DOCSLIB.ORG

Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2246 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Ryan C. Fassnacht 2010 All Rights Reserved Molecular Mechanisms Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Ryan Christopher Fassnacht, B.S. Hampden Sydney University, 2005 M.S. Virginia Commonwealth University, 2010 Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery Virginia Commonwealth University Richmond, Virginia July 9, 2010 Acknowledgement The Author wishes to thank his family and close friends for their support. He would also like to thank the members of the molecular transplant team for their help and advice. This project would not have been possible with out the help of Dr. Valeria Mas and her endearing patience. ii TABLE OF CONTENTS List of Tables………………………………………………………………………………v List of Figures…………………………………………………………………………….vi List of Abbreviations…………………………………………………………………….vii Abstract…………………………………………………………………………………...ix Introduction………………………………………………………………………………..1 What is the Hepatitis C Virus?.........................................................................................…2 Pathogenesis of Hepatitis C Virus Infection………………………………………4 Mechanisms of Hepatic Fibrosis…………………………………………………………..7 Oxidative Stress…………………………………………………………………...9 Immunomodulation………………………………………………………………11 Alcohol and HCV………………………………………………………………………..12 Hypothesis and Aims…………………………………………………………………….13 Patients Materials and Methods………………………………………………………….14 Patients and Samples……………………………………………………………..14 Sample Preparation………………………………………………………………15 Quality Assessment………………………………………………………………16 Microarray Data Analysis………………………………………………………..17 Gene Annotation…………………………………………………………………19 Verification of Microarray Data…………………………………………………20 Results……………………………………………………………………………………21 Analysis of Gene Expression patterns Between Alcoholic Cirrhotic Liver Tissue and Normal Liver Tissue………………………………………………..21 Differential Gene Expression between HCV Cirrhotic Liver Tissue and Normal Liver Tissue……………………………………………………………...23 iii Genes Involve in the Significant Interaction of HCV and Ethanol.………....………......24 Gene Expression Validation by QPCR…………………………………………..27 Discussion………………………………………………………………………………..37 List of References…………….………………………………………………………….43 Vita…………………………………………………………………………..….………241 iv List of Tables 1. Summary of More Important Findings in Each Analysis……………………………..33 S1. Genes Significantly Different Between ALD Cirrhotic Tissue Compared to Normal Liver Tissue ……………………………………………......................................50 S2. Genes Significantly Different Between HCV Cirrhotic Tissue compared to Normal Tissue…….………………………………………………..................................105 S3. Genes With Significant Estimate Value for the Interaction of HCV and Alcohol…….. …………………………………………………………………..………………………191 v List of Figures 1. Heat Map Generated From Unsupervised Cluster Analysis…………………………. 28 2. HCV Cirrhotic vs. Normal Tissue: Interferon Signaling.……………………………..29 3. Top Canonical Pathways Involved in the Interaction of HCV*EtOH………………...30 4. Significant Interaction (HCV*EtOH): Antigen Presentation Pathway………………..31 5. Toxicology Lists for the Interaction of HCV*EtOH………………………………….32 vi List of Abbreviations ADH.……………………………………………………………..Alcohol Dehydrogenase ALD….…………………………………………………………...Alcoholic Liver Disease APC……………………………………………………………….Antigen Presenting Cell C……………………………………………………………………...Core protein of HCV cDNA……………………………………………………………….Complementary DNA cRNA………………………………………………………………..Complementary RNA Ct…………………………………………………………………………...Cycle threshold CTL………………………………………………………………Cytotoxic T Lymphocyte CYP2E1…………………………………………………………….Cytochrome P450 2E1 DC.……..……………………………………………………………………Dendritic Cell dsRNA……………………………………………………………...Double Stranded RNA E………………………………………………………………....Envelope protein of HCV ECM………………………………………………………………….Extra-cellular Matrix ER…………………………………………………………………Endoplasmic Reticulum EtOH………………………………………………………………………………..Ethanol HBV……………………………………………………………………...Hepatitis B Virus HCC.……………………………………………………………Hepatocellular Carcinoma HCV……………………………………………………………………...Hepatitis C Virus HSC…………………………………………………………………...Hepatic Stellate Cell IFN.………………………………………………………………………………Interferon IPA…………………………………………………………....Ingenuity Pathway Analysis IRF…………………………………………………………...Interferon Regulatory Factor ISG…………………………………………………………….Interferon Stimulated Gene JAK…………………………………………………………………………..Janus Kinase vii KC.