Chromosomal Fragile Site FRA16D tumor suppressor gene Wwox contributes to aerobic metabolism and oxidative stress response
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE22689 | GEO | 2010/12/07
SECONDARY ACCESSION(S): PRJNA128293
REPOSITORIES: GEO
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Project description:The WWOX gene spans chromosomal fragile site FRA16D, a region of DNA instability in cancer. While WWOX has some tumor suppressor characteristics, its normal role and functional contribution to cancer are unclear. Drosophila homozygous Wwox mutants are viable with no discernable phenotype. Drosophila Wwox interactors, identified by proteomics and micro-array analyses, mainly have roles in aerobic metabolism. Functional relationships between Wwox and either isocitrate dehydrogenase (IDH) or superoxide dismutase 1 (Sod1) were confirmed by phenotype modification, including Sod1 âcrinkled-wingâ, indicative of oxidative stress response. Endogenous reactive oxygen species levels reflect Wwox levels in Drosophila. WWOX mRNA levels in Drosophila and human cells correlate with IDH and Sod1 levels. Wwox therefore contributes to pathways involving glucose metabolism and oxidative stress response. Drosophila embryos were harvested between 4-8hrs and total RNA isolated to look for gene-expression differences induced by the presence of one of two altered Wwox alleles relative to wild-type. The two alleles were Wwox (a null mutation generated by homologous recombination) and Wwoxf04545 carrying a pBac insertion in exon 2 (OâKeefe et al., 2005, 2007). Embryo pools were isolated in triplicate, providing 3 biological replicates.
2010-12-07 | E-GEOD-22689 | biostudies-arrayexpress
Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFβ responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFβ signaling in advanced breast cancer.
2013-11-28 | GSE47371 | GEO
Project description:Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of WWOX in driving breast carcinogenesis remains unknown. Here we report that ablation of Wwox in mammary tumor-susceptible mice results in increased tumorigenesis, and that the resultant tumors resemble human BLBC. Interestingly, copy number loss of Trp53 and downregulation of its transcript levels were observed in the Wwox knockout tumors. Moreover, tumors isolated from Wwox and Trp53 mutant mice were indistinguishable histologically and transcriptionally. Finally, we find that deletion of TP53 and WWOX co-occurred and is associated with poor survival of breast cancer patients. Altogether, our data uncover an essential role for WWOX as a bona fide breast cancer tumor suppressor through the maintenance of p53 stability.
2019-05-17 | GSE117387 | GEO
Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFM-NM-2 responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFM-NM-2 signaling in advanced breast cancer. We compared two independent shRNAs: shWWOX-A and shWWOX-B with 3 biological replicates each one, targeting different regions of the WWOX transcript as a means of ruling out any potential off-target effects.
2013-11-28 | E-GEOD-47371 | biostudies-arrayexpress
Project description:The WWOX gene is known for its tumor suppressor character and seems to be one of the main cellular regulators of cell cycle and apoptosis. The aim of the study was to identify cellular pathways and biological processes influenced by WWOX in glioblastoma cells. Our experiment showed that in this type of cancer WWOX, beside cell cycle and apoptosis control, may be involved in metabolism, cytoskeleton structure and differentiation.
2013-10-22 | GSE51481 | GEO
Project description:The WWOX gene is known for its tumor suppressor character and seems to be one of the main cellular regulators of cell cycle and apoptosis. The aim of the study was to identify cellular pathways and biological processes influenced by WWOX in glioblastoma cells. Our experiment showed that in this type of cancer WWOX, beside cell cycle and apoptosis control, may be involved in metabolism, cytoskeleton structure and differentiation. T98G glioblastoma cells were stably transfected with WWOX cDNA. T98G cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.
2013-10-22 | E-GEOD-51481 | biostudies-arrayexpress
Project description:The WWOX gene has been implicated in human cancers, including breast cancer.The development and tumorigenesis between human and mouse mammary glands (MGs) share similar molecular details and signal transduction pathways. We established mouse line that specifically knockout the expression of WWOX gene in the MG epithelial cells (MECs) by crossing BK5-cre mice with our WWOX flox stain. In order to study the gene expression profile in the subpopulation MECs, we isolated the organoids from the 4th MGs of both BK5-cre +; WWOX flox/flox (KO) mice and their WT counterparts (BK5-cre -; WWOX flox/flox), 3 mice each genotype. The total RNA from the mouse MG organoids was extracted and purified by TRIzol/RNeasy Kit and their integrity was checked on Agilent RNA 6000 Nanochip. The goal is to identify the significant perturbation in tumorigenic pathways in these cells induced by WWOX ablation. Mammary gland epithelial organoids samples and gene expression profiles were deribed from three WWOX-KO mice (BK5-cre +; WWOX flox/flox) and from three WWOX-WT mice (BK5-cre -; WWOX flox/flox)
2012-04-14 | E-GEOD-36665 | biostudies-arrayexpress
Project description:The WWOX gene has been implicated in human cancers, including breast cancer.The development and tumorigenesis between human and mouse mammary glands (MGs) share similar molecular details and signal transduction pathways. We established mouse line that specifically knockout the expression of WWOX gene in the MG epithelial cells (MECs) by crossing BK5-cre mice with our WWOX flox stain. In order to study the gene expression profile in the subpopulation MECs, we isolated the organoids from the 4th MGs of both BK5-cre +; WWOX flox/flox (KO) mice and their WT counterparts (BK5-cre -; WWOX flox/flox), 3 mice each genotype. The total RNA from the mouse MG organoids was extracted and purified by TRIzol/RNeasy Kit and their integrity was checked on Agilent RNA 6000 Nanochip. The goal is to identify the significant perturbation in tumorigenic pathways in these cells induced by WWOX ablation.
2012-04-15 | GSE36665 | GEO
Project description:The WWOX gene is a tumor suppressor probably involved in regulation of cell cycle and apoptosis and downregulated in variety of cancer types.However, its role in colon cancerogenesis is unknown. The aim of this study was to characterize how WWOX may be involved in colon cancerogenesis or cancer progression, how it influences the basic cancer cell features and modifies cell expression profile.Our observations suggest that in HT29 colon cancer cell line increased expression of WWOX may result in transition of cancer cells into more normal- like colon epithelium phenotype, on the other hand in SW480 WWOX revealed the well-known tumour suppressor properties. However, as the colon cancer is very heterogeneous disease, obtained discrepancies may reflect the known differences between cell lines and cancerogenesis pathway, which they undergone. HT29 colon cancer cells were stably transfected with WWOX cDNA. HT29 cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.
2014-01-23 | E-GEOD-54298 | biostudies-arrayexpress
Project description:The WWOX gene is a tumor suppressor probably involved in regulation of cell cycle and apoptosis and downregulated in variety of cancer types.However, its role in colon cancerogenesis is unknown. The aim of this study was to characterize how WWOX may be involved in colon cancerogenesis or cancer progression, how it influences the basic cancer cell features and modifies cell expression profile.Our observations suggest that in HT29 colon cancer cell line increased expression of WWOX may result in transition of cancer cells into more normal- like colon epithelium phenotype, on the other hand in SW480 WWOX revealed the well-known tumour suppressor properties. However, as the colon cancer is very heterogeneous disease, obtained discrepancies may reflect the known differences between cell lines and cancerogenesis pathway, which they undergone. SW480 colon cancer cells were stably transfected with WWOX cDNA. SW480 cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.
2014-01-23 | E-GEOD-54299 | biostudies-arrayexpress