Biological Significance of HB-EGF Expression at Cell-Cell Contact Sites in Progression of Ovarian Cancer

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Ovarian cancer, which is one of the gynecologic cancers, has been recognized as a cancer with extremely poor prognosis, although the chemotherapy using carboplatin and paclitaxel has provided the improvement of 5 year's survival rates. Up to date, many targeting therapies for ovarian cancer have been developed. Unfortunately, however, these therapies are not effective for patients with ovarian cancer. It is urgent that a novel targeting therapy for ovarian cancer is established.Ascites from patients with ovarian cancer are considered to be a rich source of growth factor activity for ovarian cancer cells. Recent biochemical analysis has revealed that LPA (Lysophosphatidic acid) id one possible ovarian cancer activating factor candidate. In principle, LPA and other GPCR (G protein-coupled receptor) ligands induce proteolytic cleavage of the extracellular domain (ectodomain shedding) of EGFR (epidermal growth factor receptor) ligands at the cell surface. The secreted EGF family ligands th … More en activate EGFR on ligation. Thus LPA signals and the EGFR system are thought to be closely connected.The aim of this study is to search for novel effective therapies targets and further establish the targeting therapy for ovarian cancer. First, we studied the expression of EGFR ligands in patients with ovarian cancer We found that among the EGFR ligands, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated, compared to the expression of other EGFR ligands. In addition to these results, tumor formation of ovarian cancer cells (SKOV3 and RMG-1) was completely blocked by pro-HB-EGF gene RNA interference and pro-HB-EGF gene with an uncleavable mutant. According to these evidences, HB-EGF is recognized as a promising target for ovarian cancer The administration of CRM197, a specific HB-EGF inhibitor, abrogated the tumor growth of ovarian cancer cells in nude mice. CRM197, which is a non-toxic mutant form of diphtheria toxin, can be safely administered for cancer patients The administration of CRM197 would allow us to improve clinical prognosis of ovarian cancer. Less