…………………………………………………………………………….Kupffer Cell MDA……………………………………………………………………..Malondialdehyde NF-κB.………………………………………………………….....Nuclear Factor-kappa B NS…………………………………………………………Non-Structural protein of HCV NK……………………………………………………………….……..Natural Killer Cell OLT……………………………………………………...Orthotopic Liver Transplantation PAMP…………………………………………….Pathogen Associated Molecular Pattern QPCR ……..Quantitative Reverse Transcriptase ‘Real Time’ Polymerase Chain Reaction RIG-1…………………………………………………….Retinoic-Acid-Inducible-Gene-1 RdRp.…………………………………………………..RNA-dependent RNA polymerase RMA………………………………………………………...Robust Multiarray Averaging rRNA……………………………………………………………………...Ribosomal RNA ROS……………………………………………………………...Reactive Oxygen Species S………………………………………………………………...Structural protein of HCV SOCS…………………………………………………...Suppressor of Cytokine Signaling ssRNA……………………………………………………………….single-stranded RNA STAT……...............................................Signal Transducer and Activator of Transcription Th……………………………………………………………………………...T helper cell TLR…………………………………………………………………….Toll-Like Receptor TRIF…………………...Toll/IL-1 Receptor-Domain-Containing Adaptor Inducing IFN-β TYK……………………………………………………………………….Tyrosine Kinase UNOS…………………………………………………..United Network of Organ Sharing viii ABSTRACT MOLECULAR MECHANISMS INVOVLED IN THE INTERACTION EFFECTS OF HCV AND ETHANOL IN LIVER CIRRHOSIS By Ryan C. Fassnacht, M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University Virginia Commonwealth University, 2010 Thesis Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery The leading causes of liver disease are Hepatitis C virus infection and chronic alcohol abuse. Alcohol accelerates liver disease in HCV but the mechanisms are poorly understood. The identification of molecular gene expression profiles on human liver tissue was performed using microarrays. Samples were obtained from alcoholic-cirrhotic, HCV-cirrhotic, HCV/alcohol-cirrhotic and control non-cirrhotic liver tissue. Probe set expression summaries were calculated using RMA. Probe set level linear models were fit where probe set expression was modeled by HCV status, alcohol status, and the interaction between HCV and Alcohol. HCV cirrhosis was associated with up-regulation of genes related to viral and immune response, apoptosis and inflammation. There were down-regulation of genes in the ubiquititin-proteasome system in alcoholic cirrhosis. The interaction of HCV and alcohol revealed negative interaction for genes involved in apoptosis and immune response. There was a negative estimate for genes involved in class II restricted antigen presentation. Introduction Chronic Liver diseases of any etiology are the 9th leading cause of death in the United States (1). The leading causes of liver disease are Alcoholic Liver Disease (ALD) and chronic Hepatitis C Virus (HCV) infection, either alone or in combination, as they account for close to two- thirds of deaths from and patients with chronic liver diseases (1,2,3). The liver is vulnerable to sustained, chronic injury because the hepatocyte is the primary site of HCV replication as well as the metabolism of ethanol; thus it is intuitive that there is an interaction in the pathogenesis of HCV and alcohol (4). Despite clinical evidence of exacerbated injury, higher mortality rates and increased risk of hepatocellular carcinoma (HCC), liver disease mediated by the interaction of alcohol and HCV is complex and not completely understood. Pathogenesis of alcohol and HCV have similar effects of injury but arrive at those effects via different mechanisms as both etiologies manifest the four sequential hallmarks of liver disease: steatosis (fatty liver), steatohepatitis (inflamed fatty liver), fibrosis and HCC (5). 1 What is the Hepatitis C virus? Hepatitis C is a single stranded positive sense RNA virus (6) that was discovered in 1989. The virus is transmitted through bodily fluids, and most of those infected are intravenous drug users (7). Over 170 million people worldwide are infected with the virus (8). The progression of the virus is slow, most people are not aware of their infection until presented with a compromised liver; the
Load more

Recommended publications
  • METACYC ID Description A0AR23 GO:0004842 (Ubiquitin-Protein Ligase
    Electronic Supplementary Material (ESI) for Integrative Biology This journal is © The Royal Society of Chemistry 2012 Heat Stress Responsive Zostera marina Genes, Southern Population (α=0.
