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Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic

Antoine M Snijders1, Yueyong Liu1,2, Li Su1

  • 1Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

Oncotarget
|November 18, 2015
PubMed

Insights

The tumor suppressor FBXW7 (F-box and leucine-rich repeat protein with WD40 repeats 7) gene impacts cancer development. Its gene signatures in mouse models predict patient survival, offering potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The FBXW7 gene is a crucial tumor suppressor, frequently altered in human cancers.
  • FBXW7 regulates oncoproteins like mTOR through ubiquitination, impacting cell growth and survival.
  • Understanding FBXW7's role is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of FBXW7 in tumor development using gene transcript profiling.
  • To assess the impact of mTOR inhibition by rapamycin on tumor gene expression and biological functions.
  • To identify conserved FBXW7 gene signatures between mouse models and human cancers.

Main Methods:

  • Gene transcript profiling of radiation-induced thymic lymphomas in Fbxw7/p53 double heterozygous mice.
  • Comparison of gene expression in tumors with and without rapamycin treatment.
  • Analysis of conserved gene signatures and their correlation with patient survival data.

Main Results:

  • Fbxw7/p53 heterozygous tumors showed deregulation of cholesterol metabolism, independent of rapamycin.
  • Cell cycle genes were upregulated in placebo-treated tumors but not in rapamycin-treated tumors.
  • Rapamycin treatment enriched for integrated stress response genes in Fbxw7/p53 heterozygous tumors.
  • FBXW7 gene signatures in mouse tumors significantly overlapped with human cancers and predicted disease-free survival.

Conclusions:

  • FBXW7 plays a significant role in tumor development, influencing metabolic and cell cycle pathways.
  • mTOR inhibition by rapamycin modulates the tumor transcriptome, impacting stress response.
  • Conserved FBXW7 gene signatures offer predictive biomarkers for patient survival and potential therapeutic targets in various cancers.
Keywords:
FBXW7mTORradiationrapamycinthymic lymphoma

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