Fhit loss-associated initiation and progression of neoplasia in vitro

Jenna R. Karras, Morgan S. Schrock, Bahadir Batar, Jie Zhang, Krista La Perle, Teresa Druck, Kay Huebner

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1590-1598
Number of pages9
JournalCancer Science
Volume107
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Keywords

  • Cell transformation
  • common fragile site
  • genome instability
  • kidney cell lines
  • tumorigenicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Karras, J. R., Schrock, M. S., Batar, B., Zhang, J., La Perle, K., Druck, T., & Huebner, K. (2016). Fhit loss-associated initiation and progression of neoplasia in vitro. Cancer Science, 107(11), 1590-1598. https://doi.org/10.1111/cas.13032