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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Association between WWOX and the risk of malignant tumor, especially among Asians: evidence from a meta-analysis

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          Abstract

          Purpose

          Many studies have been carried out to examine whether there are associations between WWOX polymorphisms (rs3764340 C>G, rs12918952 G>A, and rs383362 G>T) and malignant tumor risk, but the results from these studies remained inconsistent and even controversial. In the present study, we performed a meta-analysis to evaluate the relationships comprehensively.

          Methods

          Published reports were searched in PubMed, Google Scholar, and Chinese National Knowledge Infrastructure databases. Eight eligible case–control studies were included in the final analysis. In the analysis, pooled odds ratios (ORs) with corresponding 95% CIs were calculated in five genetic models to assess the genetic risk. Egger’s regression and Begg’s funnel plots test were conducted to appraise the publication bias.

          Results

          We found that rs12918952 G>A and rs383362 G>T polymorphisms were not associated with the susceptibility of malignant tumor. However, a significant correlation was found between WWOX rs3764340 C>G and malignant tumor risk in three genetic models (CG vs CC: OR=1.31, 95% CI: 1.12–1.53, P=0.031; GG/CG vs CC: OR=1.31, 95% CI: 1.11–1.54, P=0.014; G vs C: OR=1.28, 95% CI: 1.09–1.50, P=0.009). Furthermore, when stratified by source of control, the results were significant especially in population-based control for rs3764340.

          Conclusion

          In general, our results first indicated that the rs3764340 C>G polymorphism in WWOX gene can increase the susceptibility of tumor, while the others cannot. However, large, well-designed epidemiological studies are required to verify our findings.

          Most cited references26

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          A comprehensive review of genetic association studies.

          Most common diseases are complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. It has been proposed that common genetic variants, including single nucleotide polymorphisms (SNPs), influence susceptibility to common disease. This proposal has begun to be tested in numerous studies of association between genetic variation at these common DNA polymorphisms and variation in disease susceptibility. We have performed an extensive review of such association studies. We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases. However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility.
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            Function of WW domains as phosphoserine- or phosphothreonine-binding modules.

            Protein-interacting modules help determine the specificity of signal transduction events, and protein phosphorylation can modulate the assembly of such modules into specific signaling complexes. Although phosphotyrosine-binding modules have been well-characterized, phosphoserine- or phosphothreonine-binding modules have not been described. WW domains are small protein modules found in various proteins that participate in cell signaling or regulation. WW domains of the essential mitotic prolyl isomerase Pin1 and the ubiquitin ligase Nedd4 bound to phosphoproteins, including physiological substrates of enzymes, in a phosphorylation-dependent manner. The Pin1 WW domain functioned as a phosphoserine- or phosphothreonine-binding module, with properties similar to those of SRC homology 2 domains. Phosphoserine- or phosphothreonine-binding activity was required for Pin1 to interact with its substrates in vitro and to perform its essential function in vivo.
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              Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.

              The WWOX gene is a recently cloned tumor suppressor gene that spans the FRA16D fragile region. Wwox protein contains two WW domains that are generally known to mediate protein-protein interaction. Here we show that Wwox physically interacts via its first WW domain with the p53 homolog, p73. The tyrosine kinase, Src, phosphorylates Wwox at tyrosine 33 in the first WW domain and enhances its binding to p73. Our results further demonstrate that Wwox expression triggers redistribution of nuclear p73 to the cytoplasm and, hence, suppresses its transcriptional activity. In addition, we show that cytoplasmic p73 contributes to the proapoptotic activity of Wwox. Our findings reveal a functional cross-talk between p73 and Wwox tumor suppressor protein.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and Therapy
                OncoTargets and therapy
                Dove Medical Press
                1178-6930
                2018
                03 April 2018
                : 11
                : 1801-1811
                Affiliations
                [1 ]Pancreas Center, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University
                [2 ]Pancreas Institute, Nanjing Medical University, Nanjing, People’s Republic of China
                Author notes
                Correspondence: Kuirong Jiang; Yi Miao, Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People’s Republic of China, Tel +86 25 6813 6629; +86 25 6813 6590, Fax +86 25 8378, 1992, Email jiangkuirongnjmu@ 123456sina.com ; miaoyi@ 123456njmu.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                ott-11-1801
                10.2147/OTT.S152140
                5892619
                e90ccdd6-0b8f-4c08-bcb6-5790bbc7aaf2
                © 2018 Yuan et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Oncology & Radiotherapy
                malignant tumor,wwox,meta-analysis,polymorphism,susceptibility
                Oncology & Radiotherapy
                malignant tumor, wwox, meta-analysis, polymorphism, susceptibility

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