Abstract
Ovarian cancer is one of the most frequent causes of cancer death among all gynecologic cancers. Though standard therapy often results in temporary clinical remission, most patients suffer from recurrence and metastasis of ovarian cancer, which highlights the need for developing new therapeutic agents targeting specific molecules. Previous studies have demonstrated that the native ligand of epidermal growth factor receptor (EGFR) and ErbB4, heparin-binding EGF-like growth factor (HB-EGF), plays a critical role in the progression of ovarian cancer and is associated with prognosis of ovarian cancer. In the current study, we tried to develop a peptide-based treatment for ovarian cancer by targeting HB-EGF. After the functions of HB-EGF in promoting migration and invasion of SKOV3 and HO-8910 cells were confirmed, phage display was used to discover peptides binding to HB-EGF. Two peptides, no. 7 and no. 29 were found mildly binding to HB-EGF. Then the effects of these peptides on HB-EGF functions were examined and both peptides no. 7 and no. 29 were found indeed inhibiting the functions of HB-EGF in promoting migration and invasion of SKOV3 and HO-8910 cells in vitro. Further mechanism investigation showed that peptides no. 7 and no. 29 inhibited HB-EGF-promoted cell migration and invasion through attenuating activation of the EGFR signaling pathway manifested by decreased p-Erk1/2 and Snail levels. More importantly, peptides no. 7 and no. 29 showed strong activities in inhibiting migration of SKOV3 cells in vivo. These results provide a proof of concept method for developing novel peptide drugs to combat ovarian cancer through interfering with HB-EGF mediated signaling pathways.
Highlights
Ovarian cancer is one of the most frequent causes of cancer death among all gynecologic cancers[1]
It has been proved that heparin-binding EGF-like growth factor (HBEGF), an important ligand of epidermal growth factor receptor (EGFR), participates in tumorigenesis and development of ovarian cancer[2] and is a useful biomarker for cancer prognosis[3,4]
Synthesized as a type I transmembrane protein, proHB-EGF can be cleaved by a disintegrin and metalloprotease (ADAM) or a matrix metalloproteinase (MMP) through a process known as “ectodomain shedding” to release soluble heparinbinding EGF-like growth factor (HB-EGF) and C-terminus of proHB-EGF (HB-EGF-C)[7,8,9]
Summary
Ovarian cancer is one of the most frequent causes of cancer death among all gynecologic cancers[1]. It has been proved that heparin-binding EGF-like growth factor (HBEGF), an important ligand of epidermal growth factor receptor (EGFR), participates in tumorigenesis and development of ovarian cancer[2] and is a useful biomarker for cancer prognosis[3,4]. Among EGFR ligands, expression of HB-EGF is the highest in various ovarian cancer cell lines[5] and in malignant ovarian cancer patients[6]. Studies of knock-in mice expressing an uncleavable mutant form of HB-EGF indicated that the major functions of HB-EGF were mediated by sHB-EGF in vivo[10]. SHB-EGF was reported to significantly contribute to cancer progression through promoting survival, adhesion, invasion, and angiogenesis of cancer cells[11,12]
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