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Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
Fumarase tumor suppressor gene and MET oncogene cooperate in upholding transformation and tumorigenesis
Barbara Costa1, Daniela Dettori, Annalisa Lorenzato
1Department of Oncological Sciences, University of Torino School of Medicine, Turin, Italy.
Abstract:
Loss of the fumarate hydratase (FH) tumor suppressor gene results in the development of benign tumors that rarely, but regrettably, progress to very aggressive cancers. Using mouse embryo fibroblasts (MEFs) to model transformation, we found that fh knockdown results in increased expression of the met oncogene-encoded tyrosine kinase receptor through hypoxia-inducible factor (hif) stabilization. MET-increased expression was alone able to stabilize hif, thus establishing a feed forward loop that might enforce tumor progression. The fh-defective MEFs showed increased motility and protection from apoptosis. Motility, but not survival, relied on hif-1alpha and was greatly enhanced by MET ligand hepatocyte growth factor. Met cooperated with a weakly oncogenic ras in making MEFs transformed and tumorigenic, as shown by in vitro and in vivo assays. Loss of fh was not equally effective by itself but enhanced the transformed and tumorigenic phenotype induced by ras and MET. Consistently, the rescue of fumarase expression abrogated the motogenic and transformed phenotype of fh-defective MEFs. In conclusion, the data suggest that the progression of tumors where FH is lost might be boosted by activation of the MET oncogene, which is able to drive cell-autonomous tumor progression and is a strong candidate for targeted therapy.
Insights
Loss of fumarate hydratase (FH) promotes aggressive cancers by stabilizing hypoxia-inducible factor (HIF) and increasing MET oncogene expression. This creates a feed-forward loop driving tumor progression, suggesting MET as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Loss of the fumarate hydratase (FH) tumor suppressor gene is linked to tumor development.
- FH-deficient tumors can progress to aggressive cancers, but the underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which FH loss contributes to tumor progression.
- To explore the role of the MET oncogene and hypoxia-inducible factor (HIF) in FH-deficient cancers.
Main Methods:
- Utilized mouse embryo fibroblasts (MEFs) to model FH deficiency.
- Assessed gene expression changes, including MET and HIF stabilization.
- Performed in vitro and in vivo assays to evaluate cell motility, apoptosis resistance, transformation, and tumorigenicity.
- Investigated the cooperative effects of MET and Ras signaling.
Main Results:
- FH knockdown in MEFs led to increased MET oncogene expression via HIF stabilization, forming a positive feedback loop.
- FH-defective MEFs exhibited enhanced motility and apoptosis resistance, dependent on HIF-1alpha and hepatocyte growth factor.
- MET and Ras cooperatively induced transformation and tumorigenicity in MEFs.
- Restoring FH expression reversed the pro-tumorigenic phenotypes.
Conclusions:
- MET oncogene activation, driven by FH loss and HIF stabilization, plays a crucial role in driving cell-autonomous tumor progression.
- The MET oncogene is a potential therapeutic target for FH-deficient cancers.
- Understanding this FH-MET-HIF axis provides insights into aggressive cancer development.
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