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Fhit loss-associated initiation and progression of neoplasia in vitro.
- Source :
-
Cancer science [Cancer Sci] 2016 Nov; Vol. 107 (11), pp. 1590-1598. Date of Electronic Publication: 2016 Oct 03. - Publication Year :
- 2016
-
Abstract
- The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome "caretaker" whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit-/- and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in -/- cells, and in expression of proteins involved in epithelial-mesenchymal transition. Some Fhit-deficient cell lines showed anchorage-independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit-/- cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia-associated alterations in genes and gene expression patterns in vitro and in vivo.<br /> (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Acid Anhydride Hydrolases genetics
Acid Anhydride Hydrolases metabolism
Animals
Apoptosis genetics
Cell Movement genetics
Cells, Cultured
Epithelial-Mesenchymal Transition genetics
Female
Gene Expression Regulation, Neoplastic
Kidney metabolism
Kidney pathology
Male
Mice
Mice, Inbred C57BL
Neoplasm Metastasis genetics
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Signal Transduction genetics
Thymidine Kinase genetics
Time Factors
Transcription, Genetic
Acid Anhydride Hydrolases deficiency
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Disease Progression
Neoplasm Proteins deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 107
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 27513973
- Full Text :
- https://doi.org/10.1111/cas.13032