DOCSLIB.ORG

1 Characterization of Wwox Expression and Function in Canine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 Characterization of Wwox Expression and Function in Canine Characterization of Wwox Expression and Function in Canine Mast Cell Tumors and Malignant Mast Cell Lines THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Rebecca Lynn Makii Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2020 Master’s Examination Committee Joelle Fenger, DVM, PhD, DACVIM, Advisor Eric Green, DVM, DACVR Ryan Jennings, DVM, PhD, DACVP 1 Copyrighted by Rebecca Lynn Makii 2020 2 Abstract Mast cell tumors (MCT) are the most common skin tumor in dogs with behavior varying from benign to aggressive, metastatic disease. While activating mutations in the receptor tyrosine kinase KIT (c-KIT) have been identified in up to 30% of high-grade MCTs, the genetic alterations driving tumorigenesis in the 70% of MCTs that do not possess c-KIT mutations remains unclear. The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost or attenuated in many human cancers and cancer cell lines and data suggest that loss of WWOX impedes DNA damage response (DDR) and repair leading to genomic instability. The purpose of this study was to characterize WWOX expression in spontaneous canine mast MCTs and mastocytoma cell lines and begin to define the functional consequences of WWOX inactivation on mast cell viability and clonogenic survival in response to double-stranded DNA (dsDNA) damaging agents. qRT-PCR and Western blotting showed that WWOX is decreased in MC lines and primary MCTs compared to bone marrow-cultured MCs, suggesting that loss of WWOX is a frequent event in this disease. WWOX expression was assessed by immunohistochemistry in paired normal dermal MCs (N = 15), low-grade MCTs (N = 14), and high-grade MCTs (N = 5) and demonstrated that there is decreased percent of cells staining for Wwox in high-grade MCTs. To better define the functional consequences of WWOX loss on MC behavior, MCs transduced with control or WWOX ii lentiviral or sh-RNAs targeting WWOX were treated with ionizing radiation, and cell survival and viability were assessed by clonogenicity and MTT assays. Overexpression of WWox in the BR MC line did not alter DDR or cell viability; however, further decreasing expression of WWOX in the C2 MC line conferred a survival advantage post- irradiation. Lastly, we demonstrate validation of tissue specific WWOX knockout a mouse model to better understand the role of WWOX in normal mast cells. These findings provide insight into the functions of WWOX in MCs with the ultimate goal of identifying novel targets for therapeutic intervention. iii Dedication In loving memory of Patricia & Chester Berlin and Mildred & Melvin Makii Dedicated to my parents, Michael and Christine Makii and my siblings, Jason Makii, Justin Makii, and Amanda Fee, for their constant love, support, and encouragement throughout the years. To my nieces and nephews: I hope you fall in love with science just as much as I have. iv Acknowledgments I would like to begin by expressing my sincerest gratitude to my mentor, Dr. Joelle Fenger, for her patience, guidance, support, and encouragement through both my graduate and veterinary programs. Your willingness to take me in as a “lost” graduate student developed into an invaluable opportunity to learn how to ask questions, think critically, and gain confidence within the field of comparative medicine. The efforts of this work would not have been possible without the friendship, technical support, and morale encouragement of current and former laboratory members, Dr. Justin Breitbach, Hanna Cook, Feng Xu, and Darian Louke. I would additionally like to thank Wessel Dirksen and Dr. Tom Rosol for providing me with foundational laboratory training during my graduate programming. I am also appreciative of the guidance and technical assistance from my thesis committee, Drs. Eric Green and Ryan Jennings. Your expertise and guidance in this project has provided me with greater insight into both radiation oncology and pathology and an admiration for the collaborative nature of the veterinary profession. Additional technical help for this project was provided through Dr. Sue Knoblaugh, Chelssie Breece, and David Hart from the Comparative Pathology and Mouse Phenotyping Shared Resource, Dr. Chris Premanandan and Jenny Bolon from the Applied Pathology Services, Dr. Noopur Desai, Dr. Jillian Walz, and Nicole Pasternak of v the Integrated Oncology Service, Dr. Holly Borghese of the Blue Buffalo Clinical Trials Office Tissue Bank, and Alex Cornwell of the Analytical Cytometry Shared Resource. Each of you played an instrumental role in ensuring the completion of this project through your technical expertise, encouragement, and troubleshooting. To my veterinary classmates (particularly Lindsay Courtney, Leah Giralico, Megan Goodnight, Kelsey Bick, Sarah Bek Komnenovich, Kristen Behrens, Jessica Battyanyi, and Andrea Bessler), the fourth floor of VMAB, and the pathology and oncology residents that I have befriended in my graduate studies, thank you for the camaraderie, support, and friendship over the years. I sincerely cannot wait to see the exciting pathways