A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor.
OBJECTIVE
Wilms tumor is the most common renal neoplasm of childhood. We previously found that restricted activation of the WNT/β-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial Wilms tumor. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. We sought to define the molecular pathways activated in this process and their relationship to human renal malignancies.


METHODS
Affymetrix® expression microarray data from murine kidneys with activation of K-ras and/or Ctnnb1 (β-catenin) restricted to renal epithelium were analyzed and compared to publicly available expression data on normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry.


RESULTS
Mouse kidney tumors with activation of K-ras and Ctnnb1, and human renal malignancies had similar mRNA expression signatures and were associated with activation of networks centered on β-catenin and TP53. Up-regulation of WNT/β-catenin targets (MYC, Survivin, FOXA2, Axin2 and Cyclin D1) was confirmed by immunoblot. K-RAS/β-catenin murine kidney tumors were more similar to human Wilms tumor than to other renal malignancies and demonstrated activation of a TP53 dependent network of genes, including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in murine and human Wilms tumor samples.


CONCLUSIONS
Simultaneous activation of K-RAS and β-catenin in embryonic renal epithelium leads to neoplasms similar to human Wilms tumor and associated with activation of TP53 and up-regulation of E2F1. Further studies are warranted to evaluate the role of TP53 and E2F1 in human Wilms tumor.
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Yajun
Y
Yi
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Dina
D
Polosukhina
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Harold D
HD
Love
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Austin
A
Hembd
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Michael
M
Pickup
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Harold L
HL
Moses
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Harold N
HN
Lovvorn
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Roy
R
Zent
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: peter.clark@vanderbilt.edu.
Peter E
PE
Clark
D000818:Animals; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005838:Genotype; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
C495267:CTNNB1 protein, mouse; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Wilms tumor; animal; beta catenin; kidney; models; oncogenes