Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Tatiana M Tilli,Etel R Gimba,João Luiz Mendes Wanderley,Vanessa Ferreira Franco,Kivvi Duarte De Mello,João P B Viola,Georg F Weber,Fabrício Ribeiro De Azevedo Da Silva,Bruno Kaufmann Robbs

doi:10.1158/1541-7786.mcr-10-0463

Tatiana M Tilli, Etel R Gimba + Show 7 more

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https://doi.org/10.1158/1541-7786.mcr-10-0463

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Abstract

Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression.

Highlights

Ovarian carcinoma is composed of a heterogeneous group of tumors derived from surface epithelia or inclusions [1]
OPNc expression was not detected in benign as well as in normal ovarian tissues (Fig. 1B). These findings suggest that OPN isoforms present differential expression patterns in tumor and nontumor ovarian samples, with OPNc only expressed in tumor samples
These data, together with previous reports showing that OPN isoforms have tumor-specific expression and functional properties [16,17,18,19], prompted us to investigate their functional roles in ovarian cancer biology

Summary

Introduction

Ovarian carcinoma is composed of a heterogeneous group of tumors derived from surface epithelia or inclusions [1]. Basis of ovarian carcinogenesis and tumor progression could allow the establishment of new ovarian cancer markers and the identification of new targets for better treatment options. Many gene products are involved in ovarian cancer progression, as recently reviewed [2, 3]. Among those genes, osteopontin (OPN, 2ar, Spp1) is recognized as a key prognostic marker during ovarian cancer progression [4, 5], which is overexpressed in ovarian cancer in relation to normal ovarian tissues [6]. An increase in OPN levels has been correlated to tumor staging, invasiveness, and grade [7,8,9], as well as to the presence of ovarian cancer peritoneal metastasis [10]. Plasma OPN has been shown to have potential clinical utility in detecting recurrent ovarian cancer [11]

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