each one of us take as we embark further into our careers. Finally, with the most gratitude, I would like to thank my biggest supporter, Michael Kemp, my dearest friends (Serena Nayee, Abby McClaine, Akul Yajnik, Andy Goldfarb, Megan Huber, Brady Schoeffler and Emily Selio), and my family (the Makiis, the Fees, the Kemps, and the Martins) for their encouragement, understanding, patience, and love. You all mean more to me than you know. vi Vita 2012 ………………………………………………………..Mount de Sales Academy 2016 ………………………………………………………..B.S. Pharmaceutical Sciences, The Ohio State University 2016 – present ……………………………………………..M.S./D.V.M. candidate The Ohio State University Fields of Study Major Field: Comparative Veterinary Medicine vii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments ............................................................................................................... v Vita .................................................................................................................................... vii List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii Chapter 1. Literature Review .............................................................................................. 1 1.1 The WW-Domain Containing Oxidoreductase (WWOX) Gene ................................ 1 1.2 In Vivo Functions of WWOX ..................................................................................... 3 1.3 WWOX Dysregulation in Cancer ............................................................................. 5 1.4 WWOX Functions in DNA Damage Repair and Genomic Stability ........................ 8 1.5 Canine Mast Cell Tumors ....................................................................................... 10 1.6 Summary ................................................................................................................. 13 Chapter 2: Characterizing the Role of WWOX in Canine Mast Cell Tumors and Cell Lines .................................................................................................................................. 15 2.1 Abstract ................................................................................................................... 15 2.2 Introduction ............................................................................................................. 16 viii 2.3 Materials and Methods ............................................................................................ 20 2.3.1 Tumor microarray construction and immunohistochemistry ........................... 20 2.3.2 Cell lines and reagents ..................................................................................... 21 2.3.3 RNA isolation, cDNA synthesis, and qRT- PCR ............................................ 22 2.3.4 Immunoblotting ................................................................................................ 23 2.3.5 Recombinant stem cell factor co-culture ......................................................... 24 2.3.6 WWOX and shWWOX lentivirus infection .................................................... 24 2.3.8 Assessment of cell viability and cell proliferation ........................................... 26 2.3.9 Clonogenic survival assay ................................................................................ 27 2.3.11 Generation of CPA3-Cre;WWOXfl/fl transgenic mouse model ..................... 27 2.3.13 Statistics ......................................................................................................... 28 2.4 Results ..................................................................................................................... 28 2.4.1 Wwox expression is frequently decreased in primary canine MCTs and canine MC lines .................................................................................................................... 28 2.4.2 Loss of
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Systematic Detection of Divergent Brain Protein-Coding Genes in Human Evolution
    bioRxiv preprint doi: https://doi.org/10.1101/658658; this version posted January 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Title: Systematic detection of divergent brain protein-coding genes in human evolution 2 and their roles in cognition 3 Short title: Divergent brain protein-coding genes in human evolution 4 5 Guillaume Dumasa, Simon Malesysa and Thomas Bourgerona 6 a Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, 7 (75015) France 8 9 10 Corresponding author: 11 Guillaume Dumas 12 Human Genetics and Cognitive Functions 13 Institut Pasteur 14 75015 Paris, France 15 Phone: +33 6 28 25 56 65 16 [email protected] Dumas, Malesys and Bourgeron 1 of 37 bioRxiv preprint doi: https://doi.org/10.1101/658658; this version posted January 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 17 Abstract 18 The human brain differs from that of other primates, but the genetic basis of these differences 19 remains unclear. We investigated the evolutionary pressures acting on almost all human 20 protein-coding genes (N=11,667; 1:1 orthologs in primates) on the basis of their divergence 21 from those of early hominins, such as Neanderthals, and non-human primates.
