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Oncogenic consequences of down-modulating TIMP expression in 3T3 cells with antisense RNA
D T Denhardt1, R Khokha, S Yagel
1Department of Biochemistry, University of Western Ontario, London, Canada.
Matrix (Stuttgart, Germany). Supplement
|January 1, 1992
Summary
Impairing tissue inhibitor of metalloproteinases (TIMP) production in 3T3 cells increased invasiveness and tumor formation, suggesting TIMP acts as a tumor suppressor gene.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Tissue inhibitor of metalloproteinases (TIMP) plays a role in regulating extracellular matrix degradation.
- Metalloproteinases are implicated in cancer invasion and metastasis.
- Understanding TIMP's function is crucial for cancer research.
Purpose of the Study:
- To investigate the role of TIMP in cellular invasiveness and tumorigenic potential.
- To engineer 3T3 cell lines with varying levels of TIMP expression.
- To determine if TIMP functions as a tumor suppressor gene.
Main Methods:
- Recombinant DNA technology was used to create murine 3T3 cell lines with altered TIMP expression.
- Antisense RNA technology under a metallothionein promoter controlled TIMP expression.
- In vitro amnion invasion assays and nude mouse tumorigenicity studies were performed.
Main Results:
- Reduced TIMP production in 3T3 cells led to increased invasiveness and the ability to form tumors in nude mice.
- Impaired TIMP expression correlated with increased extracellular matrix metalloproteinase activity.
- Tumorigenic cell lines showed increased expression of matrix metalloproteinase genes.
Conclusions:
- TIMP acts as a crucial regulator of cellular invasiveness and tumorigenic potential in 3T3 cells.
- Down-regulation of TIMP confers a transformed, tumor-forming phenotype.
- TIMP exhibits properties of a tumor-suppressor gene, highlighting its anti-oncogenic role.