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M Traczyk-Borszynska, E Borkowska, Z Jablonowski, A Jedrzejczyk, M Pietrusinski, B Kaluzewski, M Sosnowski, M Borowiec
The aim of the study was to assess the genetic diversity of bladder cancer and determine the suitability of a proposed molecular marker panel to monitor the course of bladder cancer patients. The study involved 185 patients with diagnosed bladder cancer. The genetic diversity of the bladder cancer was evaluated by the prevalence of mutations in the TP53, HRAS, FGFR3 and WWOX genes. Mutations were detected in 62.2% of the tumor samples. The most frequently mutated genes were FGFR3 (49.7%) and TP53 (16.2%). No mutation was observed in the WWOX gene...
September 6, 2016: Neoplasma
Taketo Nishikawaji, Yoshimitsu Akiyama, Shu Shimada, Kazuyuki Kojima, Tatsuyuki Kawano, Yoshinobu Eishi, Yasuhito Yuasa, Shinji Tanaka
SETDB2 is a histone H3 lysine 9 (H3K9) tri-methyltransferase that is involved in transcriptional gene silencing. Since it is still unknown whether SETDB2 is linked to carcinogenesis, we studied alterations and functions of SETDB2 in human gastric cancers (GCs). SETDB2 protein was highly expressed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts by immunohistochemistry. SETDB2 overexpression was significantly associated with the late stage of GCs (P<0.05) and poor prognosis of GC patients (P<0...
August 26, 2016: Oncotarget
Virpi M Leppa, Stephanie N Kravitz, Christa Lese Martin, Joris Andrieux, Cedric Le Caignec, Dominique Martin-Coignard, Christina DyBuncio, Stephan J Sanders, Jennifer K Lowe, Rita M Cantor, Daniel H Geschwind
Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families...
September 1, 2016: American Journal of Human Genetics
Sara Del Mare, Hussam Husanie, Ortal Iancu, Mohammad Abu-Odeh, Konstantinos Evangelou, Francesca Lovat, Stefano Volinia, Jonathan Gordon, Gail Amir, Janet Stein, Gary S Stein, Carlo M Croce, Vassilis Gorgoulis, Jane B Lian, Rami I Aqeilan
Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (Wwox(Δosx1)) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts...
October 15, 2016: Cancer Research
Worapong Singchat, Ekarat Hitakomate, Budsaba Rerkarmnuaychoke, Aorarat Suntronpong, Beiyuan Fu, Winai Bodhisuwan, Surin Peyachoknagul, Fengtang Yang, Sittichai Koontongkaew, Kornsorn Srikulnath
Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines...
2016: PloS One
Loai Elsaadany, Mahmoud El-Said, Rehab Ali, Hussein Kamel, Tawfeg Ben-Omran
BACKGROUND: WW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death. CASE PRESENTATION: Clinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death...
2016: BMC Medical Genetics
Gang Li, Longfeng Sun, Zhongyi Mu, Yan Huang, Cheng Fu, Bin Hu
WW domain-containing oxidoreductase (WWOX) gene located in the common fragile site FRA16D region exhibits loss or reduction of expression in multiple types of carcinomas including bladder cancer. However, the role of WWOX in the tumorigenesis and development of bladder cancer remains elusive. In this study, WWOX overexpression construct was transfected into 5637 bladder cancer cell line in which WWOX expression was compromised. Constitutive expression of ectopic WWOX in 5637 cells suppressed cell proliferation and cell cycle progression, which was associated with downregulation of Cyclin B, D1, and E...