    [Show full text]
  • A Multi-Exon Deletion Within WWOX Is Associated with a 46,XY Disorder of Sex
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Ghent University Academic Bibliography ͳ A multi-exon deletion within WWOX is associated with a 46,XY Disorder of Sex ʹ Development. ͵ Ͷ Stefan White1,2, Jacqueline Hewitt1,3, Erin Turbitt1, Yvonne van der Zwan4, RemKo ͷ Hersmus4, Sten Drop4, Peter Koopman5, Vincent Harley6, Martine Cools7, Leendert ͸ Looijenga4, Andrew Sinclair1,3 ͹ ͺ 1. Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne, VIC, ͻ Australia ͳͲ 2. Monash Institute of Medical Research, Melbourne, VIC, Australia ͳͳ 3. The University of Melbourne, Melbourne, VIC, Australia ͳʹ 4. Erasmus MC-University Medical Center, Rotterdam, The Netherlands ͳ͵ 5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, ͳͶ Australia ͳͷ 6. Prince Henrys Institute, Melbourne, VIC, Australia ͳ͸ 7. University Hospital Ghent, Ghent, Belgium ͳ͹ ͳͺ Corresponding author: ͳͻ Dr Stefan White ʹͲ Monash Institute of Medical Research ʹͳ 27-31 Wright Street ʹʹ Clayton VIC 3168 ʹ͵ AUSTRALIA ʹͶ Email [email protected] ʹͷ Tel +61 3 9902 4812 ʹ͸ Fax +61 3 9594 7114 ʹ͹ Running title: WWOX and Disorders of Sex Development ʹͺ ʹͻ Abstract ͵Ͳ Disorders of sex development (DSD) are congenital conditions where chromosomal, ͵ͳ gonad or genital development is atypical. In a significant proportion of 46,XY DSD ͵ʹ cases it is not possible to identify a causative mutation, maKing genetic counseling ͵͵ difficult and potentially hindering optimal treatment. We present here the analysis of a ͵Ͷ 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological ͵ͷ analysis of the surgically-removed gonads showed bilateral undifferentiated gonadal ͵͸ tissue and immature testis, both containing malignant germ cells.
    [Show full text]
  • Entry by Multiple Picornaviruses Is Dependent on a Pathway That Includes TNK2, WASL, and NCK1 Hongbing Jiang*, Christian Leung, Stephen Tahan, David Wang*
    RESEARCH ARTICLE Entry by multiple picornaviruses is dependent on a pathway that includes TNK2, WASL, and NCK1 Hongbing Jiang*, Christian Leung, Stephen Tahan, David Wang* Department of Molecular Microbiology, Pathology and Immunology, School of Medicine, Washington University, St. Louis, United States Abstract Comprehensive knowledge of the host factors required for picornavirus infection would facilitate antiviral development. Here we demonstrate roles for three human genes, TNK2, WASL, and NCK1, in infection by multiple picornaviruses. CRISPR deletion of TNK2, WASL, or NCK1 reduced encephalomyocarditis virus (EMCV), coxsackievirus B3 (CVB3), poliovirus and enterovirus D68 infection, and chemical inhibitors of TNK2 and WASL decreased EMCV infection. Reduced EMCV lethality was observed in mice lacking TNK2. TNK2, WASL, and NCK1 were important in early stages of the viral lifecycle, and genetic epistasis analysis demonstrated that the three genes function in a common pathway. Mechanistically, reduced internalization of EMCV was observed in TNK2 deficient cells demonstrating that TNK2 functions in EMCV entry. Domain analysis of WASL demonstrated that its actin nucleation activity was necessary to facilitate viral infection. Together, these data support a model wherein TNK2, WASL, and NCK1 comprise a pathway important for multiple picornaviruses. Introduction Picornaviruses cause a wide range of diseases including the common cold, hepatitis, myocarditis, *For correspondence: [email protected] (HJ); poliomyelitis, meningitis, and encephalitis (Melnick, 1983). Although vaccines exist for poliovirus [email protected] (DW) and hepatitis A virus, there are currently no FDA approved antivirals against picornaviruses in the United States. As obligate intracellular pathogens, viruses are dependent on the host cellular Competing interests: The machinery to complete their lifecycle.
