DOCSLIB.ORG

Download (4MB)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Download (4MB) THE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN TUMOR METASTASIS by Ahmad Suhail Khazali Bachelor of Science, Rochester Institute of Technology, 2010 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2017 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Ahmad Suhail Khazali It was defended on July 17, 2017 and approved by Douglass Lansing Taylor, PhD., Computational and Systems Biology Zhou Wang, PhD., Department of Pathology Reza Zarnegar, PhD., Department of Pathology Committee Chair: Donna Beer Stolz, PhD. Department of Cell Biology Dissertation Advisor: Alan Wells, MD. DMSc, Department of Pathology ii Copyright © by Ahmad Suhail Khazali 2017 iii THE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN TUMOR METASTASIS Ahmad Suhail Khazali, PhD University of Pittsburgh, 2017 Metastasis is often a deadly disease but highly inefficient as it involves several complex sequential processes such as invasion, hematogenous dissemination and distant organ colonization. Tumor suppressor E-cadherin, which is the key biomarker for epithelial- mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), plays essential roles in cancer invasion and colonization. Organ colonization has been proposed to be the rate- limiting step of metastasis as most cancer cells undergo apoptosis in these restrictive foreign microenvironments. However, some metastatic cells manage to evade apoptosis by undergoing cellular quiescence and later grow out to form deadly overt metastases. Herein, we investigated the roles of chemokines and chemokine receptors in mediating tumor phenotypic transition during cancer invasion and tumor escape from dormancy during liver colonization. Chemokine receptor CXCR3 mediates immune cell chemotaxis but inhibits adherent cell locomotion. These opposing effects on cellular motility are accomplished via two CXCR3 isoforms. We hypothesized that the anti-migratory isoform CXCR3B promoted E- cadherin expression to allow cancer cell seeding. CXCR3B overexpression induced E-cadherin expression and CXCR3B-knockdown reduced total and membranous E-cadherin. We also found that the correlation between CXCR3B and E-cadherin expression was significantly conserved in human prostate cancer liver metastasis in mice. iv Next, we utilized in vitro and ex vivo co-culture systems to uncover the soluble factors that mediate tumor emergence from dormancy. In vitro co-culture with hepatic stellate cells (HSCs) significantly elevated tumor growth. Protein analyses of primary liver non-parenchymal cells and immortalized HSCs revealed increased secretion of pro-inflammatory chemokines IL-8 and MCP-1. We further noted that IL-8, not MCP-1, directly augmented cancer cell growth and mediated tumor escape from dormancy, potentially through ERK activation. In summary, we establish novel functions for CXCR3 and IL-8 during tumor metastasis. CXCR3B can induce E-cadherin re-expression that may facilitate cancer cell seeding and protect the cells from drug-induced apoptosis. HSC-derived pro-inflammatory chemokine IL-8 can drive tumor escape from dormancy in the liver. These findings may have substantial implications on the management and treatment of metastatic disease. Targeting IL-8 or inflammation in general, may prove beneficial to curb cancer outgrowth at this rate-limiting step of metastasis. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIII 1.0 OVERVIEW: CANCER AND METASTASIS ......................................................... 1 1.1 PRIMARY AND METASTATIC CANCERS: INCIDENCE, PREVALENCE AND MORTALITY RATE ..................................................................... 4 1.2 BREAST CANCER ............................................................................................. 5 1.2.1 Breast Cancer Pathogenesis ............................................................................ 5 1.2.2 Breast Cancer Recurrence and Metastasis ................................................... 7 1.2.3 Breast Cancer Treatment ............................................................................... 8 1.3 PROSTATE CANCER ...................................................................................... 12 1.3.1 Prostate Cancer Pathogenesis ....................................................................... 13 1.3.2 Prostate Cancer Recurrence and Metastasis .............................................. 15 1.3.3 Prostate Cancer Treatment .......................................................................... 16 1.4 CANCER METASTASIS ................................................................................. 17 1.4.1 Metastatic Sequence ...................................................................................... 17 1.4.2 Cancer Invasion: MMPs Secretion and EMT ............................................. 19 1.4.3 Cancer Circulation: Intra- and Extravasation and Evading Anoikis ...... 22 1.4.4 Cancer Colonization: MET........................................................................... 24 1.4.5 Cancer Survival and Proliferation in Distant Organs ............................... 25 vi 1.5 LIVER AS A METASTATIC SITE ................................................................. 27 1.5.1 Liver Physiology ............................................................................................ 28 1.5.2 Primary Liver Malignancy ........................................................................... 