Role of hepatocyte growth factor activator (HGF activator) in invasive growth of human glioblastoma cells in vivo
Role of hepatocyte growth factor activator (HGF activator) in invasive growth of human glioblastoma cells in vivo
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DOI：
10.1002/ijc.21362
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Kataoka, H
中科院分区：
文献类型：
--
作者：
Uchinokura, S;Miyata, S;Kataoka, H
肝细胞生长因子/分散因子(HGF/SF)是一种多功能生长因子，通过其受体MET(原癌基因蛋白产物)参与肿瘤细胞的侵袭性生长。肝细胞生长因子激活剂(HGFA)是一种丝氨酸蛋白酶，负责激活HGF/SF的前体(proHGF/SF)。在我们的研究中，我们检测了hGFA基因工程表达对2个人胶质母细胞瘤细胞系(YKG-1和U251)的影响。两种细胞均表达MET，仅YKG-1表达内源性proHGF/SF。在凝血酶的存在下，体外培养的YKG-1细胞中HGFA的表达增强了MET的磷酸化和迁移活性，凝血酶是已知的前HGFA的激活剂。相反，在缺乏内源性HGF/SF的U251中，始终观察到MET的磷酸化，这表明该细胞系中MET的激活不依赖于配体。因此，即使用凝血酶治疗，U251中HGFA的表达也不能增强MET的磷酸化和后续的细胞反应。然而，在凝血酶存在的情况下，外源性proHGF/SF的加入可以增强表达HGFA的U251细胞的迁移活性。当YKG-1细胞移植到裸鼠脑内时，工程化hGFA的表达显著促进了肿瘤的生长，并增加了体内的血管密度。在缺乏内源性proHGF/SF的U251中未观察到这种作用。这些结果表明，胶质母细胞瘤中可能存在多种MET激活机制，并且proHGF/SF激活系统在表达内源性proHGF/SF并需要配体依赖的MET激活的胶质母细胞瘤的进展中起重要作用。(C)2005年Wiley-Liss，Inc.
Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that is involved in invasive growth of tumor cells via its receptor MET, a protein product of c-met proto-oncogene. HGF activator (HGFA) is a serine proteinase responsible for the activation of proform of HGF/SF (proHGF/SF). In our study, we examined the effects of engineered expression of HGFA on 2 human glioblastoma cell lines (YKG-1 and U251). Both cells expressed MET, while only YKG-1 expressed endogenous proHGF/SF. Enhanced MET phosphorylation and increased migratory activity were induced by the expression of HGFA in YKG-1 cells in vitro in the presence of thrombin, which is a known activator of proHGFA. In contrast, MET phosphorylation was consistently observed in U251 that lacked endogenous HGF/SF, suggesting ligand-independent activation of MET in this cell line. Consequently, the expression of HGFA in U251 did not enhance the MET phosphorylation and following cellular response even with the thrombin treatment. However, addition of exogenous proHGF/SF resulted in enhanced migratory activity of HGFA-expressing U251 cells in the presence of thrombin in vitro. The engineered HGFA expression resulted in significantly enhanced tumor growth with increased vascular density in vivo when YKG-1 cells were implanted in nude mouse brain. This effect was not observed in U251 lacking endogenous proHGF/SF. These results indicate the possible existence of multiple mechanisms of MET activation in glioblastomas and that the activation system of proHGF/SF is important in progression of glioblastomas that express endogenous proHGF/SF and require ligand-dependent MET activation. (c) 2005 Wiley-Liss, Inc.