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Published on: October 4, 2019
Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte
R Abounader1, S Ranganathan, B Lal
1Department of Neuroscience and Kennedy Krieger Research Institute, Baltimore, MD 21205, USA.
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<.01). Inhibition of SF/HGF or c-met expression in glioblastoma cells possessing an SF/HGF-c-met autocrine loop reduced tumor cell clonogenicity (P =.005 for SF/HGF and P=.009 for c-met) and substantially inhibited tumorigenicity (P<.0001) and tumor growth in vivo (P<.0001).
Conclusions:
To our knowledge, this is the first successful inhibition of SF/HGF and c-met expression in a tumor model directly demonstrating a role for endogenous SF/HGF and c-met in human glioblastoma. Our results suggest that targeting the SF/HGF-c-met signaling pathway may be an important approach in controlling tumor progression.
Insights
Inhibiting scatter factor (SF)/hepatocyte growth factor (HGF) and c-met in glioblastoma reduced tumor growth and malignancy. Targeting this pathway may offer a new approach for controlling brain tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Scatter factor (SF)/hepatocyte growth factor (HGF) and its receptor c-met are linked to malignant progression in human tumors, including gliomas.
- Overexpression of SF/HGF in experimental gliomas promotes tumorigenicity and angiogenesis.
- The role of endogenous SF/HGF or c-met in glioma progression remained largely unexamined.
Purpose of the Study:
- To test if human glioblastomas are dependent on the SF/HGF-c-met pathway.
- To investigate if reducing endogenous SF/HGF or c-met expression inhibits glioblastoma growth and tumorigenicity.
Main Methods:
- Glioblastoma cells were transfected with chimeric transgenes to inhibit SF/HGF and c-met gene expression.
- Effects on SF/HGF-dependent immediate early gene induction (signal transduction), anchorage-independent colony formation (clonogenicity), and intracranial tumor formation were quantified.
Main Results:
- Transgene introduction reduced SF/HGF and c-met gene expression significantly (down to 2% of control levels).
- Reduced c-met expression inhibited SF/HGF-dependent signal transduction (P<.01).
- Inhibition of SF/HGF or c-met suppressed glioblastoma clonogenicity (P=.005 and P=.009, respectively) and significantly inhibited tumorigenicity and tumor growth in vivo (P<.0001).
Conclusions:
- This study demonstrates the first successful inhibition of SF/HGF and c-met expression in a tumor model, confirming their role in human glioblastoma.
- Targeting the SF/HGF-c-met signaling pathway presents a promising strategy for controlling glioblastoma progression.
