Functional characterization of GRB7 and its variant, GRB7v, in ovarian cancer

Abstract

Ovarian cancer is one of the most lethal gynecological malignancies for female overall in the world. Most of ovarian cancer cases have poor prognosis and patients die at late stage. Therefore, understanding the molecular mechanisms in the development of ovarian cancer through identification and characterization of oncogenes and tumor suppressor genes will help discovery of novel targets for therapies. We have recently identified Growth factor Receptor Bound protein 7 (GRB7) and its variant GRB7v (deletion of SH2 domain) overexpressed in ovarian cancer cells and clinical samples by quantitative RT-PCR analysis. Clinicopathological correlation revealed that the overexpressed GRB7 (P=0.019) and GRB7v (P=0.018) were significantly correlated with high grade ovarian cancer. In addition, the overexpressed GRB7 was also associated with clear cell subtype of ovarian cancer (P=0.024). GRB7 is an adaptor protein which plays an important role in mediating signal transductions from multiple cell surface receptors to various downstream signaling pathways. We thus hypothesized that the overexpressed GRB7 and GRB7v may play important roles in the development and progression of ovarian cancer. Subcellular localization studies using immunofluorescent analysis showed that GRB7 and GRB7v localized mainly in cytoplasm, consistent with their roles as activated receptor binding proteins. Functionally, we demonstrated that the ectopic overexpression of GRB7 promoted cell migration and invasion, whereas enforced expression of GRB7v increased cell proliferation instead of promoting cell migration and invasion. This indicates that GRB7 and GRB7v function differentially and may be involved in different signaling pathways in the pathogenesis of high grade ovarian cancer cells. Further investigations of the functions and the underlying molecular mechanisms of GRB7 and GRB7v in ovarian cancer are warranted.