Abstract 396: Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Ovarian carcinoma (OC) is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is overexpressed in OC and is involved in tumorigenesis and metastasis. Alternative splicing of OPN generates 3 isoforms, OPNa, OPNb, and OPNc. Objective: This study aims to characterize the expression profile and functional role of OPN splicing isoforms (OPN-SI) in OC. Methodology: The expression patterns of OPN-SI and a series of genes involved in cancer pathways were analyzed by real-time PCR. In vitro and in vivo functional assays were performed using the ovarian cancer cell line OvCar-3, stably overexpressing the three OPN-SI. Results: OPNc, but not OPNa and OPNb, was specifically expressed on OC samples. We then demonstrated that OPNc isoform has stimulatory effects on OvCar-3 cell proliferation, migration, invasion and anchorage independent cells growth, besides activating tumor formation in nude mice. We also found that these features are mainly mediated by PI3K/Akt signaling pathway. Moreover, OvCar-3 OPNc-overexpressing cells are able to modulate the expression of 34 genes involved in key cancer pathways. Notably, tumors formed by OPNc-overexpressing cells present high expression levels of typical angiogenic markers, such as VEGF-A, VEGFR-2 and CD34. Based on this observation, we also investigated the molecular mechanisms by which OPNc stimulates angiogenic processes. Our data showed that OPNc overexpression activates VEGF-A expression and secretion, also through the PI3K/Akt pathway. This splicing isoform is also able to activate the expression of c-Fos, c-Jun and phospho-c-Jun. OPNc role on activating the phosphorylation of c-Jun is mediated by integrin receptor, in an RGD-dependent manner. In addition, OPNc-conditioned medium is able to induce HUVEC endothelial cell proliferation, migration and adhesion. Conclusion: Thus, the specific targeting of OPNc and its regulated signaling network could be a putative novel strategy to inhibit key steps involved in OC progression and may represent a putative strategy for developing new therapeutic approaches using OPNc as interesting target for OC treatment strategies. Citation Format: Tatiana M. Tilli, Kivvi D. Mello, Vanessa Franco, Bruno Robbs, Joao Luiz Wanderley, Fabricio R A Silva, Joao P B Viola, Georg Weber, Vincent Castronovo, Akeila Bellahcene, Etel R P Gimba. Osteopontin-c splicing isoform contributes to ovarian cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 396. doi:10.1158/1538-7445.AM2013-396