Inactivation of the FHIT gene favors bladder cancer development.
The fragile histidine triad (FHIT) gene located on chromosome 3p14.2 is frequently deleted in human tumors. We have previously reported deletions at the FHIT locus in 50% of bladder carcinoma derived cell lines and reduced expression in 61% of primary transitional carcinomas of the urinary bladder. To additionally investigate the role of FHIT alterations in the development of bladder cancer, we used heterozygous and nullizygous Fhit-deficient mice in a chemically induced carcinogenesis model. Results showed that 8 of 28 (28%) and 6 of 13 (46%) of the Fhit -/- and +/-, respectively, versus 2 of 25 (8%) Fhit +/+ mice developed invasive carcinoma after treatment with N-butyl-N-(4-hydroxybutyl) nitrosamine. To explore the possibility of a FHIT-based gene therapy for bladder cancer, we studied the effects of restored Fhit protein expression on cell proliferation, cell kinetics, and tumorigenicity in BALB/c nude mice, with human SW780 Fhit-null transitional carcinoma derived cells. In vitro transduction of SW780 Fhit-negative cells with adenoviral-FHIT inhibited cell growth, increased apoptotic cell population, and suppressed s.c. tumor growth in nude mice. These findings suggest the important role of Fhit in bladder cancer development and support the effort to additionally investigate a FHIT-based gene therapy.
Vecchione
Andrea
A
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Sevignani
Cinzia
C
Giarnieri
Enrico
E
Zanesi
Nicola
N
Ishii
Hideshi
H
Cesari
Rossano
R
Fong
Louise Y Y
LY
Gomella
Leonard G
LG
Croce
Carlo M
CM
Baffa
Raffaele
R
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002085:Butylhydroxybutylnitrosamine / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D002085:Butylhydroxybutylnitrosamine; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase