Discovery of HB-EGF binding peptides and their functional characterization in ovarian cancer cell lines
Discovery of HB-EGF binding peptides and their functional characterization in ovarian cancer cell lines
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HB-EGF 结合肽的发现及其在卵巢癌细胞系中的功能表征
DOI：
10.1038/s41420-019-0163-9
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发表时间：
2019-03-25
影响因子：
7
通讯作者：
Liu, Hanqing
中科院分区：
文献类型：
--
作者：
Shen, Yanting;Ruan, Lingling;Liu, Hanqing
卵巢癌是所有妇科癌症中最常见的癌症死亡原因之一。虽然标准治疗通常导致暂时的临床缓解，但大多数患者患有卵巢癌的复发和转移，这突出了开发靶向特定分子的新治疗剂的需要。既往研究表明，表皮生长因子受体（EGFR）和ErbB 4的天然配体肝素结合EGF样生长因子（HB-EGF）在卵巢癌的发生发展中起着重要作用，并与卵巢癌的预后相关。在目前的研究中，我们试图通过靶向HB-EGF开发一种基于肽的卵巢癌治疗方法。在确定HB-EGF促进SKOV 3和HO-8910细胞迁移和侵袭的功能后，利用噬菌体展示技术筛选HB-EGF结合肽。发现两种肽，7号和29号与HB-EGF轻度结合。然后检测这些肽对HB-EGF功能的影响，发现7号和29号肽确实抑制HB-EGF促进SKOV 3和HO-8910细胞体外迁移和侵袭的功能。进一步的机制研究表明，肽7号和肽29号通过减弱EGFR信号通路的激活来抑制HB-EGF促进的细胞迁移和侵袭，所述EGFR信号通路表现为降低p-Erk 1/2和Snail水平。更重要的是，7号和29号肽在体内抑制SKOV 3细胞迁移方面显示出强活性。这些结果为开发新的肽类药物通过干扰HB-EGF介导的信号通路来对抗卵巢癌提供了概念验证方法。
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.