33 1.5.3 Liver Metastases ............................................................................................ 34 1.5.4 Modeling the Liver for Cancer Study and Drug Discovery....................... 37 1.5.5 Conclusions..................................................................................................... 41 2.0 THE ROLES OF CHEMOKINE RECEPTOR CXCR3 IN MESENCHYMAL- EPITHELIAL TRANSITION ................................................................................................... 44 2.1 CHEMOKINE RECEPTORS AND LIGANDS ............................................. 45 2.2 CXCR3 RECEPTORS AND LIGANDS ......................................................... 46 2.2.1 CXCR3 Isoforms............................................................................................ 46 2.2.2 CXCR3 Ligands ............................................................................................. 47 2.2.3 CXCR3 Signal Transductions ...................................................................... 49 2.2.4 CXCR3 Roles in Cancers .............................................................................. 50 2.2.4.1 CXCR3 in Prostate Cancer ................................................................ 51 2.2.4.2 CXCR3 in Breast Cancer ................................................................... 51 2.2.4.3 CXCR3 in Colorectal Cancer............................................................. 52 2.2.4.4 CXCR3 in Lung Cancer ..................................................................... 53 2.2.4.5 CXCR3 in Ovarian Cancer ................................................................ 54 2.2.4.6 CXCR3 in Renal Cancer .................................................................... 55 2.2.4.7 CXCR3 in Melanoma.......................................................................... 55 2.3 CXCR3B DRIVES E-CADHERIN RE-EXPRESSION TO FACILITATE PROSTATE CANCER LIVER METASTASIS .............................................................. 56 vii 2.3.1 CXCR3B Increases E-cadherin Protein Level ............................................ 58 2.3.2 CXCR3B is Elevated in DU145-Ecadherinhigh Cells ................................... 59 2.3.3 DU145 Cells Increase CXCR3B Expression in Liver Metastases ............. 62 2.3.4 CXCR3B Correlates with E-cadherin in DU145 and PC3 Cells In vivo... 63 2.3.5 CXCR3B Expression in Metastatic Liver Nodules Increases Chemoresistance. ........................................................................................................ 65 2.3.6 Elevated CXCR3B does not Promote Cancer Dormancy .......................... 67 2.3.7 Discussions and Conclusions......................................................................... 68 2.3.8 Future works .................................................................................................. 70 2.3.9 Conclusions..................................................................................................... 71 3.0 CANCER CELL SURVIVAL IN LIVER MICROENVIRONMENT .................. 72 3.1 CANCER CELL DEATH AND METASTATIC PROLIFERATION ......... 72 3.2 CANCER DORMANCY ................................................................................... 74 3.2.1 Dormancy: Definition .................................................................................... 74 3.2.2 Dormancy: Clinical and Experimental Evidence ....................................... 74 3.2.3 Dormancy: Mechanisms................................................................................ 75 3.2.4 Dormancy: Modeling Human Tumor Dormancy Ex vivo ......................... 77 3.2.5 Dormancy: Emergence .................................................................................. 78 3.3 STELLATE CELL-DERIVED IL8 PROMOTES CANCER ESCAPE FROM DORMANCY IN THE LIVER ............................................................................ 80 3.3.1 Hepatic
Load more

Recommended publications
  • Basic Helix-Loop-Helix Transcription Factors DEC1 and DEC2 Regulate the Paclitaxel-Induced Apoptotic Pathway of MCF-7 Human Breast Cancer Cells
    INTERNATIONAL JOURNAL OF MoleCular MEDICine 27: 491-495, 2011 Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells YUNYAN WU1,2, FUYUKI SATO1, UJJAL KUMAR BHAWAL3, TAKESHI KAWAMOTO4, KATSUMI FUJIMOTO4, MITSUHIDE NOSHIRO4, SATOKO MOROHASHI1, YUKIO KATO4 and HIROSHI KIJIMA1 1Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; 2Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang 110001, P.R. China; 3Department of Oral and Maxillofacial Surgery and High-Tech Research Center, Kanagawa Dental College, Yokosuka 238-8580; 4Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Science, Hiroshima 734-8553, Japan Received November 17, 2010; Accepted January 10, 2011 DOI: 10.3892/ijmm.2011.617 Abstract. Differentiated embryonic chondrocyte gene Introduction (DEC) 1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/ Sharp1) are basic helix-loop-helix (bHLH) transcription Paclitaxel is an anti-tumor drug that is used against a wide factors that are associated with the regulation of apoptosis, cell variety of solid tumors (1,2) and affects the expression of proliferation and circadian rhythms, as well as malignancy Bcl-2, Bcl-xL and phosphorylated-c-Jun NH2-terminal kinase in various cancers. However, the roles of DEC1 and DEC2 (JNK), and the activation of caspases and poly (ADP-ribose) expression in breast cancer are poorly understood. In this polymerase PARP (3-6), resulting in the induction of apop- study, we sought to examine the roles of DEC1 and DEC2 tosis by p53-dependent or -independent mechanisms (7-9).