November 2015: Cell Biochemistry and Biophysics
Shenq-Shyang Huang, Wan-Pei Su, Hsin-Pin Lin, Hsiang-Ling Kuo, Hsiao-Ling Wei, Nan-Shan Chang
Whether tumor suppressor WWOX (WW domain-containing oxidoreductase) stimulates immune cell maturation is largely unknown. Here, we determined that Tyr-33-phosphorylated WWOX physically binds non-phosphorylated ERK and IκBα in immature acute lymphoblastic leukemia MOLT-4 T cells and in the naïve mouse spleen. The IκBα·ERK·WWOX complex was shown to localize, in part, in the mitochondria. WWOX prevents IκBα from proteasomal degradation. Upon stimulating MOLT-4 with ionophore A23187/phorbol myristate acetate, endogenous IκBα and ERK undergo rapid phosphorylation in <5 min, and subsequently WWOX is Tyr-33 and Tyr-287 de-phosphorylated and Ser-14 phosphorylated...
August 12, 2016: Journal of Biological Chemistry
Lingqing Luo, Yan Chen, Xiao Cheng, Yazhen Lin, Xiaodan Fu, Dan Li, Zhaolei Cui, Donghong Lin
The role of the WW domain-containing oxidoreductase (WWOX) gene in multiple types of solid human cancers has been documented extensively thus far. Recently, we investigated the in vitro effects of WWOX overexpression and observed marked growth arrest in human leukemia cells; however, the clinical characterization of WWOX in leukemia remains poorly investigated. The present study evaluated the WWOX expression profiles of 182 patients with leukemia of different types and 5 leukemic cell lines, using reverse transcription-polymerase chain reaction and immunofluorescence analysis...
June 2016: Oncology Letters
Idit Hazan, Mohammad Abu-Odeh, Thomas G Hofmann, Rami I Aqeilan
Common fragile sites (CFSs) tend to break upon replication stress and have been suggested to be "hot spots" for genomic instability. Recent evidence, however, implies that in the wake of DNA damage, WW domain-containing oxidoreductase (WWOX, the gene product of the FRA16D fragile site), associates with ataxia telangiectasia-mutated (ATM) and regulates its activation to maintain genomic integrity.
October 2015: Molecular & Cellular Oncology
Yongxiu Chen, Xiaochang Tan, Yongli Ding, Bi Mai, Xiaowen Huang, Guiying Hu, Xiping Luo
Copy number variations (CNVs) have attracted increasing evidences to represent their roles as cancer susceptibility regulators. However, little is known about the role of CNV in epithelia ovarian cancer (EOC). Recently, the CNV-67048 of WW domain-containing oxidoreductase (WWOX) was reported to alter cancer risks. Considering that WWOX also plays a role in EOC, we hypothesized that the CNV-67048 was associated with EOC risk. In a case-control study of 549 EOC patients and 571 age (±5 years) matched cancer-free controls, we found that the low copy number of CNV-67048 (1-copy and 0-copy) conferred a significantly increased risk of EOC (OR = 1...
2016: BioMed Research International
Asem M Alkhateeb, Samah K Aburahma, Wesal Habbab, I Richard Thompson
Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software...
August 2016: Metabolic Brain Disease
Niannian Zhang, Zhenghui Jiang, Weifeng Ren, Li Yuan, Yangyi Zhu
The WW domain-containing oxidoreductase (WWOX) gene is a tumor suppressor gene, the abnormal expression of which will lead to osteosarcoma tumorigenesis. Polymorphisms of the WWOX gene are associated with the risk of several malignancies. We hypothesized that genetic variations in the WWOX gene were related to osteosarcoma risk and outcome. In this case-control study, we recruited 276 young osteosarcoma patients and 286 controls from the East Chinese population and genotyped seven tag single-nucleotide polymorphisms (SNPs) of the WWOX gene (rs10220974C>T, rs12918952G>A, rs3764340C>G, rs1074963C>G, rs383362G>T, rs1424110A>G, and rs12828A>G)...
2016: OncoTargets and Therapy
Jin Fan, Wen Sun, Min Lin, Ke Yu, Jian Wang, Dan Duan, Bo Zheng, Zhenghui Yang, Qingsong Wang
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...
