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Article ; Online: WWOX, the tumour suppressor gene affected in multiple cancers.

Lewandowska, U / Zelazowski, M / Seta, K / Byczewska, M / Pluciennik, E / Bednarek, A K

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society

2009 Volume 60 Suppl 1, Page(s) 47–56

Abstract: WWOX is a tumour suppressor gene affected in multiple cancers, especially in breast, prostate and ... chromosomal fragile site FRA16D. WWOX turned out to possess tumour suppressor features despite the fact that the most basic ... classical) way of tumour suppressor gene inactivation involves both alleles (e.g. through deletions ...

Abstract	WWOX is a tumour suppressor gene affected in multiple cancers, especially in breast, prostate and ovary. This gene is located at the chromosomal area 16q23.3-24.1, which was identified as a common chromosomal fragile site FRA16D. WWOX turned out to possess tumour suppressor features despite the fact that the most basic (classical) way of tumour suppressor gene inactivation involves both alleles (e.g. through deletions, point mutations and promoter methylation), which is very rare event in a case of WWOX, occurring only in few cell lines. A large number of papers corroborate the phenomenon of correlation between the loss of WWOX expression and more aggressive/worse prognosis in many different types of tumours, for example breast cancer, nonsmall cell lung cancer, bladder cancer, gastric cancer or sporadic meningiomas. Ectopically increased WWOX expression promotes migration through basal membrane, however suppresses anchorage independent growth and induces normal-like colony formation in matrigel.
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Female ; Genes, Tumor Suppressor ; Humans ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidoreductases/genetics ; Tumor Suppressor Proteins/genetics ; WW Domain-Containing Oxidoreductase
Chemical Substances	Tumor Suppressor Proteins ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-)
Language	English
Publishing date	2009-05
Publishing country	Poland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1125221-2
ISSN	1899-1505 ; 0867-5910 ; 0044-6033
ISSN (online)	1899-1505
ISSN	0867-5910 ; 0044-6033
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Article ; Online: Functional genetic variant of WW domain-containing oxidoreductase (WWOX) gene is associated with hepatocellular carcinoma risk.

Lee, Hsiang-Lin / Cheng, Hsin-Lin / Liu, Yu-Fan / Chou, Ming-Chih / Yang, Shun-Fa / Chou, Ying-Erh

PloS one

2017 Volume 12, Issue 4, Page(s) e0176141

Abstract: ... Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene ... in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk ... polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion ...

Abstract	Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk. Methodology/principal findings: Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion. Conclusions: In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alleles ; Amino Acid Sequence ; Biomarkers, Tumor/genetics ; Carcinoma, Hepatocellular/genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Liver Neoplasms/genetics ; Male ; Middle Aged ; Oxidoreductases/chemistry ; Oxidoreductases/genetics ; Polymorphism, Single Nucleotide ; Sequence Homology, Amino Acid ; Tumor Suppressor Proteins/chemistry ; Tumor Suppressor Proteins/genetics ; WW Domain-Containing Oxidoreductase
Chemical Substances	Biomarkers, Tumor ; Tumor Suppressor Proteins ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-)
Language	English
Publishing date	2017-04-20
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0176141
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Article: WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies.

Aldaz, C Marcelo / Ferguson, Brent W / Abba, Martin C

Biochimica et biophysica acta

2014 Volume 1846, Issue 1, Page(s) 188–200

Abstract: ... Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse ... WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D ... Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel ...

Abstract	WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers and uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer. Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism. Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.
MeSH term(s)	Animals ; Central Nervous System Diseases/genetics ; Evolution, Molecular ; Humans ; Metabolic Syndrome/genetics ; Mice ; Mutation ; Neoplasms/genetics ; Oxidoreductases/physiology ; Quantitative Trait Loci ; Tumor Suppressor Proteins/physiology ; WW Domain-Containing Oxidoreductase
Chemical Substances	Tumor Suppressor Proteins ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-)
Language	English
Publishing date	2014-06-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbcan.2014.06.001
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Article ; Online: Upregulation of tumor suppressor WWOX promotes immune response in glioma.

Yang, Zhao / Zhao, Tianzhi / Liu, Yong

Cellular immunology

2013 Volume 285, Issue 1-2, Page(s) 1–5

Abstract: ... surveillance system, result in aggressive proliferation. WWOX, a tumor suppressor gene affected in multiple cancers ... induces tumor apoptosis and suppresses growth in vitro and in vivo. However, the effect of WWOX expression ... in glioma cells to immune cells is still unknown. In the present study, we transduced WWOX into human glioma ...

