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

卵巢癌是妇科癌症之一，虽然卡铂和紫杉醇的化疗提高了5年生存率，但一直被认为是一种预后极差的癌症。迄今为止，已经开发了许多针对卵巢癌的靶向治疗方法。然而，不幸的是，这些疗法对卵巢癌患者无效。建立一种新的卵巢癌靶向治疗方法迫在眉睫。卵巢癌患者的腹水被认为是卵巢癌细胞生长因子活性的丰富来源。最近的生化分析显示LPA（溶血磷脂酸）是一种可能的卵巢癌激活因子候选物。原则上，LPA和其他GPCR （G蛋白偶联受体）配体诱导细胞表面表皮生长因子受体（EGFR）配体胞外结构域的蛋白水解裂解（ectodomain脱落）。分泌的EGF家族配体可以在结扎过程中激活EGFR。因此，LPA信号和EGFR系统被认为是紧密相连的。本研究旨在寻找新的有效的治疗靶点，进一步建立卵巢癌的靶向治疗方法。首先，我们研究了EGFR配体在卵巢癌患者中的表达情况。我们发现，在EGFR配体中，与其他EGFR配体的表达相比，癌组织中HB-EGF基因表达和患者腹水中HB-EGF蛋白水平显著升高。除了这些结果，卵巢癌细胞（SKOV3和RMG-1）的肿瘤形成被pro-HB-EGF基因RNA干扰和pro-HB-EGF基因完全阻断，具有不可切割的突变体。根据这些证据，HB-EGF被认为是卵巢癌治疗的一个有希望的靶点，给予特异性HB-EGF抑制剂CRM197，可以抑制裸鼠卵巢癌细胞的肿瘤生长。CRM197是一种无毒的白喉毒素突变体，可以安全地用于癌症患者，使用CRM197可以改善卵巢癌的临床预后。少

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