Aberrations of the FHIT gene and Fhit protein in canine lymphoma cell lines.

The fragile histidine triad (FHIT) gene is a tumor-associated gene, and aberrant FHIT gene and protein expression have been described in many types of human tumors. Furthermore, it has been reported that FHIT gene inactivation is induced by hypermethylation of 5' CpG islands in the gene or by genomic deletion around the open reading frame (ORF). In this study, we explored the aberrations in the canine FHIT gene and Fhit protein expression and assessed the methylation status and genomic deletions by using 5 canine lymphoma cell lines. We found that the decrease in the expression of the Fhit protein in canine lymphoma cell lines was similar to that in human tumors. The expression of the wild-type FHIT transcript was reduced in all 5 cell lines. However, we could not confirm the involvement of aberrant methylation events in the 5' CpG islands of the canine FHIT gene. We were able to identify homozygous or heterozygous deletions in the canine FHIT genes in all 5 cell lines. Moreover, a widespread genomic deletion of the FHIT gene, which included the ORF region, was detected in 1 cell line. In the present study, we detected aberrations in the FHIT gene and Fhit protein expression in all 5 canine lymphoma cell lines, and this phenomenon might be an important factor in promoting canine lymphoma.

[1]  N. Kaneko,et al.  Molecular cloning of the canine fragile histidine triad (FHIT) gene and Fhit protein expression in canine peripheral blood mononuclear cells. , 2009, The Journal of veterinary medical science.

[2]  R. Gaynor,et al.  Loss of FHIT Expression in Breast Cancer Is Correlated with Poor Prognostic Markers , 2005, Cancer Epidemiology Biomarkers & Prevention.

[3]  J. Minna,et al.  5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. , 2001, Cancer research.

[4]  A. Hasegawa,et al.  Establishment and characterization of a canine T-lymphoblastoid cell line derived from malignant lymphoma. , 1997, Veterinary immunology and immunopathology.

[5]  C. Croce,et al.  Fhit modulates the DNA damage checkpoint response. , 2006, Cancer research.

[6]  C. Croce,et al.  The tumor spectrum in FHIT-deficient mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Iliopoulos,et al.  Roles of FHIT and WWOX fragile genes in cancer. , 2006, Cancer letters.

[8]  R. Espinosa,et al.  Identification of unstable sequences within the common fragile site at 3p14.2: implications for the mechanism of deletions within fragile histidine triad gene/common fragile site at 3p14.2 in tumors. , 2002, Cancer research.

[9]  O. Huber,et al.  The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity , 2007, Proceedings of the National Academy of Sciences.

[10]  Jin-Hwang Liu,et al.  Decreased FHIT protein expression correlates with a worse prognosis in patients with diffuse large B-cell lymphoma. , 2004, Oncology Report.

[11]  H. Kantarjian,et al.  Clinical significance of fragile histidine triad gene expression in adult acute lymphoblastic leukemia. , 2001, Leukemia research.

[12]  C. Croce,et al.  Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Nakaichi,et al.  Establishment and characterization of a new canine B-cell leukemia cell line. , 1996, The Journal of veterinary medical science.

[14]  J. Lee,et al.  Histone H3 messenger RNA in situ hybridization correlates with in vivo bromodeoxyuridine labeling of S-phase cells in rat colonic epithelium. , 1996, Cancer research.

[15]  T. Taki,et al.  Pattern of FHIT gene expression in normal and leukaemic cells , 1999, International journal of cancer.

[16]  H. Hoffman,et al.  Decreased fragile histidine triad gene protein expression is associated with worse prognosis in oral squamous carcinoma. , 2009, Archives of pathology & laboratory medicine.

[17]  M. Day,et al.  Development and application of multiple internal reference (housekeeper) gene assays for accurate normalisation of canine gene expression studies. , 2007, Veterinary immunology and immunopathology.

[18]  K. Miyagawa,et al.  Decreased or Altered Expression of the FHIT Gene in Human Leukemias , 1997, Stem cells.

[19]  G. Giaccone,et al.  FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. , 1997, Cancer research.

[20]  C. Croce,et al.  Cancer and the FRA3B/FHIT fragile locus: it's a HIT , 2003, British Journal of Cancer.

[21]  C. Croce,et al.  Muir-Torre-like syndrome in Fhit-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Tsujimoto,et al.  Quantitative assessment of minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction. , 2008, Veterinary immunology and immunopathology.

[23]  D. Iliopoulos,et al.  CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors , 2004, Oncogene.

[24]  Luoping Zhang,et al.  Hypermethylation of the 5′ CpG Island of the FHIT Gene Is Associated with Hyperdiploid and Translocation-Negative Subtypes of Pediatric Leukemia , 2004, Cancer Research.

[25]  G. Cutter,et al.  Inactivation of the p16 Cyclin-Dependent Kinase Inhibitor in High-Grade Canine Non-Hodgkin's T-Cell Lymphoma , 2007, Veterinary pathology.

[26]  A. Gazdar,et al.  Aberrant methylation during cervical carcinogenesis. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  S. Kern,et al.  High resolution analysis of chromosome 3p alterations in cervical carcinoma. , 1997, Cancer research.

[28]  J. Minna,et al.  Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands. , 1997, Cancer research.

[29]  J. V. van Dongen,et al.  Aberrant methylation in promoter-associated CpG islands of multiple genes in acute lymphoblastic leukemia. , 2006, Leukemia research.

[30]  David I. Smith,et al.  Large common fragile site genes and cancer. , 2007, Seminars in cancer biology.

[31]  T. Glover,et al.  Common fragile sites as targets for chromosome rearrangements. , 2006, DNA repair.

[32]  M. Lozano,et al.  Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer , 2004, Modern Pathology.

[33]  M. Taniwaki,et al.  Frequent aberration of FHIT gene expression in acute leukemias. , 1998, Cancer research.

[34]  C. Hallas,et al.  Loss of FHIT expression in acute lymphoblastic leukemia. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  F. Sarkar,et al.  Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors. , 1996, Cancer research.

[36]  M. Tschan,et al.  Aberrant FHIT mRNA transcripts are present in malignant and normal haematopoiesis, but absence of FHIT protein is restricted to leukaemia , 1999, Oncogene.

[37]  Freeman,et al.  Inactivation of the p 16 Cyclin-Dependent Kinase Inhibitor in High-Grade Canine Non-Hodgkin ’ s T-Cell Lymphoma , 2007 .

[38]  R. Gartenhaus Allelic loss determination in chronic lymphocytic leukemia by immunomagnetic bead sorting and microsatellite marker analysis , 1997, Oncogene.

[39]  H. Ishii,et al.  A Fhit-ing Role in the DNA Damage Checkpoint Response , 2007, Cell cycle.