Temporal blastemal cell gene expression analysis in the kidney reveals new Wnt and related signaling pathway genes to be essential for Wilms' tumor onset

Maschietto, Mariana; Trapé, Adriana Priscila; Piccoli, Fabio S.; Ricca, Tatiana Iervolino; Dias, Adriana Abalen Martins; Coudry, Renata A.; Galante, Pedro A. F.; Torres, Carolina Paes; Fahhan, L; Lourenço, Sílvia Vanessa; Grundy, Paul E.; Camargo, Beatriz de; Souza, Sandro de; Neves, E. Jordão; Soares, Fernando Augusto; Brentani, Helena; Carraro, Dirce Maria

doi:10.1038/cddis.2011.105

Cited by 27 publications

(23 citation statements)

References 39 publications

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“…We and others have demonstrated that nephrogenesis and Wilms tumorigenesis share gene expression regulation patterns32333435. Furthermore, repression of miRNA maturation through inhibition of DROSHA and DICER1 expression impairs accurate kidney differentiation363738 and promotes tumorigenesis in several cell lines39.…”

Section: Discussionmentioning

confidence: 98%

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

et al. 2014

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Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.

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Section: Discussionmentioning

confidence: 98%

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

et al. 2014

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“…Wilms tumor is often associated with mutations in 11p15.5 and LOI of the IGF2 locus is found in nearly 90 % of Wilms tumor patients [54]. Previously, expression analysis of Wilm's tumor patients vs normal kidney showed a strong increase in IGF2 mRNA and a corresponding decrease in TIMP3 [55].…”

Section: Discussionmentioning

confidence: 99%

IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes

et al. 2016

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Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

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“…Of additional interest, HDGF (hepatoma-derived growth factor) was also sequenced from the list of peptide signatures, the gene locus for which is located at 1q22–23, as is CRABP2 , a region that if a gain in copy number occurs in FH WT, both event-free and overall survival are reduced. (24, 25) Interestingly, CRABP2 and HDGF have been previously shown to be upregulated at the mRNA level in WT blastema relative to embryonic kidneys.…”

Section: Resultsmentioning

confidence: 98%

Race Disparities in Peptide Profiles of North American and Kenyan Wilms Tumor Specimens

Libes

Seeley

et al. 2014

Journal of the American College of Surgeons

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Background Wilms tumor (WT) is the most common childhood kidney cancer worldwide and arises in children of black African ancestry with greater frequency and severity than other race groups. A biologic basis for this pediatric cancer disparity has not been previously determined. We hypothesized that unique molecular fingerprints might underlie the variable incidence and distinct disease characteristics of WT observed between race groups. Study Design To evaluate molecular disparities between WTs of different race groups, the Children’s Oncology Group provided 80 favorable histology specimens divided evenly between black and white patients and matched for disease characteristics. As a surrogate of sub-Saharan African patients, we also analyzed 18 Kenyan WT specimens. Tissues were probed for peptide profiles using MALDI-TOF imaging mass spectrometry. To control for histologic variability within and between specimens, cellular regions were analyzed separately as triphasic (containing blastema, epithelia, and stroma), blastema-only, and stroma-only. Data were queried using ClinProTools and statistically analyzed. Results Peptide profiles, detected in triphasic WT regions, recognized race with good accuracy, which increased for blastema- or stroma-only regions. Peptide profiles from North American WTs differed between black and white race groups but were far more similar in composition than Kenyan specimens. Individual peptides were identified that also associated with WT patient and disease characteristics (eg, treatment failure and stage). Statistically significant peptide fragments were used to sequence proteins, revealing specific cellular signaling pathways and candidate drug targets. Conclusions WT specimens arising among different race groups show unique molecular fingerprints that could explain disparate incidences and biological behavior and that could reveal novel therapeutic targets.

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Temporal blastemal cell gene expression analysis in the kidney reveals new Wnt and related signaling pathway genes to be essential for Wilms' tumor onset

Cited by 27 publications

References 39 publications

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes

Race Disparities in Peptide Profiles of North American and Kenyan Wilms Tumor Specimens

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