    [Show full text]
  • Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer Joshua W
    Published OnlineFirst September 21, 2018; DOI: 10.1158/0008-5472.CAN-18-0687 Cancer Priority Report Research Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer Joshua W. Russo1,CeGao2, Swati S. Bhasin2, Olga S. Voznesensky1, Carla Calagua3, Seiji Arai1,4, Peter S. Nelson5, Bruce Montgomery6, Elahe A. Mostaghel5, Eva Corey6, Mary-Ellen Taplin7, Huihui Ye3, Manoj Bhasin2, and Steven P. Balk1 Abstract The standard treatment for metastatic prostate cancer, cleaves dipeptides from multiple growth factors, resulting in androgen deprivation therapy (ADT), is designed to suppress their increased degradation. DPP4 mRNA and protein were androgen receptor (AR) activity. However, men invariably also decreased in clinical CRPC cases, and inhibition of progress to castration-resistant prostate cancer (CRPC), and DPP4 with sitagliptin enhanced the growth of prostate AR reactivation contributes to progression in most cases. To cancer xenografts following castration. Significantly, DPP4 identify mechanisms that may drive CRPC, we examined a inhibitors are frequently used to treat type 2 diabetes as they VCaP prostate cancer xenograft model as tumors progressed increase insulin secretion. Together, these results implicate from initial androgen sensitivity prior to castration to castra- DPP4 as an AR-regulated tumor suppressor gene whose tion resistance and then on to relapse after combined therapy loss enhances growth factor activity and suggest that treat- with further AR-targeted drugs (abiraterone plus enzaluta- ment with DPP4 inhibitors may accelerate emergence of mide). AR activity persisted in castration-resistant and abir- resistance to ADT. aterone/enzalutamide–resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice Significance: These findings identify DPP4 as an AR-stim- variant.
    [Show full text]
  • The Title of the Dissertation
    UNIVERSITY OF CALIFORNIA SAN DIEGO Novel network-based integrated analyses of multi-omics data reveal new insights into CD8+ T cell differentiation and mouse embryogenesis A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Kai Zhang Committee in charge: Professor Wei Wang, Chair Professor Pavel Arkadjevich Pevzner, Co-Chair Professor Vineet Bafna Professor Cornelis Murre Professor Bing Ren 2018 Copyright Kai Zhang, 2018 All rights reserved. The dissertation of Kai Zhang is approved, and it is accept- able in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California San Diego 2018 iii EPIGRAPH The only true wisdom is in knowing you know nothing. —Socrates iv TABLE OF CONTENTS Signature Page ....................................... iii Epigraph ........................................... iv Table of Contents ...................................... v List of Figures ........................................ viii List of Tables ........................................ ix Acknowledgements ..................................... x Vita ............................................. xi Abstract of the Dissertation ................................. xii Chapter 1 General introduction ............................ 1 1.1 The applications of graph theory in bioinformatics ......... 1 1.2 Leveraging graphs to conduct integrated analyses .......... 4 1.3 References .............................. 6 Chapter 2 Systematic
    [Show full text]
  • Propranolol-Mediated Attenuation of MMP-9 Excretion in Infants with Hemangiomas
