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The roles of betacellulin in epithelial ovarian cancer migration and proliferation Zhao, Jianfang

Abstract

Epithelial ovarian cancer is the most lethal gynecological malignancy in developed countries. Although extensive studies have been done in the past decades to develop early detection methods and novel therapeutic strategies for epithelial ovarian cancer, 5-year survival rate of patients diagnosed in late stages remains lower than 30%. The epidermal growth factor (EGF) family of ligands and receptors is well-known for its roles in oncogenesis and cancer progression. As a unique member in this family, betacellulin has been shown to stimulate cell proliferation in several types of human tumors, and has also been suggested to associate with poor clinical outcome in breast cancer. However, little is known about the role and mechanism of betacellulin in epithelial ovarian cancer cell activities. In the current study, we hypothesized that betacellulin enhances epithelial ovarian cancer migration and proliferation by modulating several key target genes. Epithelial ovarian cancer cell lines OVCAR3, OVCAR4, OVCAR5 and SKOV3 were used as study models. Cancer cell migration was assessed by transwell assays; and cell proliferation was measured by MTT assays. Our results showed that betacellulin induced epithelial ovarian cancer cell migration by down-regulating E-cadherin and up-regulating Connexin43 expression; and these effects were mainly mediated by MEK/ERK and PI3K/Akt signaling via EGFR. Moreover, the potential role of ERBB4 in betacellulin signaling and ovarian cancer cell migration has also been suggested. On the other hand, we also demonstrated that betacellulin stimulated cell proliferation by up-regulating CCN1 expression. Taken together, our findings provide important insight into ovarian cancer biology and fill in the gaps of our knowledge of betacellulin, which may lead to the development of novel therapeutic tools for epithelial ovarian cancer.

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