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Replacement of Fhit in cancer cells suppresses tumorigenicity
Z Siprashvili1, G Sozzi, L D Barnes
1Kimmel Cancer Center and Departments of Microbiology-Immunology and Pathology, Jefferson Medical College, Philadelphia, PA 19107, USA.
Abstract:
The candidate tumor suppressor gene, FHIT, encompasses the common human chromosomal fragile site at 3p14.2, the hereditary renal cancer translocation breakpoint, and cancer cell homozygous deletions. Fhit hydrolyzes dinucleotide 5',5"'-P1,P3-triphosphate in vitro and mutation of a central histidine abolishes hydrolase activity. To study Fhit function, wild-type and mutant FHIT genes were transfected into cancer cell lines that lacked endogenous Fhit. No consistent effect of exogenous Fhit on growth in culture was observed, but Fhit and hydrolase "dead" Fhit mutant proteins suppressed tumorigenicity in nude mice, indicating that 5',5"'-P1, P3-triphosphate hydrolysis is not required for tumor suppression.
Insights
The fragile histidine triad (FHIT) gene, a potential tumor suppressor, was studied. Its protein product, Fhit, suppressed tumor formation in mice even when its enzymatic activity was abolished, suggesting a novel tumor suppression mechanism.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The fragile histidine triad (FHIT) gene is a candidate tumor suppressor located at the 3p14.2 chromosomal fragile site.
- FHIT is frequently altered in various cancers, suggesting its role in tumorigenesis.
- The Fhit protein possesses hydrolase activity on dinucleotide 5',5''-P1,P3-triphosphate.
Purpose of the Study:
- To investigate the functional role of the FHIT gene and its protein product, Fhit, in tumor suppression.
- To determine if the hydrolase activity of Fhit is essential for its tumor-suppressive function.
Main Methods:
- Transfection of wild-type and catalytically inactive mutant FHIT genes into cancer cell lines lacking endogenous Fhit.
- Assessment of cellular growth in vitro.
- Evaluation of tumor formation and suppression in nude mouse models.
Main Results:
- Exogenous Fhit expression did not consistently affect cancer cell growth in vitro.
- Both wild-type Fhit and a hydrolase-deficient Fhit mutant suppressed tumor formation in nude mice.
- These findings indicate that the enzymatic activity of Fhit is not required for its tumor suppressor function.
Conclusions:
- The FHIT gene product, Fhit, can suppress tumorigenicity independently of its 5',5''-P1,P3-triphosphate hydrolase activity.
- This suggests alternative mechanisms by which FHIT may function as a tumor suppressor.
- Further research is warranted to elucidate the precise molecular pathways involved in Fhit-mediated tumor suppression.