    [Show full text]
  • Systematic Detection of Brain Protein-Coding Genes Under Positive Selection During Primate Evolution and Their Roles in Cognition
    Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Title: Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition Short title: Evolution of brain protein-coding genes in humans Guillaume Dumasa,b, Simon Malesysa, and Thomas Bourgerona a Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, (75015) France b Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada. Corresponding author: Guillaume Dumas Human Genetics and Cognitive Functions Institut Pasteur 75015 Paris, France Phone: +33 6 28 25 56 65 [email protected] Dumas, Malesys, and Bourgeron 1 of 40 Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N=11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein- coding genome with recent datasets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism.
    [Show full text]
  • Proximity-Dependent Biotinylation to Elucidate the Interactome of TNK2 Non-Receptor Tyrosine Kinase
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.30.450607; this version posted July 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Proximity-dependent biotinylation to elucidate the interactome of TNK2 non-receptor tyrosine kinase Raiha Tahir1,2,7, Anil K. Madugundu3,4,5,8,10, Savita Udainiya3,8,10, Jevon A. Cutler3,6, Santosh Renuse3,10,11, Li Wang10, Nicole A. Pearson10, Chris Mitchell7, Nupam Mahajan13 Akhilesh Pandey2,3,8,9,10,11*, Xinyan Wu2,3,10,12* 1Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India 5Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India 6Pre-Doctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 7Ginkgo Bioworks, Boston, MA, USA 8Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, India. 9Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 10Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA 11Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA 12Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA 13 Siteman Cancer Center, Washington University, St.
    [Show full text]
  • TNK2 Tyrosine Kinase: Molecular Signaling and Evolving Role in Cancers
    Oncogene (2015) 34, 4162–4167 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers K Mahajan1,2 and NP Mahajan1,2 Deregulated tyrosine kinase signaling alters cellular homeostasis to drive cancer progression. The emergence of a non-receptor tyrosine kinase (non-RTK), ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) as an oncogenic kinase, has uncovered novel mechanisms by which tyrosine kinase signaling promotes cancer progression. Although early studies focused on ACK1 as a cytosolic effector of activated transmembrane RTKs, wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator. ACK1 interacts with the estrogen receptor (ER)/histone demethylase KDM3A (JHDM2a) complex, which modifies KDM3A by tyrosine phosphorylation to regulate the transcriptional outcome at HOXA1 locus to promote the growth of tamoxifen-resistant breast cancer. It is also well established that ACK1 regulates the activity of androgen receptor (AR) by tyrosine phosphorylation to fuel the growth of hormone-refractory prostate cancers. Further, recent explosion in genomic sequencing has revealed recurrent ACK1 gene amplification and somatic mutations in a variety of human malignancies, providing a molecular basis for its role in neoplastic transformation. In this review, we will discuss the various facets of ACK1 signaling, including its newly uncovered epigenetic regulator function, which enables cells to bypass the blockade to major survival pathways to promote resistance to standard cancer treatments.