    Supplementary Online Content Thaivalappil S, Bauman N, Saieg A, Movius E, Brown KJ, Preciado D. Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas. JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2013.4773 eTable. List of All of the Proteins Identified by Proteomics This supplementary material has been provided by the authors to give readers additional information about their work. © 2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable. List of All of the Proteins Identified by Proteomics Protein Name Prop 12 mo/4 Pred 12 mo/4 Δ Prop to Pred mo mo Myeloperoxidase OS=Homo sapiens GN=MPO 26.00 143.00 ‐117.00 Lactotransferrin OS=Homo sapiens GN=LTF 114.00 205.50 ‐91.50 Matrix metalloproteinase‐9 OS=Homo sapiens GN=MMP9 5.00 36.00 ‐31.00 Neutrophil elastase OS=Homo sapiens GN=ELANE 24.00 48.00 ‐24.00 Bleomycin hydrolase OS=Homo sapiens GN=BLMH 3.00 25.00 ‐22.00 CAP7_HUMAN Azurocidin OS=Homo sapiens GN=AZU1 PE=1 SV=3 4.00 26.00 ‐22.00 S10A8_HUMAN Protein S100‐A8 OS=Homo sapiens GN=S100A8 PE=1 14.67 30.50 ‐15.83 SV=1 IL1F9_HUMAN Interleukin‐1 family member 9 OS=Homo sapiens 1.00 15.00 ‐14.00 GN=IL1F9 PE=1 SV=1 MUC5B_HUMAN Mucin‐5B OS=Homo sapiens GN=MUC5B PE=1 SV=3 2.00 14.00 ‐12.00 MUC4_HUMAN Mucin‐4 OS=Homo sapiens GN=MUC4 PE=1 SV=3 1.00 12.00 ‐11.00 HRG_HUMAN Histidine‐rich glycoprotein OS=Homo sapiens GN=HRG 1.00 12.00 ‐11.00 PE=1 SV=1 TKT_HUMAN Transketolase OS=Homo sapiens GN=TKT PE=1 SV=3 17.00 28.00 ‐11.00 CATG_HUMAN Cathepsin G OS=Homo
    [Show full text]
  • Tnfa-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer María F
    Published OnlineFirst October 3, 2016; DOI: 10.1158/1078-0432.CCR-16-0970 Cancer Therapy: Clinical Clinical Cancer Research TNFa-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer María F. Mercogliano1, Mara De Martino1, Leandro Venturutti1, Martín A. Rivas2, Cecilia J. Proietti1, Gloria Inurrigarro3, Isabel Frahm3, Daniel H. Allemand4, Ernesto Gil Deza5, Sandra Ares5, Felipe G. Gercovich5, Pablo Guzman 6, Juan C. Roa6,7, Patricia V. Elizalde1, and Roxana Schillaci1 Abstract Purpose: Although trastuzumab administration improved the Results: TNFa overexpression turned trastuzumab-sensitive outcome of HER2-positive breast cancer patients, resistance cells and tumors into resistant ones. Histopathologic findings events hamper its clinical benefits. We demonstrated that TNFa revealed mucin foci in TNFa-producing tumors. TNFa induced stimulation in vitro induces trastuzumab resistance in HER2- upregulation of MUC4 that reduced trastuzumab binding to its positive breast cancer cell lines. Here, we explored the mechanism epitope and impaired ADCC. Silencing MUC4 enhanced trastu- of TNFa-induced trastuzumab resistance and the therapeutic zumab binding, increased ADCC, and overcame trastuzumab and strategies to overcome it. trastuzumab-emtansine antiproliferative effects in TNFa-overex- Experimental Design: Trastuzumab-sensitive breast cancer pressing cells. Accordingly, administration of TNFa-blocking cells, genetically engineered to stably overexpress TNFa,and antibodies downregulated MUC4 and sensitized de novo trastu- de novo trastuzumab-resistant tumors, were used to evaluate zumab-resistant breast cancer cells and tumors to trastuzumab. In trastuzumab response and TNFa-blocking antibodies effective- HER2-positive breast cancer samples, MUC4 expression was ness respectively. Immunohistochemistry and antibody-depen- found to be an independent predictor of poor disease-free survival dent cell cytotoxicity (ADCC), together with siRNA strategy, (P ¼ 0.008).
