Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression
Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression
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DOI：
10.1093/jnci/91.18.1548
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发表时间：
1999-09-15
期刊：
影响因子：
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通讯作者：
Laterra, J
中科院分区：
文献类型：
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作者：
Abounader, R;Ranganathan, S;Laterra, J
背景资料：分散因子（SF）（也称为肝细胞生长因子（HGF））及其受体c-met的表达通常与人类肿瘤（包括神经胶质瘤）的恶性进展相关。实验性神经胶质瘤中SF/HGF的过表达增强致瘤性和肿瘤相关的血管生成（即，新血管的生长）。然而，内源性SF/HGF或c-met表达在胶质瘤恶性进展中的作用尚未直接研究。在本研究中，我们测试了人胶质母细胞瘤可以是SF/HGF-c-met依赖性的假设，并且内源性SF/HGF或c-met表达的降低可以导致肿瘤生长和致瘤性的抑制。用由U1小核RNA、锤头状核酶和反义序列组成的嵌合转基因转染胶质母细胞瘤细胞，可抑制SF/HGF和c-met基因的表达; SF/HGF和c-met表达降低对1）SF/HGF依赖的立即早期基因诱导的影响（c-fos和c-jun），指示信号转导; 2）锚定非依赖性集落形成（克隆形成），实体瘤恶性的体外相关物;和3）免疫缺陷小鼠中的颅内肿瘤形成被定量。统计检验是双侧的。结果如下：将转基因导入胶质母细胞瘤细胞中可将SF/HGF和c-met基因的表达降低至对照细胞水平的2%。c-met表达降低特异性抑制SF/HGF依赖的信号转导（P
Background: Expression of scatter factor (SF), also known as hepatocyte growth factor (HGF), and its receptor, c-met, is often associated with malignant progression of human tumors, including gliomas, Overexpression of SF/HGF in experimental gliomas enhances tumorigenicity and tumor-associated angiogenesis (i.e., growth of new blood vessels). However, the role of endogenous SF/HGF or c-met expression in the malignant progression of gliomas has not been examined directly, In this study, we tested the hypothesis that human glioblastomas can be SF/HGF-c-met dependent and that a reduction in endogenous SF/HGF or c-met expression can lead to inhibition of tumor growth and tumorigenicity, Methods: Expression of the SF/HGF and c-met genes was inhibited by transfecting glioblastoma cells with chimeric transgenes consisting of U1 small nuclear RNA, a hammerhead ribozyme, and antisense sequences; The effects of reduced SF/HGF and c-met expression on 1) SF/HGF-dependent induction of immediate early genes (c-fos and c-jun), indicative of signal transduction; 2) anchorage-independent colony formation (clonogenicity), an in vitro correlate of solid tumor malignancy; and 3) intracranial tumor formation in immunodeficient mice were quantified. Statistical tests were two-sided. Results: Introduction of the transgenes into glioblastoma cells reduced expression of the SF/HGF and c-met genes to as little as 2% of control cell levels. Reduction in c-met expression specifically inhibited SF/HGF-dependent signal transduction (P