cancer cells, where transfection of PSCA into PSCA-negative cells leads to reduced cell proliferation10. In contrast, knockdown of PSCA in a bladder cancer cell line results in induction of inflammatory gene expression, accompanied by a reduction in cell grown42. The role of PSCA in tumorigenesis therefore appears complex, involving pro-tumorigenic and anti-tumorigenic effects in different contexts43.…”

A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population

“…We hypothesize that, in response to damage in mucosal cells in the duodenum, the tissue repair system is switched on by the aggrega tion of platelets and the release of growth factors, which is followed by the proliferation and migration of epithelial cells. PSCA is highly expressed in various cancer tissues, and cells treated with small interfering RNA (siRNA) targeting PSCA or with antibody against PSCA exhibited a substantially suppressed growth 22,23 , indicating a role for cell surface PSCA in cell proliferation. Our findings suggest that individuals with homozygous C alleles might have insufficient epithelial proliferation to counteract the damage because of a lack of functional cell surface PSCA, causing slow recovery from duodenal tissue damage.…”