    [Show full text]
  • UTX Regulates Mesoderm Differentiation of Embryonic Stem Cells Independent of H3K27 Demethylase Activity
    UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity Chaochen Wanga, Ji-Eun Leea,1, Young-Wook Chob,1, Ying Xiaoc, Qihuang Jina, Chengyu Liud, and Kai Gea,2 aLaboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; bKorea Basic Science Institute Chuncheon Center, Chuncheon, Kangwon, Korea 200-701; cDermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and dTransgenic Core, Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892 Edited by Mark Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved August 3, 2012 (received for review March 9, 2012) To investigate the role of histone H3K27 demethylase UTX in male cells. UTY is a paralog of the X-linked UTX and shares embryonic stem (ES) cell differentiation, we have generated UTX 88% sequence homology with UTX protein. Unlike UTX, UTY knockout (KO) and enzyme-dead knock-in male ES cells. Deletion lacks detectable histone demethlase activity in vitro (8, 12). The of the X-chromosome-encoded UTX gene in male ES cells markedly viability data from male and female UTX KO mice indicate a decreases expression of the paralogous UTY gene encoded by Y largely functional redundancy between UTX and UTY during chromosome, but has no effect on global H3K27me3 level, Hox male embryonic development (13). gene expression, or ES cell self-renewal. However, UTX KO cells UTX has been shown to regulate myocyte differentiation, heart show severe defects in mesoderm differentiation and induction of development, and T-box transcription factor target gene expres- Brachyury, a transcription factor essential for mesoderm develop- sion (13–15).
    [Show full text]
  • A Stealth Cloak for Cancer Cells
    BMB Rep. 2021; 54(7): 344-355 BMB www.bmbreports.org Reports Invited Mini Review Mucin in cancer: a stealth cloak for cancer cells Dong-Han Wi1, Jong-Ho Cha2,3 & Youn-Sang Jung1,* 1Department of Life Science, Chung-Ang University, Seoul, 06974, 2Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, 3Department of Biomedical Science, Program in Biomedical Science and Engineering, Graduate school, Inha University, Incheon 22212, Korea Mucins are high molecular-weight epithelial glycoproteins and mucinous colorectal carcinoma (MCC) (3). Since tumor growth are implicated in many physiological processes, including epit- sites induce inhospitable conditions for them to survive, helial cell protection, signaling transduction, and tissue home- mucins are suggested as an oncogenic microenvironment that ostasis. Abnormality of mucus expression and structure contri- avoids hypoxia, acidic, and other biological hurdles. The com- butes to biological properties related to human cancer progress- position and structure of mucins enable them to mimic the ion. Tumor growth sites induce inhospitable conditions. Many surface of tumor cells like the surface of normal epithelial cells kinds of research suggest that mucins provide a microenviron- (4). Additionally, the mucus layer captures growth factors or ment to avoid hypoxia, acidic, and other biological conditions cytokines, contributing to cell growth of the tumor. Alter- that promote cancer progression. Given that the mucus layer natively, these properties interfere with the interaction bet- captures growth factors or cytokines, we propose that mucin ween the immune system and tumor cells. Indeed, a high helps to ameliorate inhospitable conditions in tumor-growing concentration of soluble mucins downregulates the motility sites.
    [Show full text]
  • Speaker Abstracts 2018 International Chordoma Research Workshop | Speaker Abstracts 1
    Sixth International Chordoma Research Workshop Speaker abstracts 2018 International Chordoma Research Workshop | Speaker abstracts 1 TABLE OF CONTENTS EPIGENETIC CONTROL OF BRACHYURY AND METABOLIC STRESS RESPONSE: NOVEL THERAPEUTIC TARGETS FOR CHORDOMA ........................................................................................................................................................... 2 SYSTEMATIC DISCOVERY OF NOVEL VULNERABILITIES IN CHORDOMA .................................................................. 3 RATIONALE FOR THE ADVANCEMENT OF PTEN/AKT PATHWAY INHIBITORS AND COMBINATIONS FOR PERSONALIZED CHORDOMA THERAPY ................................................................................................................... 4 THE ROLE OF PHILANTHROPY IN TRANSFORMING CANCER RESEARCH .................................................................. 5 BRACHYURY IN CHORDOMA AND CARCINOMAS: BIOLOGY AND POTENTIAL TARGETING APPROACHES ............... 6 CHARTING BRACHYURY-MEDIATED DEVELOPMENTAL PATHWAYS DURING EARLY MOUSE EMBRYOGENESIS ...... 7 CRYSTAL STRUCTURES OF BRACHYURY: A PRELUDE TO DRUG DISCOVERY ............................................................ 8 A BRACHYURY TRANSCRIPTIONAL REPORTER TO GUIDE DRUG DISCOVERY........................................................... 9 INVESTIGATING BRACHYURY GENE REGULATION TO IDENTIFY THERAPEUTIC TARGETS IN CHORDOMA ............. 10 DELINEATING AND TARGETING THE BRACHYURY-YAP REGULATORY AXIS IN CANCER ......................................... 11 OPEN ACCESS