March 29, 2016: Oncotarget
Chenli Xie, Xiaoliang Chen, Fuman Qiu, Lisha Zhang, Di Wu, Jiansong Chen, Lei Yang, Jiachun Lu
Single nucleotide polymorphisms (SNPs) in the WW domain containing oxidoreductase (WWOX) gene were recently identified to be quantitative trait loci for lung function and thus likely to be susceptible biomarkers for COPD. However, the associations between WWOX SNPs and COPD risk are still unclear. Here, by conducting a two-center case-control study including 1511 COPD cases and 1677 controls and a family-based analysis comprising 95 nuclear pedigrees, we tested the associations between five SNPs that are rs10220974C >T, rs3764340C >G, rs12918952G >A, rs383362G >T, rs12828G >A of WWOX and COPD risk as well as the hereditary inclination of these loci among COPD families...
2016: Scientific Reports
Markus A Schirmer, Claudia M Lüske, Sebastian Roppel, Alexander Schaudinn, Christian Zimmer, Ruben Pflüger, Martin Haubrock, Jacobe Rapp, Cenap Güngör, Maximilian Bockhorn, Thilo Hackert, Thomas Hank, Oliver Strobel, Jens Werner, Jakob R Izbicki, Steven A Johnsen, Jochen Gaedcke, Jürgen Brockmöller, B Michael Ghadimi
BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects. METHODS: This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy...
May 2016: Journal of the National Cancer Institute
E Płuciennik, M Nowakowska, M Gałdyszyńska, M Popęda, A K Bednarek
The purpose of the present study was to investigate the role of WW domain containing oxidoreductase (WWOX) downregulation in biological cancer-related processes in normal (non-malignant) and cancer endometrial cell lines. We created an in vitro model using the normal endometrial cell line, THESC, and 2 endometrial cancer cell lines with varying degrees of differentiation, the Ishikawa (well-differentiated) and the MFE296 (moderately differentiated) cells, in which the WWOX tumor suppressor gene was silenced using Gipz lentiviral shRNA...
March 2016: International Journal of Molecular Medicine
Mohammad Abu-Odeh, Nyla A Hereema, Rami I Aqeilan
For many decades genomic instability is considered one of the hallmarks of cancer. Role of the tumor suppressor WWOX (WW domain-containing oxidoreductase) in DNA damage response upon double strand breaks has been recently revealed. Here we demonstrate unforeseen functions for WWOX upon DNA single strand breaks (SSBs) checkpoint activation. We found that WWOX levels are induced following SSBs and accumulate in the nucleus. WWOX deficiency is associated with reduced activation of ataxia telangiectasia and Rad3-related protein (ATR) checkpoint proteins and increased chromosomal breaks...
January 26, 2016: Oncotarget
Bo Zhu, Danna Wang, Qiong Zhang, Shiwu Wu, Lan Yu, Yisheng Tao
OBJECTIVE: To investigate the expressions of WWOX and CD133 in colorectal cancer (CRC) and their relationship with the clinicopathologic characteristics of CRC. METHODS: The expressions of WWOX and CD133 proteins were examined by immunohistochemistry in 174 specimens of CRC tissues and 80 normal colorectal mucosa tissues. RESULTS: The positivity rates of WWOX and CD133 proteins were 41.4% and 53.4% in CRC tissues, respectively, significantly different from the rates in normal colorectal mucosa tissues (87...
November 2015: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Hye-Jin Choi, Jung-Hwan Park, Jong-Hwan Park, Kyung Bok Lee, Sang-Muk Oh
Tumor suppressor WW domain-containing oxidoreductase (WWOX) is depleted in various cancer types. Here we report that WWOX is modified by small ubiquitin-like modifier (SUMO) proteins and represses DU145 prostate cancer tumorigenesis in a SUMOylation-dependent manner. Ectopic WWOX was shown to associate with SUMO2/3 or E2 Ubc9. Furthermore, we revealed that WWOX SUMOylation was promoted by E3 ligase polycomb2 (Pc2), and that WWOX associated with Pc2. Meanwhile, anisomycin-induced activator protein-1 (AP-1) activity was markedly diminished by co-expression of SUMO and WWOX...
December 21, 2015: FEBS Letters
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