Upregulation of tumor suppressor WWOX promotes immune response in glioma

Yang, Zhao; Zhao, Tianzhi; Liu, Yong

doi:10.1016/j.cellimm.2013.07.015

Cited by 6 publications

(8 citation statements)

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“…WWOX and FHIT have long been known to reside at common fragile sites and have been demonstrated to act as suppressors of tumor development by gene knockout mouse models [ 18 ]. Moreover, WWOX overexpression was shown to promote the immune response in a glioma model [ 19 ] while FHIT positively regulates expression of MHC class I molecules on cancer cells [ 20 ]. These data suggest that loss of function of WWOX and FHIT help to escape immunosurveillance.…”

Section: Discussionmentioning

confidence: 99%

High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

Broek

Dijkstra²,

Krijgsman

et al. 2015

PLoS ONE

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BackgroundCancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes.MethodsPrimary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases.ResultsIn total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR <0.1). MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis.ConclusionsWe conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC.

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Section: Discussionmentioning

confidence: 99%

High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

Broek

Dijkstra²,

Krijgsman

et al. 2015

PLoS ONE

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“…12,24,25 Yang et al found that the up-regulation of WWOX could increase proliferation of Jurkat T cells and decrease the FasL and TGF-beta expression of U251 cells, and result in inhibiting apoptosis of Jurkat T cells. 12 These suggested that loss of WWOX expression not only resulted in glioma carcinogenesis, but also suppressed immune cell attack by inducing Fas/ FasL mediated apoptotic signaling. Findings of our study fit with current research about gliomagenesis in the context of immune function.…”

Section: Epidemiologymentioning

confidence: 99%

“…It plays an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing . Multiple tumors have been identified to be associated with expression of WWOX gene and this gene frequently loses function in the initiation of tumorigenesis as well as neoplastic process, including gliomas …”

mentioning

confidence: 99%

“…7 Multiple tumors have been identified to be associated with expression of WWOX gene and this gene frequently loses function in the initiation of tumorigenesis as well as neoplastic process, including gliomas. [8][9][10][11][12][13] Considering the potential function of WWOX gene in the process of tumorigenesis, it is possible that CNVs in this gene are associated with glioma risk. To test this hypothesis, we performed a case-control study among Chinese people.…”

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confidence: 99%

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Association study of a functional copy number variation in the WWOX gene with risk of gliomas among Chinese people

Fan

Ding

et al. 2014

Intl Journal of Cancer

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Gliomas represents more than 80% of all malignant brain tumors. However, the etiology still remains largely unknown. Human WW domain-containing oxidoreductase (WWOX), which is located at 16q23.1-16q23.2, the common fragile site 16D (FRA16D), an area with a high frequency of gene deletions or chromosomal alterations, has been identified as a tumor suppressor gene in multiple cancers. In current study, we analyzed the WWOX deletion (CNV-67048) in a large, case-control study of 3,622 adult Chinese people (including 1,798 glioma cases and 1,824 healthy controls). All participants were genotyped using realtime qualitative PCR (qPCR), and its biological effect was validated with mRNA expression assays. The deletion was significantly associated with glioma risk, with ORs (95% CIs) of 1.21 (1.05-1.41) associated with 1 copy deletion and 1.94 (1.37-2.75) associated with 2 copy deletion as compared with subjects with no deletion (p for trend 5 8.05 3 10 26 ). Additional adjustments and stratified analyses did not change the results materially. The mRNA levels of WWOX in glioma tissues were significantly lower than that of their border tissues (p 5 0.007), especially in the loss genotyped subjects. Our data suggest that the loss genotypes of CNV-67048 in WWOX gene predispose their carriers to gliomas, and WWOX gene deletion may be a new biomarker for predicting risk of gliomas.

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“…92 The ectopic expression of WWOX in U251MG cells decreases FasL and TGFb expression, resulting in inhibiting apoptosis and increasing the proliferation of co-cultured Jurkat T cells. 93 The loss of WWOX in GBM not only enhances carcinogenesis but also suppresses immune cell attack by apoptotic signaling. The overexpression of WWOX induces apoptosis in p53-mt U373MG cells via mitochondria-independent and caspase 3-independent pathways but not in p53-wt U87MG cells.…”

Section: Therapeutic Potential Of Wwox In Gbmmentioning

confidence: 99%

Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma

Liu

Chiang

Chen

2014

Exp Biol Med (Maywood)

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Glioblastoma multiforme (GBM) is the most aggressive and malignant brain tumor. Delicate microenvironment and lineage heterogeneity of GBM cells including infiltration, hypoxia, angiogenesis, and stemness make them highly resistant to current conventional therapies, with an average life expectancy for GBM patients of less than 15 months. Poor response to cytotoxic agents of GBM cells remains the major challenge of GBM treatment. Resistance of GBM to clinical treatment is a result of genomic alternation and deregulated signaling pathways, such as p53 mutation and apoptosis signaling blockage, providing cancer cells more opportunities for survival rather than cell death. WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene, commonly downregulated in various types of tumors, including GBM. It has been found that the reintroduction of WWOX induced p53-mutant GBM cells to undergo apoptosis, but not in p53 wild-type GBM cells, indicating WWOX is likely to reopen apoptosis pathways in a p53-independent manner in GBM. Identifying the crucial target modulated by WWOX deficiency provides a potential therapeutic target for GBM treatment. Here, we have reviewed the literatures about the role of WWOX in development, signaling pathway, prognosis, and treatment response in malignant glioma.

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Upregulation of tumor suppressor WWOX promotes immune response in glioma

Cited by 6 publications

References 31 publications

High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

Association study of a functional copy number variation in the WWOX gene with risk of gliomas among Chinese people

Role of WW domain proteins WWOX in development, prognosis, and treatment response of glioma

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