    [Show full text]
  • Bangor University DOCTOR of PHILOSOPHY Brachyury in the Human Colon and Colorectal Cancer Williams, Jason
    Bangor University DOCTOR OF PHILOSOPHY Brachyury in the Human Colon and Colorectal Cancer Williams, Jason Award date: 2018 Awarding institution: Bangor University Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 Brachyury in the Human Colon and Colorectal Cancer Ph. D. Thesis 2017 Jason Saunders Williams i Declaration and Consent Details of the Work I hereby agree to deposit the following item in the digital repository maintained by Bangor University and/or in any other repository authorized for use by Bangor University. Author Name: Title: Supervisor/Department: Funding body (if any): Qualification/Degree obtained: PhD This item is a product of my own research endeavours and is covered by the agreement below in which the item is referred to as “the Work”. It is identical in content to that deposited in the Library, subject to point 4 below.
    [Show full text]
  • Digitalcommons@UNMC Regulation of the Transmembrane Mucin MUC4
    University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-18-2015 Regulation of the transmembrane mucin MUC4 by Wnt/β-catenin in gastrointestinal cancers Priya Pai University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Biochemistry Commons, and the Molecular Biology Commons Recommended Citation Pai, Priya, "Regulation of the transmembrane mucin MUC4 by Wnt/β-catenin in gastrointestinal cancers" (2015). Theses & Dissertations. 58. https://digitalcommons.unmc.edu/etd/58 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. i Regulation of the transmembrane mucin MUC4 by Wnt/β- catenin in gastrointestinal cancers By PRIYA PAI A DISSERTATION Presented to the Faculty of The University of Nebraska Graduate College In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy Department of Biochemistry and Molecular Biology Graduate Program Under the Supervision of Professor Surinder K. Batra University of Nebraska Medical Center Omaha, Nebraska November, 2015 ii Regulation of the transmembrane mucin MUC4 by Wnt/β-catenin in gastrointestinal cancers Priya Pai, PhD. University of Nebraska Medical Center, 2015 Supervisor: Surinder K. Batra, PhD. The transmembrane mucin MUC4 is a high molecular weight glycoprotein that is expressed de novo in pancreatic ductal adenocarcinoma (PDAC). MUC4 has been shown to play a tumor-promoting role in malignancies such as PDAC, ovarian cancer and breast cancer.
    [Show full text]
  • And HPV18-Infected Early Stage Cervical Cancers and Normal
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Virology 331 (2005) 269–291 www.elsevier.com/locate/yviro Gene expression profiles of primary HPV16- and HPV18-infected early stage cervical cancers and normal cervical epithelium: identification of novel candidate molecular markers for cervical cancer diagnosis and therapy Alessandro D. Santina,*, Fenghuang Zhanb, Eliana Bignottia, Eric R. Siegelc, Stefania Cane´ a, Stefania Bellonea, Michela Palmieria, Simone Anfossia, Maria Thomasd, Alexander Burnetta, Helen H. Kaye, Juan J. Romana, Timothy J. O’Briena, Erming Tianb, Martin J. Cannonf, John Shaughnessy Jr.b, Sergio Pecorellig aDivision of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA bMyeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA cDepartment of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA dDepartment of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA eDepartment of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA fDepartment of Microbiology and Immunology, University of Arkansas, Little Rock, AR 72205, USA gDivision of Gynecologic Oncology, University of Brescia, Brescia, Italy Received 2 July 2004; returned to author for revision 18 August 2004; accepted 9 September 2004 Available online 21 November 2004 Abstract With the goal of identifying genes with a differential pattern of expression between invasive cervical carcinomas (CVX) and normal cervical keratinocytes (NCK), we used oligonucleotide microarrays to interrogate the expression of 14,500 known genes in 11 primary HPV16 and HPV18-infected stage IB–IIA cervical cancers and four primary normal cervical keratinocyte cultures.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]