Abstract	Previous studies demonstrate that human glioma cells could evade the host's immune surveillance system, result in aggressive proliferation. WWOX, a tumor suppressor gene affected in multiple cancers, induces tumor apoptosis and suppresses growth in vitro and in vivo. However, the effect of WWOX expression in glioma cells to immune cells is still unknown. In the present study, we transduced WWOX into human glioma cell line U251, and cocultured with Jurkat T cells together. We demonstrated that upregulation of WWOX could increase proliferation of Jurkat T cells and decrease the FasL and TGF-β expression of U251 cells, result in inhibiting apoptosis of Jurkat T cells. Therefore, our results 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.
MeSH term(s)	Animals ; Apoptosis ; Carcinogenesis/genetics ; Caspase 3/immunology ; Cell Line, Tumor ; Cell Proliferation ; Fas Ligand Protein/biosynthesis ; Fas Ligand Protein/metabolism ; Genes, Tumor Suppressor ; Glioma/genetics ; Glioma/immunology ; Humans ; Jurkat Cells ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation ; Oxidoreductases/biosynthesis ; Oxidoreductases/genetics ; Oxidoreductases/metabolism ; Signal Transduction/immunology ; Transforming Growth Factor beta/biosynthesis ; Tumor Escape ; Tumor Suppressor Proteins/biosynthesis ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; WW Domain-Containing Oxidoreductase
Chemical Substances	FASLG protein, human ; Fas Ligand Protein ; Transforming Growth Factor beta ; Tumor Suppressor Proteins ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-) ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2013-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2013.07.015
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Article ; Online: Genetic association study identifies a functional CNV in the WWOX gene contributes to the risk of intracranial aneurysms.

Fan, Jin / Sun, Wen / Lin, Min / Yu, Ke / Wang, Jian / Duan, Dan / Zheng, Bo / Yang, Zhenghui / Wang, Qingsong

Oncotarget

2016 Volume 7, Issue 13, Page(s) 16104–16111

Abstract: ... domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple ... 67048 could also affect susceptibility of IAs. Based on a two-stage, case- control study with a total ... used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes ...

Abstract	Intracranial aneurysms (IAs) accounts for 85% of hemorrhagic stroke. Genetic factors have been known to play an important role in the development of IAs. A functional CNV (CNV-67048) of human WW domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple cancers, was identified to be associated with gliomas risk previously. Here, we hypothesized that the CNV-67048 could also affect susceptibility of IAs. Based on a two-stage, case- control study with a total of 976 patients of IAs and 1,200 matched healthy controls, we found the effect size for per copy deletion was 1.35 (95% CI = 1.16-1.57; Ptrend = 1.18 × 10-4). Compared with the individuals having no deletion, significantly higher risk of IAs was detected for both subjects carrying 1 copy deletion (OR = 1.24, 95% CI = 1.02-1.52) and subjects carrying 2 copy deletion (OR = 1.77, 95% CI = 1.24-2.53). Real-time PCR was used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes of CNV-67048. The expression level of WWOX in IA tissues was significantly lower than that in corresponding normal tissues (P = 0.004), and the deletion genotypes of CNV-67048 have lower WWOX mRNA levels in both tumor tissues and border tissues (P < 0.01). Our data suggests that the deletion genotypes of CNV-67048 in WWOX predispose their carriers to IAs, which might be a genetic biomarker to predict risk of IAs in Chinese.
Language	English
Publishing date	2016-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.7546
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Article ; Online: Functional genetic variant of WW domain-containing oxidoreductase (WWOX) gene is associated with hepatocellular carcinoma risk.

Hsiang-Lin Lee / Hsin-Lin Cheng / Yu-Fan Liu / Ming-Chih Chou / Shun-Fa Yang / Ying-Erh Chou

PLoS ONE, Vol 12, Iss 4, p e

2017 Volume 0176141

Abstract: ... domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple ... Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression ... at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and ...

Abstract	Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk.Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion.In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Functional genetic variant of WW domain-containing oxidoreductase (WWOX) gene is associated with hepatocellular carcinoma risk.

Hsiang-Lin Lee / Hsin-Lin Cheng / Yu-Fan Liu / Ming-Chih Chou / Shun-Fa Yang / Ying-Erh Chou

PLoS ONE, Vol 12, Iss 4, p e

2017 Volume 0176141

Abstract: ... Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene ... in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk. METHODOLOGY ... polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion. CONCLUSIONS ...

Abstract	BACKGROUND:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk. METHODOLOGY/PRINCIPAL FINDINGS:Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion. CONCLUSIONS:In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase.

Lin, Jen-Tai / Li, Hao-Yi / Chang, Nan-Shan / Lin, Cheng-Han / Chen, Yu-Chia / Lu, Pei-Jung

Cell cycle (Georgetown, Tex.)

