Abstract 5256: Osteopontin-c and Osteopontin-b splicing isoforms activate important hallmarks of cancer contributing to prostate carcinoma progression

Abstract

Abstract Introduction: Osteopontin (OPN) is a secreted glycophosphoprotein and is involved in tumorigenesis and metastasis in many solid tumors, including prostate cancer (PCa). Alternative splicing of OPN mRNA leads to the expression of 3 isoforms, named OPNa, OPNb and OPNc. However, the expression pattern and the roles of these isoforms have not been previously characterized in PCa. Objective and Methodology: Herein we evaluated the expression pattern of these OPN isofoms in PCa and BPH (benign prostate hyperplasia) tissue samples by using qRT-PCR. ROC curve analysis evaluated the performance of OPN isoforms tissue levels as compared to PSA serum levels for the diagnosis of PCa. Additionally, we investigated the roles of these isoforms on PCa progression using PC3 cells ectopically overexpressing each OPN isoform and in vitro and in vivo assays. Results: Our data demonstrate that these 3 isoforms are overexpressed in PCa in relation to BPH tissue samples and that OPNc presents the highest expression level. ROC curve analysis demonstrate that OPNa, OPNb and OPNc expression levels perform better (AUC 0,9; 0,81 and 0,88, respectively, p< 0,0001) than PSA serum levels (AUC 0,52; p< 0,0001) for the differential diagnosis of PCa and BPH patients. Furthermore, OPN isoforms expression levels are positively correlated to tumor Gleason Score (p < 0,001). Cells overexpressing OPNc and OPNb, but not OPNa, significantly activate cell features typically related to key hallmarks of cancer, such as cell proliferation, migration, anchorage-independent growth and tumor formation in vivo in nude mice, reflecting the potential of these isoforms to active PCa tumor progression. Besides, OPNc seems also to in involved in PCa tumorigenesis, once stimulate the proliferation of RWPE1 prostate non- tumoral cells. Trying to describe the signaling pathways involved on OPNc and OPNb roles on activating PCa progression steps, we demonstrated that the use LY-294002 inhibitor significantly inhibited the proliferation of cells overexpressing OPNc and OPNb, suggesting that these OPN splicing isoforms on activating cell proliferation occurs via PI3K/Akt signaling pathways. Conclusions: Taken together, these results suggest that the evaluation of OPN splicing isoforms expression levels could be used as molecular parameter to improve the differential diagnosis of PCa in relation to BPH. Besides, we provide evidence that OPNc and OPNb activate important steps in PCa progression and hence could be important targets for the development of therapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5256. doi:10.1158/1538-7445.AM2011-5256