Changes in WT1 splicing are associated with a specific gene expression profile in Wilms' tumour

Baudry, Dominique; Faussillon, Marine; Cabanis, Marie-Odile; Rigolet, Muriel; Zucker, Jean‐Michel; Patte, Catherine; Sarnacki, Sabine; Boccon‐Gibod, Liliane; Junien, Claudine; Jeanpierre, Marc

doi:10.1038/sj.onc.1205752

Cited by 30 publications

(19 citation statements)

References 37 publications

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“…WT1 is an essential regulator of nephrogenesis (40)(41)(42) and has been suggested to play an important regulatory role in angiogenesis (34,39,43). WT1 and VEGF are co-expressed in normal podocytes, but also in some Wilms' tumors (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1

Hanson

Gorman²,

Reese³

et al. 2007

Front Biosci

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Understanding angiogenesis and growth control is central for elucidating prostate tumorigenesis. However, the mechanisms of activation of the angiogenic gene, vascular endothelial growth factor (VEGF) are complex and its regulation in prostate cancer is not well understood. In previous studies, VEGF expression levels were correlated with altered levels of the zinc finger transcription factor, WTl. Since the VEGF promoter has several potential WTl binding sites and WT1 regulates many growth control genes, here we assessed whether WTl might also regulate VEGF transcription. Using transfection and DNA binding assays, functional WTl binding sites were localized within the proximal VEGF promoter. Transfection of the DDS-WTl (R394W) zinc finger mutant had no significant effect on VEGF-luciferase reporter activity, suggesting that an intact zinc finger DNA binding domain was required. Interestingly, WTl-mediated regulation of VEGF reporter constructs varied in different cell types. In androgen-responsive, LNCaP prostate cancer cells, hormone treatment enhanced WTl-mediated activation of the VEGF promoter constructs. Overall, these results suggest that WTl transcriptionally regulates VEGF through interaction of its zinc finger DNA binding domain with the proximal GC-rich VEGF promoter. These findings may shed light on the role of WTl in angiogenesis and prostate cancer progression.

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Section: Discussionmentioning

confidence: 99%

Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1

Hanson

Gorman²,

Reese³

et al. 2007

Front Biosci

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“…We believe these observations to be completely accurate based on published experimental work that describes decreased VEGF expression in Wilms' tumor [11] using RT-PCR. Compared to clear-cell renal cell carcinoma (ccRCC) (Lenburg et al [12]), which is a highly vascularized tumor [13], Wilms' tumor is an early childhood nephroblastoma that is non-invasive; elevated VEGF would be expected in ccRCC, but not necessarily so in Wilms' tumor.…”

Section: Utility and Discussionmentioning

confidence: 84%

GCOD - GeneChip Oncology Database

et al. 2011

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BackgroundDNA microarrays have become a nearly ubiquitous tool for the study of human disease, and nowhere is this more true than in cancer. With hundreds of studies and thousands of expression profiles representing the majority of human cancers completed and in public databases, the challenge has been effectively accessing and using this wealth of data.DescriptionTo address this issue we have collected published human cancer gene expression datasets generated on the Affymetrix GeneChip platform, and carefully annotated those studies with a focus on providing accurate sample annotation. To facilitate comparison between datasets, we implemented a consistent data normalization and transformation protocol and then applied stringent quality control procedures to flag low-quality assays.ConclusionThe resulting resource, the GeneChip Oncology Database, is available through a publicly accessible website that provides several query options and analytical tools through an intuitive interface.

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“…and VEGF are coexpressed in both normal podocytes and some Wilms tumors (18,20,97). These findings of coordinate expression led to suggestions that WT1 plays an important regulatory role in developmental and tumor angiogenesis (20,51,98).…”

Section: Coexpression Of Wt1 and Vegfmentioning

confidence: 98%

“…These findings of coordinate expression led to suggestions that WT1 plays an important regulatory role in developmental and tumor angiogenesis (20,51,98). For all these reasons, it seemed likely that VEGF was a physiologically relevant target of WT1 regulation in the prostate.…”

Section: Coexpression Of Wt1 and Vegfmentioning

confidence: 99%

“…Within the developing kidney and genitourinary system, the timing of WT1 expression is exquisitely controlled, and once kidney development occurs, WT1 expression is tightly restricted to podocytes (16). WT1 is an essential regulator of nephrogenesis (17)(18)(19) and is expressed in both normal podocytes and in some Wilms tumors (18,20). In addition to the kidney, WT1 is normally expressed in many other organs (6), including hematopoietic tissues such as the spleen, fetal liver, bone marrow, and lymph nodes, gonads, and peripheral nervous system (3,(21)(22)(23)(24)(25).…”

Section: Developmental Expression Of Wt1mentioning

confidence: 99%

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Functional Role of WT1 in Prostate Cancer

et al. 2016

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Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. AbstractAlthough initial discoveries of Wilms tumor 1 (WT1) expression in extrarenal disease generated controversy, we and others have examined WT1 expression in non-Wilms cancers and have demonstrated that the WT1(A) isoform, lacking the lysine-threonine-serine tripeptide (KTS) insertion, transcriptionally regulates the expression of growth control genes in other cancer types. Here, we review our evidence that WT1 is expressed in prostate cancer (PC) epithelial cells and regulates PC critical genes. That WT1 may promote metastatic disease is consistent with previous findings that WT1 suppressed E-cadherin and enhanced motility of PC cells with low migratory and metastatic potential. Recent findings led us to askFraizer et al. 236whether WT1 acts as an angiogenic switch in PC. Although vascular endothelial growth factor (VEGF) is regulated at several levels and by a number of different factors, a mechanistic understanding of WT1-mediated transcriptional regulation in PC cells was previously lacking. Here, we discuss the evidence of WT1-and androgen receptor (AR)-binding sites in the VEGF promoter and show the potential for cooperation between hormone and WT1. These findings revealed that in AR-intact PC cells, WT1 was sufficient to upregulate VEGF transcription, and WT1 expression enhanced the hormone activation of VEGF expression. This notion that WT1 can activate an angiogenic switch in PC cells, to enhance tumor growth and progression to metastatic disease, is consistent with our understanding of the oncogenic nature of WT1 overexpression in inappropriate tissues or at inappropriate times. The potential for WT1 to promote both tumor angiogenesis and PC cell migration suggests that WT1 regulates genes that promote PC progression to lethal metastatic disease. Therapies targeting WT1 in PC may reduce metastatic spread and increase overall survival.

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Changes in WT1 splicing are associated with a specific gene expression profile in Wilms' tumour

Cited by 30 publications

References 37 publications

Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1

Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1

GCOD - GeneChip Oncology Database

Functional Role of WT1 in Prostate Cancer

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