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

卵巢癌是妇科恶性肿瘤之一，虽然卡铂和紫杉醇联合化疗提高了5年生存率，但卵巢癌的预后极差。迄今为止，已经开发了许多针对卵巢癌的靶向治疗。然而，不幸的是，这些疗法对卵巢癌患者无效。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，因此，建立一种新的卵巢癌靶向治疗方法迫在眉睫。最近的生化分析表明，溶血磷脂酸（LPA）是一种可能的卵巢癌激活因子候选者。原则上，LPA和其他GPCR（G蛋白偶联受体）配体诱导EGFR（表皮生长因子受体）配体的胞外结构域（胞外域脱落）在细胞表面的蛋白水解裂解。分泌型EGF家族配体 ...更多信息 在连接时激活EGFR。本研究的目的是寻找新的有效治疗靶点，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。我们发现，在EGFR配体中，癌组织中HB-EGF基因的表达和患者腹水中HB-EGF蛋白的水平与其他EGFR配体的表达相比显著升高。此外，pro-HB-EGF基因RNA干扰和pro-HB-EGF基因不可切割突变体完全阻断了卵巢癌细胞（SKOV 3和RMG-1）的肿瘤形成。因此，HB-EGF被认为是卵巢癌治疗的一个有希望的靶点。CRM 197是白喉毒素的无毒突变形式，可以安全地用于癌症患者。CRM 197的施用将使我们能够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