Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells
Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells
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DOI：
10.1111/j.1349-7006.2010.01748.x
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发表时间：
2011-01-01
期刊：
影响因子：
5.7
通讯作者：
Seiki, Motoharu
中科院分区：
文献类型：
--
作者：
Koshikawa, Naohiko;Mizushima, Hiroto;Seiki, Motoharu
肝素结合表皮生长因子样生长因子（HB-EGF）和膜型基质金属蛋白酶-1（MT 1-MMP）的表达增加常与各种类型的恶性肿瘤相关。HBEGF样生长因子已被报道促进卵巢癌的恶性进展。基于这一发现，CRM 197对HB-EGF活性的抑制目前正在进行I期临床评价。另一方面，在卵巢癌细胞中表达的MT 1-MMP被认为通过降解细胞外基质促进肿瘤细胞的侵袭和生长。然而，我们最近发现，MT 1-MMP和HB-EGF在胃癌细胞中的共表达导致HB-EGF在其N-末端肝素结合区域内裂解，将其转化为有效的肝素非依赖性生长因子。在这项研究中，我们评估的重要性，HB-EGF的调节MT 1-MMP在卵巢癌的临床样本。我们检测到HB-EGF和MT 1-MMP在卵巢透明细胞癌组织中的共表达，特别是在浸润前沿和扩散到腹水中的肿瘤细胞中，而HB-EGF单独在非浸润性交界性卵巢肿瘤组织中表达。此外，在转移性卵巢癌患者的恶性腹水中检测到与MT 1-MMP处理的片段相对应的可溶性HB-EGF片段。表达MT 1-MMP和HB-EGF的卵巢癌细胞在3D胶原基质中表现出增强的细胞生长和悬浮液中的锚定非依赖性生长。这些结果表明，MT 1-MMP与HB-EGF在卵巢癌细胞中共表达增强了HB-EGF的活性，从而促进了体内侵袭性肿瘤的生长和扩散。（Cancer Sci 2011; 102：111-116）。
Increased expression of heparin-binding EGF-like growth factor (HB-EGF) and membrane-type matrix metalloproteinase-1 (MT1-MMP) is frequently associated with various types of malignant tumor. HB EGF-like growth factor has been reported to promote the malignant progression of ovarian carcinoma. Based on this finding, inhibition of HB-EGF activity with CRM197 is now under phase I clinical evaluation. On the other hand, MT1-MMP expressed in ovarian carcinoma cells is thought to promote invasion and growth of tumor cells by degrading the extracellular matrix. However, we recently demonstrated that co-expression of MT1-MMP and HB-EGF in gastric carcinoma cells leads to cleavage of HB-EGF within its N-terminal heparin-binding region, converting it into a potent heparin-independent growth factor. In this study, we evaluated the importance of regulation of HB-EGF by MT1-MMP in clinical samples of ovarian carcinoma. We detected co-expression of HB-EGF and MT1-MMP in clear cell ovarian carcinoma tissues, particularly at the invasion front and in tumor cells that had disseminated into the ascites, whereas HB-EGF alone was expressed in non-invasive borderline ovarian tumor tissue. Furthermore, a soluble HB-EGF fragment that corresponds to that processed by MT1-MMP was detected in malignant ascites obtained from patients with metastatic ovarian carcinoma. Ovarian carcinoma cells that express MT1-MMP and HB-EGF exhibited enhanced cell growth in a 3D-collagen matrix and anchorage-independent growth in suspension. These results indicate that MT1-MMP co-expressed with HB-EGF in ovarian carcinoma cells potentiates the activity of HB-EGF to promote invasive tumor growth and spreading in vivo. (Cancer Sci 2011; 102: 111-116).