    [Show full text]
  • Strategies to Increase ß-Cell Mass Expansion
    This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents .................................................................................................
    [Show full text]
  • The Cross-Talk Between Methylation and Phosphorylation in Lymphoid-Specific Helicase Drives Cancer Stem-Like Properties
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties Na Liu1,2,3, Rui Yang1,2, Ying Shi1,2, Ling Chen1,2, Yating Liu1,2, Zuli Wang1,2, Shouping Liu1,2, Lianlian Ouyang4, Haiyan Wang1,2, Weiwei Lai1,2, Chao Mao1,2, Min Wang1,2, Yan Cheng5, Shuang Liu4, Xiang Wang6, Hu Zhou7, Ya Cao1,2, Desheng Xiao1 and Yongguang Tao1,2,6 Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.
    [Show full text]
  • Supporting Information
    Supporting Information Celhar et al. 10.1073/pnas.1507052112 SI Materials and Methods using a Nanodrop spectrophotometer (Thermo Fisher Scien- Proteinuria. Proteinuria was assessed using Albustix (Bayer). Al- tific). A TaqMan RNA-to-CT 1-Step Kit (Applied Biosystems) bumin levels in urine were assayed using an Albumin Mouse was used to perform the reverse transcription and quantitative ELISA Kit (Abcam) according to the manufacturer’s instructions; PCR reactions according to the manufacturer’s instructions samples were assayed at a dilution of 1:400. Samples were nor- using TaqMan gene expression assays (Applied Biosystems) to malized for creatinine using a Creatinine (urinary) Colorimetric either Tlr7 (Mm00446590) or the B2m housekeeping gene Assay Kit (Cayman Chemical) according to the manufacturer’s (Mm00437762). Real-time PCR was performed on the 7900H instructions; initial sample dilution of 1:10. fast real-time PCR system and analyzed using SDS 2.4 (Applied Biosystems). Relative mRNA expression was calculated using the Cell Sorting, RNA Isolation, and RT-PCR. Splenic B cells were comparative C method. + − + + t sorted as live CD45 Gr1 B220 CD19 , splenic T cells as live + − + + CD45 Gr1 CD3 CD5 and peritoneal macrophages as live Imaging. Kidney sections from OCT embedded tissue were fixed + − CD45 Gr1 CD11bhiF4/80hi. Sorted cells were centrifuged, re- with 4% paraformaldehyde before permeabilization with acetone suspended in TRIzol (Life Technologies) and stored at −80°. RNA and stained with Phalloidin (AF647) and anti-CD3d (unlabeled was extracted by TRIzol/chloroform and purified with the Qiagen Ab followed by secondary staining with donkey anti-goat Dylight RNeasy Mini purification kit according to the manufacturer’s 550).
    [Show full text]
  • Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
    International Journal of Molecular Sciences Review Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression Guang Yang, Rachel Shi and Qing Zhang * Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] (G.Y.); [email protected] (R.S.) * Correspondence: [email protected]; Tel.: +1-214-645-4671 Received: 6 October 2020; Accepted: 29 October 2020; Published: 31 October 2020 Abstract: Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer. Keywords: hypoxia; PHDs; TETs; JmjCs; HIFs 1. Introduction Molecular oxygen serves as a co-factor in many biochemical processes and is fundamental for aerobic organisms to maintain intracellular ATP levels [1,2].
    [Show full text]
  • Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy
    Cancers 2011, 3, 1691-1707; doi:10.3390/cancers3021691 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy Monica Mann 1, Valerie Cortez 1 and Ratna K. Vadlamudi 2,* 1 Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; E-Mails: [email protected] (M.M.); [email protected] (V.C.) 2 Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-210-567-4930; Fax: +1-210-567-4958. Received: 4 January 2011; in revised form: 11 March 2011 / Accepted: 25 March 2011 / Published: 29 March 2011 Abstract: Estrogen receptor (ER) signaling plays a key role in hormonal cancer progression. ER is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ER signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ER target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ER-mediated epigenetic pathway could play a vital role in ER driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERdriven epigenetic changes In this review, we summarize current knowledge on mechanisms by which ER signaling potentiates epigenetic changes in cancer cells via histone modifications.
