Functional Roles of Wilms’ Tumor 1 (WT1) in Malignant Brain Tumors

Abstract

Copyright: The Authors.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. AbstractThe pleiotropic transcription factor, Wilms' tumor 1 (WT1), is expressed in the majority of glioblastomas, the most common malignant brain tumors of adulthood. Despite intensive treatment, including surgery and chemoradiotherapy, the prognosis for patients with glioblastoma remains very poor. Encouragingly, immunotherapy targeting WT1 has proven to be effective in recurrent glioblastoma, suggesting that Kijima et al. 262 this approach may be an important new treatment modality for the disease. However, WT1 appears to function as a context-dependent tumor suppressor or oncogene, and the functional roles of WT1 in the pathogenesis of glioblastoma, and other types of brain tumors, have not been extensively studied. With this in mind, we briefly review WT1 expression data for a range of different brain tumor classes and address the role of WT1 in the regulation of proliferation and apoptosis in glioblastoma. We generated WT1 knockdown glioblastoma cells by using shRNA-expressing lentivirus. Proliferation was reduced and apoptosis increased in WT1 knockdown glioblastoma cells compared with control cells in vitro. Consistent with these data, when WT1 knockdown glioblastoma cells or control glioblastoma cells were intracranially injected into the immunodeficient mice, tumor growth was significantly reduced in WT1 knockdown cells compared with that in control cells. Thus, WT1 is an oncogene that regulates cell proliferation and apoptosis in glioblastoma.

Irradiation of pediatric glioblastoma cells promotes radioresistance and enhances glioma malignancyviagenome-wide transcriptome changes

“…G protein-coupled receptor kinase 5 (GRK5) plays an important role in tumor cells’ proliferation [ 14 ]. Fibroblast growth factor 4 (FGF4) also has been correlated with a greater malignancy profile in high-grade gliomas [ 15 ].The radioresistant cells had upregulated expression of many anti-apoptotic genes, including BCL2, CD74, and WT1, which regulates GBM cells proliferation and apoptosis [ 16 ]. A significant upregulation (10-fold) of the AIM2 gene, a tumor-associated antigen, was found.…”

Encouraging Clinical Evolution of a Pediatric Patient With Relapsed Diffuse Midline Glioma Who Underwent WT1-Targeting Immunotherapy: A Case Report and Literature Review

“…Four of these 14 clinical trials, which provided clinical outcomes from pediatric patients with newly diagnosed DIPG/DMG, are summarized in Table 2 —( 1 ) the glioma-associated antigen-based vaccine ( 2 , 19 ) the autologous dendritic cell vaccine ( 3 , 20 ) pidilizumab ( 21 ); and ( 4 ) pegylated IFN-γ-2b ( 22 ). Our pediatric patient, who had relapsed DMG, showed an encouraging clinical evolution presumably due to the following facts: ( 1 ) the vaccine is specific to tumor-overexpressed WT1 that is highly immunogenic, tumorigenic, and angiogenic, and that regulates the apoptosis of many malignant brain tumors ( 23 )—the features that drive us to consider that the WT1 peptide vaccine suppresses tumorigenesis in the patient and tumor angiogenesis and enhances immunogenicity of the patient and tumor apoptosis; ( 2 ) steroid dose reductions were possible; and ( 3 ) the vaccine has a good safety profile. In general, greater refractoriness to treatments is observed in patients with relapsed DMG than in those with newly diagnosed DMG.…”

Wilms' Tumor Protein 1 and Enzymatic Oxidation of 5-Methylcytosine in Brain Tumors: Potential Perspectives

“…WT1 overexpression was observed in 98% of glioblastoma primary cell samples and 83% of anaplastic astrocytomas compared to 53% of grade II oligodendroglioma and pilocytic astrocytomas (Schittenhelm et al, 2008 ). Short hairpin RNA (shRNA) molecules targeting WT1 mRNA transiently silence WT1 gene expression and reduce glioblastoma cell proliferation, viability, and invasion ability suggesting an oncogenic role for WT1 in these malignancies as opposed to the tumor suppressor role this protein plays in Wilms' tumor (Schittenhelm et al, 2008 ; Clark et al, 2010 ; Kijima et al, 2016 ).…”