Fumarase tumor suppressor gene and MET oncogene cooperate in upholding transformation and tumorigenesis.
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.
Costa
Barbara
B
Department of Oncological Sciences, University of Torino School of Medicine, Turin, Italy.
Dettori
Daniela
D
Lorenzato
Annalisa
A
Bardella
Chiara
C
Coltella
Nadia
N
Martino
Cosimo
C
Cammarata
Cristina
C
Carmeliet
Peter
P
Olivero
Martina
M
Di Renzo
Maria Flavia
MF
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000209:etiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D005649:Fumarate Hydratase