The E2F3-Oncomir-1 Axis Is Activated in Wilms' Tumor

Abstract

Oncomir-1 is an oncogenic cluster of microRNAs (miRNA) located on chromosome 13. Previous in vitro studies showed that it is transcriptionally regulated by the transcription factor E2F3. In this report, we combine expression profiling of both mRNA and miRNAs in Wilms' tumor (WT) samples to provide the first evidence that the E2F3-Oncomir-1 axis, previously identified in cell culture, is deregulated in primary human tumors. Analysis of RNA expression signatures showed that an E2F3 gene signature was activated in all WT samples analyzed, in contrast to other kidney tumors. This finding was validated by immunohistochemistry on the protein level. Expression of E2F3 was lowest in early-stage tumors and highest in metastatic tissue. Expression profiling of miRNAs in WT showed that expression of each measured member of the Oncomir-1 family was highest in WT relative to other kidney tumor subtypes. Quantitative PCR confirmed that these miRNAs were overexpressed in WT relative to normal kidney tissue. These results suggest that the E2F3-Oncomir-1 axis is activated in WT. Our study also shows the utility of integrated genomics combining gene signature analysis with miRNA expression profiling to identify protein-miRNA interactions that are perturbed in disease states. [Cancer Res 2008;68(11):4034-8]

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

“…amjpathol.org; P Ͻ 0.05; stages I and II versus stage III; only one case with stage IV was included in the dataset). 33 None of the other six genes showed any correlation to stage.…”

“…Of the six genes, only IRX3, IRX5 and IRX6 showed a significant reduction of expression in tumors with 16q deletions ( Figure 4A). 33 Of the ten most common recurrent genomic imbalances in our material (trisomies 12 and 13, segmental gains in 1q, 7q, and 18q, segmental loss in 7p, 11p, 11q, and 16q, and copy number neutral imbalance of 11p; present in 11 to 34% of cases; Supplemental Tables 1 and 3 at http://ajp. amjpathol.org), only 16q deletion was associated with differential IRXB gene cluster expression (P Ͼ 0.06 for all other aberrations).…”

“…The external dataset (GEO ID GSE11024) consisted of 27 WTs, 33 profiled on the Affymetrix HG-U133 Plus 2.0 GeneChip and normalized by the RMA algorithm. Comparisons between groups were made on normalized intensity values by the Mann-Whitney U-test.…”

“…To identify possible candidate genes in the SRO with a role in differentiation block of blastic-anaplastic cells and the development of aggressive disease, a bioinformatic evaluation was first performed using a recently published Wilms tumor mRNA expression microarray dataset, comprising 27 WTs. 33 We based our analysis on the assumption that a suitable candidate gene should fulfill two criteria: (1) its expression should correlate to clinic-pathological features, and (2) its expression should correlate to genes involved in differentiation/morphogenesis. The external dataset contained mRNA expression profiles of eight of the nine Table 1 genes in the SRO (ie, IRX3, IRX5, LPCAT2, SLC6A2, MMP2, CES1, CES4, and CES7).…”

465 Rna Sequencing Reveals Up-Regulation of Runx1-Runx1t1 Gene Signatures in Clear Cell Renal Cell Carcinoma

“…To determine whether the RUNX1-RUNX1T1 gene sets were specifically upregulated in the clear cell subtype, we performed another in silico study based on a second cohort of microarray data which included the most common subtypes of kidney cancers, including 27 Wilms' tumor, 10 ccRCC, 6 chromophobe, 7 oncocytoma, 17 papillary renal cell carcinoma, and 12 normal kidney samples [26]. The upregulation of VHL/HIF and RUNX1-RUNX1T1 gene sets was only observed in the clear cell subtype (Figures 1(b) and 1(c)).…”