    [Show full text]
  • PARTICLE Triplexes Cluster in the Tumor Suppressor WWOX and May Extend Throughout the Human Genome
    www.nature.com/scientificreports OPEN PARTICLE triplexes cluster in the tumor suppressor WWOX and may extend throughout the human Received: 20 January 2017 Accepted: 6 July 2017 genome Published online: 2 August 2017 Valerie Bríd O’Leary1, Jan Smida1, Fabian Andreas Buske2,3, Laura Garcia Carrascosa4, Omid Azimzadeh1, Doris Maugg1,5, Sarah Hain1,6, Soile Tapio 1, Wolfgang Heidenreich1, James Kerr4, Matt Trau7, Saak Victor Ovsepian8,9 & Michael John Atkinson1,10 The long non-coding RNA PARTICLE (Gene PARTICL- ‘Promoter of MAT2A-Antisense RadiaTion Induced Circulating LncRNA) partakes in triple helix (triplex) formation, is transiently elevated following low dose irradiation and regulates transcription of its neighbouring gene - Methionine adenosyltransferase 2A. It now emerges that PARTICLE triplex sites are predicted in many diferent genes across all human chromosomes. In silico analysis identifed additional regions for PARTICLE triplexes at >1600 genomic locations. Multiple PARTICLE triplexes are clustered predominantly within the human and mouse tumor suppressor WW Domain Containing Oxidoreductase (WWOX) gene. Surface plasmon resonance difraction and electrophoretic mobility shift assays were consistent with PARTICLE triplex formation within human WWOX with high resolution imaging demonstrating its enrichment at this locus on chromosome 16. PARTICLE knockdown and over-expression resulted in inverse changes in WWOX transcripts levels with siRNA interference eliminating PARTICLEs elevated transcription to irradiation. The evidence for a second functional site of PARTICLE triplex formation at WWOX suggests that PARTICLE may form triplex-mediated interactions at multiple positions in the human genome including remote loci. These fndings provide a mechanistic explanation for the ability of lncRNAs to regulate the expression of numerous genes distributed across the genome.
    [Show full text]
  • Impact of MLL5 Expression on Decitabine Efficacy and DNA Methylation in Acute Myeloid Leukemia
    Acute Myeloid Leukemia SUPPLEMENTARY APPENDIX Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia Haiyang Yun,1 Frederik Damm,2 Damian Yap,3,4 Adrian Schwarzer,5 Anuhar Chaturvedi,1 Nidhi Jyotsana,1 Michael Lübbert,6 Lars Bullinger,7 Konstanze Döhner,7 Robert Geffers,8 Samuel Aparicio,3,4 R. Keith Humphries,9,10 Arnold Ganser,1 and Michael Heuser1 1Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Germany; 2Department of Hematology, Oncology, and Tumor Immunology, Charité, Berlin, Germany; 3Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada; 4Department of Pathology and Laboratory Medi- cine, University of British Columbia, Vancouver, BC, Canada; 5Institute of Experimental Hematology, Hannover Medical School, Germany; 6Division of Hematology and Oncology, University of Freiburg Medical Center, Germany; 7Department of Internal Medicine III, University Hospital of Ulm, Germany; 8Department of Cell Biology and Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; 9Terry Fox Laboratory, British Columbia Cancer Agency, Vancou- ver, BC, Canada; and 10Department of Medicine, University of British Columbia, Vancouver, BC, Canada ©2014 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2013.101386 *These authors contributed equally to this work. †These authors contributed equally to this work. Manuscript received on November 19, 2013. Manuscript accepted on May 23, 2014. Correspondence: [email protected] Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia Haiyang Yun1, Frederik Damm2, Damian Yap3,4, Adrian Schwarzer5, Anuhar Chaturvedi1, Nidhi Jyotsana1, Michael Lübbert6, Lars Bullinger7, Konstanze Döhner7, Robert Geffers8, Samuel Aparicio3,4, R.
    [Show full text]
  • Title: Chemotherapy Response and the Role of the WWOX Tumour Suppressor Name: Haroon Farooq
    Title: Chemotherapy response and the role of the WWOX tumour suppressor Name: Haroon Farooq This is a digitised version of a dissertation submitted to the University of Bedfordshire. It is available to view only. This item is subject to copyright. CHEMOTHERAPY RESPONSE AND THE ROLE OF THE WWOX TUMOUR SUPPRESSOR HAROON FAROOQ PhD 2017 University of Bedfordshire i CHEMOTHERAPY RESPONSE AND THE ROLE OF THE WWOX TUMOUR SUPPRESSOR By HAROON FAROOQ A thesis submitted to the University of Bedfordshire in fulfilment of the requirement of the degree of Doctor of Philosophy August 2017 ii Author’s Declaration I, Haroon Farooq declare that this thesis and the work presented in it are my own and have been generated by me as the result of my own original research. ………………………………………………………………………………………………..………… ……..…………………………………………………………………………………… I confirm that: 1. This work was done wholly or mainly while in candidature for a research degree at this University; 2. Where any part of this thesis has previously been submitted for a degree or any other qualification at this University or any other institution, this has been clearly stated; 3. Where I have cited the published work of others, this is always clearly attributed; 4. Where I have quoted from the work of others, the source is always given. With the exception of such quotations, this thesis is entirely my own work; 5. I have acknowledged all main sources of help; 6. Where the thesis is based on work done by myself jointly with others, I have made clear exactly what was done by others and what I have contributed myself; 7.