2014 Volume 14, Issue 3, Page(s) 408–416

Abstract: WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple ... cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and ... phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown ...

Abstract	WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.
MeSH term(s)	Animals ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cyclin D1/metabolism ; Disease Progression ; G1 Phase ; Gene Silencing ; Humans ; Male ; Mice, Nude ; Oxidoreductases/metabolism ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins c-jun/metabolism ; Tumor Suppressor Proteins/metabolism ; WW Domain-Containing Oxidoreductase
Chemical Substances	CCND1 protein, human ; Proto-Oncogene Proteins c-jun ; Tumor Suppressor Proteins ; Cyclin D1 (136601-57-5) ; Oxidoreductases (EC 1.-) ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-)
Language	English
Publishing date	2014-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/15384101.2014.977103
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Article: Upregulation of tumor suppressor WWOX promotes immune response in glioma

Yang, Zhao / Zhao, Tianzhi / Liu, Yong

Cellular immunology. 2013 , v. 285, no. 1-2

2013

Abstract	Previous studies demonstrate that human glioma cells could evade the host’s immune surveillance system, result in aggressive proliferation. WWOX, a tumor suppressor gene affected in multiple cancers, induces tumor apoptosis and suppresses growth in vitro and in vivo. However, the effect of WWOX expression in glioma cells to immune cells is still unknown. In the present study, we transduced WWOX into human glioma cell line U251, and cocultured with Jurkat T cells together. We demonstrated that upregulation of WWOX could increase proliferation of Jurkat T cells and decrease the FasL and TGF-β expression of U251 cells, result in inhibiting apoptosis of Jurkat T cells. Therefore, our results 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.
Keywords	T-lymphocytes ; apoptosis ; carcinogenesis ; coculture ; humans ; immune response ; monitoring ; neoplasms ; transforming growth factor beta ; tumor suppressor genes
Language	English
Dates of publication	2013-09
Size	p. 1-5.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2013.07.015
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Article: WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.

Bednarek, A K / Keck-Waggoner, C L / Daniel, R L / Laflin, K J / Bergsagel, P L / Kiguchi, K / Brenner, A J / Aldaz, C M

Cancer research

2001 Volume 61, Issue 22, Page(s) 8068–8073

Abstract: ... prostate, and other cancers affecting this region suggests that WWOX is a candidate tumor suppressor gene ... as a potent suppressor of tumor growth and suggest that abnormalities affecting this gene at the genomic and ... in chromosome 16q23.3-24.1. It was observed that the genomic area spanned by WWOX is affected ...

Abstract	We recently reported the cloning of WWOX, a gene that maps to the common fragile site FRA16D region in chromosome 16q23.3-24.1. It was observed that the genomic area spanned by WWOX is affected by chromosomal translocations and homozygous deletions. Furthermore, the high incidence of allelic loss in breast, ovarian, prostate, and other cancers affecting this region suggests that WWOX is a candidate tumor suppressor gene. Expression of WWOX is highly variable in breast cancer cell lines, with some cases showing low or undetectable levels of expression. In this report, we demonstrate that ectopic WWOX expression strongly inhibits anchorage-independent growth in soft agar of breast cancer cell lines MDA-MB-435 and T47D. Additionally, we observed that WWOX induces a dramatic inhibition of tumorigenicity of MDA-MB-435 breast cancer cells when tested in vivo. We also detected the common occurrence of aberrant WWOX transcripts with deletions of exons 5-8 or 6-8 in various carcinoma cell lines, multiple myeloma cell lines, and primary breast tumors. These aberrant mRNA forms were not detected in normal tissues. Interestingly, we further observed that proteins encoded by such aberrant transcripts display an abnormal nuclear localization in contrast to the wild-type WWOX protein that localizes to the Golgi system. Our data indicate that WWOX behaves as a potent suppressor of tumor growth and suggest that abnormalities affecting this gene at the genomic and transcriptional level may be of relevance in carcinogenesis.
MeSH term(s)	Alternative Splicing ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Carrier Proteins/biosynthesis ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Division/genetics ; Chromosomes, Human, Pair 16/genetics ; DNA Methylation ; Exons ; Gene Deletion ; Genes, Tumor Suppressor ; Green Fluorescent Proteins ; Humans ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Microscopy, Confocal ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Promoter Regions, Genetic ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Transfection ; Tumor Cells, Cultured
Chemical Substances	Carrier Proteins ; Luminescent Proteins ; Neoplasm Proteins ; RNA, Messenger ; Recombinant Fusion Proteins ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2001-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
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