RNA interference targeting PSCA suppresses primary tumor growth and metastasis formation of human prostate cancer xenografts in SCID mice.

ABSTRACT

BACKGROUND AND OBJECTIVES: Prostate stem cell antigen (PSCA) is a cell surface, glycosylphosphatidylinositol (GPI)-anchored glycoprotein. Its overexpression has been detected in both local and metastatic prostate cancer (PCa), making it a potential therapeutic target. We previously reported that silencing PSCA by small interfering RNA targeting human PSCA (siRNA-PSCA) inhibited biological activity of PSCA-positive PCa cells leading to reduced proliferation, motility and invasion in vitro. In this study, we extended this in vitro findings to in vivo settings in order to investigate the effects of this specific siRNA on the tumor growth and metastasis development of PCa in vivo. MATERIALS AND METHODS: The siRNA-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa PC-3M and LNCaP cells, respectively, and were subcutaneously inoculated into the male SCID mice. Tumor growth was measured with a caliper, and formation of metastasis in mice bearing xenograft tumors was studied by magnetic resonance imaging (MRI) and autopsy analysis. Western blot and immunohistochemistry were used to assess the expression levels of PSCA protein in tumor tissues from xenograft and distant metastases. RESULTS: Consistent with our previous in vitro findings, the subcutaneous xenografts of PC-3M-siPSCA exhibited the almost completely inhibited expression of PSCA protein in their tumors tissues (P < 0.001 and P < 0.001, respectively), and consequently had a significant reduction in tumor growth volumes (P < 0.05 for all), and metastasis onset and sites (P < 0.001 for all) compared to those of PC-3M and PC-3M-siScrm. Conversely, LNCaP-PSCA showed significantly enhanced primary tumor growth and metastasis formation of xenografts compared to LNCaP-vehicle and LNCaP cells (P < 0.001 for all). Moreover, the up-regulated expression of PSCA protein was detected in the distant metastases of xenograft tumors from all groups. CONCLUSIONS: Taken together, these observations suggest that PSCA has a promoting role in the growth and metastasis of PCa and siRNA-PSCA may be a potential therapeutic strategy for PSCA-positive PCa.