Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy
Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy
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DOI：
10.1158/0008-5472.can-04-0811
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Mekada, E
中科院分区：
文献类型：
--
作者：
Miyamoto, S;Hirata, M;Mekada, E
卵巢癌是所有妇科癌症中最常见的癌症死亡原因。我们在这里证明，溶血磷脂酸（LPA）诱导的肝素结合EGF样生长因子（HB-EGF）的胞外域脱落是卵巢癌肿瘤形成的关键。我们发现，在表皮生长因子受体（EGFR）家族的生长因子，HB-EGF基因在癌组织中的表达和HB-EGF蛋白水平在患者的腹水显着升高。人卵巢癌细胞系SKOV 3和RMG-1在裸鼠中形成肿瘤。这些细胞的肿瘤形成被pro-HB-EGF的外源性表达增强，并被pro-HB-EGF基因RNA干扰或被特异性HB-EGF抑制剂CRM 197完全阻断。用突变形式的HB-EGF转染表明，可溶性HB-EGF的释放是肿瘤形成所必需的。卵巢癌细胞组成性产生的LPA诱导SKOV 3和RMG-1细胞中HB-EGF胞外域脱落，导致EGFR和下游激酶细胞外信号调节激酶/丝裂原活化蛋白激酶的反式激活。LPA诱导的反式激活被HB-EGF基因RNA干扰或CRM 197废除。脂质磷酸水解酶，水解LPA的引入，降低HB-EGF的组成性脱落，EGFR的反式激活，以及SKOV 3和RMG-1细胞的致瘤潜力。这些结果表明，HB-EGF是卵巢癌中表达的生长因子的EGFR家族的主要成员，并且LPA诱导的该生长因子的胞外域脱落是肿瘤形成的关键步骤，使得HB-EGF成为卵巢癌的新的治疗靶点。
Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.