Osteopontin-c splicing isoform contributes to ovarian cancer progression.
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.
Instituto Nacional de Câncer, Coordenação de Pesquisa, Divisão de Medicina Experimental and Biologia Celular, Centro-Rio de Janeiro, Brazil.
Tatiana M
TM
Tilli
Vanessa Ferreira
VF
Franco
Bruno Kaufmann
BK
Robbs
João Luiz Mendes
JL
Wanderley
Fabrício Ribeiro de Azevedo
FR
da Silva
Kivvi Duarte
KD
de Mello
João P B
JP
Viola
Georg F
GF
Weber
Etel R
ER
Gimba
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D018014:Gene Transfer Techniques / Q000401:mortality; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000145:classification / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
D020033:Protein Isoforms; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt