Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Li, Wenliang; Kessler, Patricia M.; Williams, Bryan R.G.

doi:10.1038/sj.onc.1208228

Cited by 44 publications

(40 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, we suggest that CRABP-II may differentially regulate the function of MycN, leading to the increased cell migration phenotype observed in tumors overexpressing CRABP-II. Other reports have also shown that in Wilms tumors, very high levels of CRABP-II correlate with poor clinical outcome (46), and a decrease in cell invasion occurs after CRABP-II inhibition in head and neck sarcoma (19).…”

Section: Discussionmentioning

confidence: 99%

“…From analysis of the published microarray data, we found that CRABP-II was expressed in these cell lines, irrespective of the estrogen status but that all of these cell lines expressed high c-myc levels. A previous study from our lab identified both MycN and CRABP-II overexpression in Wilms tumors (46), and expression of MycN correlates with CRABP-II levels in these tumors. 3 Moreover, CRABP-II overexpression in tumors is not explained by their sensitivity or resistance to RA.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cellular Retinoic Acid–Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma

et al. 2006

View full text Add to dashboard Cite

Neuroblastoma is a heterogeneous disease in which 22% of tumors show MycN oncogene amplification and are associated with poor clinical outcome. MycN is a transcription factor that regulates the expression of a number of proteins that affect the clinical behavior of neuroblastoma. We report here that cellular retinoic acid-binding protein II (CRABP-II) is a novel MycN target, expressed at significantly higher levels in primary neuroblastoma tumors with mycN oncogene amplification as compared with non-MycN-amplified tumors. Moreover, regulated induction and repression of MycN in a neuroblastoma-derived cell line resulted in temporal and proportionate expression of CRABP-II. CRABP-II is expressed in several cancers, but its role in tumorigenesis has not been elucidated. We show that MycN binds to the promoter of CRABP-II and induces CRABP-II transcription directly. In addition, CRABP-II-transfected neuroblastoma cell lines show an increase in MycN protein levels resulting in increased cell motility. Gene expression profiling of CRABP-II-expressing cell lines uncovered increased expression of the HuB (Hel N1) gene. Hu proteins have been implicated in regulating the stability of MycN mRNA and other mRNAs by binding to their 3 ¶ untranslated regions. We did not, however, observe any change in MycN mRNA stability or protein half-life in response to CRABP-II expression. In contrast, de novo MycN protein synthesis was increased in CRABP-II-expressing neuroblastoma cells, thereby suggesting an autoregulatory loop that might exacerbate the effects of MycN gene amplification and affect the clinical outcome. Our findings also suggest that CRABP-II may be a potential therapeutic target for neuroblastoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cellular Retinoic Acid–Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma

et al. 2006

View full text Add to dashboard Cite

show abstract

“…In total, genomic abnormalities were found in 29/38 tumors using this approach. Eight tumors with segmental 16q loss of heterozygosity due to deletion were detected (patients 4,7,13,14,20,21,26, and 27 in Table 1). In addition, one tumor (patient 28) exhibited copy-number neutral imbalance of the entire chromosome 16.…”

Section: Q Deletions Are Confined To Immature Tumor Tissue Elementsmentioning

confidence: 99%

“…Gene expression studies have provided additional evidence for the hypothesis that Wilms tumor results from a differentiation block in embryonic kidney formation; genes overexpressed in Wilms tumor are also expressed at the time of the first contact between the ureteric bud and the metanephric mesenchyme, while genes underrepresented in WTs are typically expressed later in kidney development. 3,4 The origin of WTs from potential renal precursors is also supported by the association of Wilms tumor with persistent patches of embryonic tissue in adjacent normal kidney tissue, known as nephrogenic rests. 5 Considering the similarities between Wilms tumor and the developing kidney, it is not surprising that several of the genes affected by somatic mutations in WTs are involved in embryonic kidney development and have been implicated in syndromes of genito-urinary malformation.…”

mentioning

confidence: 97%

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

Mengelbier

Karlsson

Lindgren

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Wilms tumor accounts for more than 95% of kidney tumors in children. The majority of patients receiving modern multimodal therapy are cured, but 10 to 15% still die of disease.1 Histologically, most WTs mimic the fetal developing kidney in which immature cells of the metanephric mesenchyme differentiate into stromal and epithelial elements, the latter of which ultimately give rise to the nephronic tubules and glomeruli.2 The notion that Wilms tumor originates from pluripotent immature cells is supported by its characteristic triphasic histology, including blastemal, epithelial, and stromal components. The blastema consists of undifferentiated mesenchymal cells, resembling the metanephric mesenchyme, while the epithelial component might show different degrees of differentiation, including primitive tubular and glomeruloid formations. Gene expression studies have provided additional evidence for the hypothesis that Wilms tumor results from a differentiation block in embryonic kidney formation; genes overexpressed in Wilms tumor are also

show abstract

“…Failure in FGF/EGF feedback control by genes such as Sprouty might contribute to the undifferentiated metanephric blastema found in Wilms' tumor, where the advanced stage of the disease is known to be correlated with persistent expression of early blastemal markers such as Cited1 and Meox1 (Williams et al, 2004;Li et al, 2005;Lovvorn et al, 2007a;Lovvorn et al, 2007b). The FGF/EGF signaling pathway components that are disrupted by Spry1, or genes that alter Spry1 activity, might represent novel therapeutic targets to combat Wilms' tumor and other cancers that arise from parent stem cells that normally display a requirement for FGF signaling during self-renewal.…”

Section: Research Articlementioning

confidence: 99%

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

et al. 2011

View full text Add to dashboard Cite

SUMMARYRecent studies indicate that nephron progenitor cells of the embryonic kidney are arranged in a series of compartments of an increasing state of differentiation. The earliest progenitor compartment, distinguished by expression of CITED1, possesses greater capacity for renewal and differentiation than later compartments. Signaling events governing progression of nephron progenitor cells through stages of increasing differentiation are poorly understood, and their elucidation will provide key insights into normal and dysregulated nephrogenesis, as well as into regenerative processes that follow kidney injury. In this study, we found that the mouse CITED1 + progenitor compartment is maintained in response to receptor tyrosine kinase (RTK) ligands that activate both FGF and EGF receptors. This RTK signaling function is dependent on RAS and PI3K signaling but not ERK. In vivo, RAS inactivation by expression of sprouty 1 (Spry1) in CITED1 + nephron progenitors results in loss of characteristic molecular marker expression and in increased death of progenitor cells. Lineage tracing shows that surviving Spry1-expressing progenitor cells are impaired in their subsequent epithelial differentiation, infrequently contributing to epithelial structures. These findings demonstrate that the survival and developmental potential of cells in the earliest embryonic nephron progenitor cell compartment are dependent on FGF/EGF signaling through RAS.

show abstract

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Cited by 44 publications

References 74 publications

Cellular Retinoic Acid–Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma

Cellular Retinoic Acid–Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma

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

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

Contact Info

Product

Resources

About