    [Show full text]
  • WWOX Loses the Ability to Regulate Oncogenic AP-2Γ and Synergizes with Tumor Suppressor AP-2Α in High-Grade Bladder Cancer
    cancers Article WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer Damian Kołat * , Zaneta˙ Kałuzi ´nska , Andrzej K. Bednarek and Elzbieta˙ Płuciennik Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland; [email protected] (Z.K.);˙ [email protected] (A.K.B.); [email protected] (E.P.) * Correspondence: [email protected] Simple Summary: A prognostic factor of bladder cancer which can benefit from research on molecu- lar markers is the histologic grade. WWOX, AP-2α and AP-2γ are known to have a grade-dependent effect but have not been investigated in that aspect in bladder cancer. Depending on the specific collaboration, their role was found to promote or inhibit grade 2 bladder cancer. As further research is needed on higher grades, the aim of the present study was to examine the functionality of WWOX and two AP-2 factors in grade 3 and grade 4 bladder cancer. It was found that WWOX, AP-2α and their combination mainly demonstrated anti-cancer properties; in contrast, AP-2γ promoted cancer development, which was not inhibited by WWOX in their combined variant. Next-generation sequencing was performed to identify the genes worth investigating as biomarkers. To conclude, WWOX and AP-2α demonstrate tumor suppressor synergism in high-grade bladder cancer, similar ˙ Citation: Kołat, D.; Kałuzi´nska, Z.; to intermediate grade. However, WWOX does not appear to guide oncogenic AP-2γ, which was the Bednarek, A.K.; Płuciennik, E.
    [Show full text]
  • The Tumor Suppressor Gene WWOX at FRA16D Is Involved in Pancreatic Carcinogenesis
    Vol. 10, 2459–2465, April 1, 2004 Clinical Cancer Research 2459 The Tumor Suppressor Gene WWOX at FRA16D Is Involved in Pancreatic Carcinogenesis Tamotsu Kuroki,1 Sai Yendamuri,1 Furthermore, transfection with WWOX inhibited colony for- Francesco Trapasso,1 Ayumi Matsuyama,1 mation of pancreatic cancer cell lines by triggering apoptosis. Rami I. Aqeilan,1 Hansjuerg Alder,1 Conclusion: These results indicate that the WWOX gene 1 1 2 may play an important role in pancreatic tumor devel- Shashi Rattan, Rossano Cesari, Maria L. Nolli, opment. Noel N. Williams,3 Masaki Mori,4 5 1 Takashi Kanematsu, and Carlo M. Croce INTRODUCTION 1 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pancreatic cancer is one of the most common human can- Pennsylvania; 2Areta International srl, Gerenzano, Italy; 3Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; cers and carries a poor prognosis (1). Although complete sur- 4Department of Surgery, Medical Institute of Bioregulation, Kyushu gical resection is the only therapeutic option for a long-term University, Beppu, Japan; and 5Department of Surgery, Nagasaki survival, the 5-year survival rate with curative resection is University, Graduate School of Biomedical Sciences, Nagasaki, Japan Ͻ20% (2). The precise molecular mechanisms of development and/or progression of pancreatic cancer remain unknown, al- ABSTRACT though multiple genetic and epigenetic changes have been de- tected in pancreatic cancer. Therefore, additional elucidation of Purpose: WWOX (WW domain containing oxidoreduc- the molecular mechanisms involved in pancreatic cancer is tase) is a tumor suppressor gene that maps to the common urgently needed for more effective treatment. fragile site FRA16D. We showed previously that WWOX is The tumor suppressor gene FHIT spans the FRA3B fragile frequently altered in human lung and esophageal cancers.
    [Show full text]