Reversion of Human Glioblastoma Malignancy by U1 Small Nuclear RNA/Ribozyme Targeting of Scatter Factor/Hepatocyte Growth Factor and c-met Expression

作者：Roger Abounader, Srikanth Ranganathan, Bachchu Lal, Katherine Fielding, Adam A Book, Harry C. Dietz, P.M. Burger, John Laterra · 发表于：JNCI Journal of the National Cancer Institute · 年份：1999 · DOI：10.1093/jnci/91.18.1548 · 被引用次数：179 · 研究领域：Liver physiology and pathology、Glioma Diagnosis and Treatment、Cancer Cells and Metastasis

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-de...