Discovery of HB-EGF binding peptides and their functional characterization in ovarian cancer cell lines

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.

Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer

“…As the full picture of miRNA-mRNA networks has yet to be accomplished [56], the results presented here may be helpful to find key regulators of OC network. In line with our findings, all 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) have been previously shown to play an essential role in ovarian carcinogenesis with respect to different aspects such as OS, histological subtype, clinical stage, chemoresistance, or treatment [19,20,27,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71]. We reported previously that hsa-miR-23a-5p, hsa-miR-27a-5p, and hsa-miR-126-3p, were significantly associated with OS in the same EOC cohort (p < 0.01, univariate Cox regression analysis) [27].…”

“…Vert et al demonstrated that activating transcription factor 3 (ATF3) in OC cell lines has a crucial role for antitumor activity and to strengthen the antiviral properties of an RNA-damaging drug, Onconase [67]. The inhibition of heparin-binding epidermal growth factor-like growth factor (HBEGF) has been proposed as a novel therapeutic strategy for patients with paclitaxel-resistant OC [68,69]. Overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been described across a broad range of solid tumors including ovarian, colorectal, breast, gastric, prostate, and endometrial carcinomas in addition with melanoma, gliomas, and astrocytomas indicating that inhibition of NAMPT may be used as a cancer treatment strategy [70].…”

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

“…Similar to NGF and other neurotrophins, HB-EGF is synthesized in a premature transmembrane form (pro-HB-EGF) before it is cleaved by numerous metalloproteinases (MMP3, MMP9, ADM9, ADAM10, ADAM12, ADAM17) into its mature, soluble form (215). While the membrane anchored pro-HB-EGF functions as juxtacrine growth factor and receptor for diphtheria toxin in some species, soluble HB-EGF has recently been described to modulate cell migration, differentiation, and inflammatory functions in multiple cell types (216)(217)(218)(219)(220)(221)(222). In addition, HB-EGF enhances neurogenesis in models of ischemic injury and promotes the survival of dopaminergic neurons (223,224) (Figure 2).…”

Food-Derived Opioid Peptides in Human Health: A Review

“…The phage displayed random peptide library identification is an effective way of detecting peptides that can bind and control target molecular behaviors. This method has been practiced in identifying receptor-bound bioactive peptides [ 166 ], disease-specific antigen mimics [ 166 , 167 ], cell-specific peptides, non-protein-bound peptides [ 168 ], or organ-specific peptides [ 169 ], as well as in the designing of peptide-mediated drug delivery systems [ 165 ]. Consequently, analysis for bioactive peptides applying phage display technology is an advantageous approach that can be used in basic research.…”