    [Show full text]
  • Mouse Germ Line Mutations Due to Retrotransposon Insertions Liane Gagnier1, Victoria P
    Gagnier et al. Mobile DNA (2019) 10:15 https://doi.org/10.1186/s13100-019-0157-4 REVIEW Open Access Mouse germ line mutations due to retrotransposon insertions Liane Gagnier1, Victoria P. Belancio2 and Dixie L. Mager1* Abstract Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differences and similarities between the mutational role of TEs in mice and humans. Keywords: Endogenous retroviruses, Long terminal repeats, Long interspersed elements, Short interspersed elements, Germ line mutation, Inbred mice, Insertional mutagenesis, Transcriptional interference Background promoter and polyadenylation motifs and often a splice The mouse and human genomes harbor similar types of donor site [10, 11]. Sequences of full-length ERVs can TEs that have been discussed in many reviews, to which encode gag, pol and sometimes env, although groups of we refer the reader for more in depth and general infor- LTR retrotransposons with little or no retroviral hom- mation [1–9]. In general, both human and mouse con- ology also exist [6–9]. While not the subject of this re- tain ancient families of DNA transposons, none view, ERV LTRs can often act as cellular enhancers or currently active, which comprise 1–3% of these genomes promoters, creating chimeric transcripts with genes, and as well as many families or groups of retrotransposons, have been implicated in other regulatory functions [11– which have caused all the TE insertional mutations in 13].
    [Show full text]
  • A Functional C-Terminal TRAF3-Binding Site in MAVS Participates in Positive and Negative Regulation of the IFN Antiviral Response
    Cell Research (2011) 21:895-910. © 2011 IBCB, SIBS, CAS All rights reserved 1001-0602/11 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response Suzanne Paz1, 2, Myriam Vilasco3, Steven J Werden1, Meztli Arguello1, Deshanthe Joseph-Pillai1, 2, Tiejun Zhao1, Thi Lien-Anh Nguyen1, Qiang Sun1, Eliane F Meurs3, Rongtuan Lin1, 4, John Hiscott1, 2, 4 1Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec H3T1E2, Canada; 2Department of Microbiology and Immunology, McGill University Montreal, Quebec H3A 2B4, Canada; 3Department of Virology, Unit of Hepacivirus and Innate Immunity, Pasteur Institute, Paris 75724 France; 4Department of Medicine, McGill University Montreal, Quebec H3A 2B4, Canada Recognition of viral RNA structures by the cytosolic sensor retinoic acid-inducible gene-I (RIG-I) results in the activation of signaling cascades that culminate with the generation of the type I interferon (IFN) antiviral response. Onset of antiviral and inflammatory responses to viral pathogens necessitates the regulated spatiotemporal recruitment of signaling adapters, kinases and transcriptional proteins to the mitochondrial antiviral signaling protein (MAVS). We previously demonstrated that the serine/threonine kinase IKKε is recruited to the C-terminal region of MAVS following Sendai or vesicular stomatitis virus (VSV) infection, mediated by Lys63-linked polyubiquitination of MAVS at Lys500, resulting in inhibition of downstream IFN signaling (Paz et al, Mol Cell Biol, 2009). In this study, we demonstrate that C-terminus of MAVS harbors a novel TRAF3-binding site in the aa450- 468 region of MAVS.
    [Show full text]
  • Serum Levels of Spexin and Kisspeptin Negatively Correlate with Obesity and Insulin Resistance in Women
    Physiol. Res. 67: 45-56, 2018 https://doi.org/10.33549/physiolres.933467 Serum Levels of Spexin and Kisspeptin Negatively Correlate With Obesity and Insulin Resistance in Women P. A. KOŁODZIEJSKI1, E. PRUSZYŃSKA-OSZMAŁEK1, E. KOREK4, M. SASSEK1, D. SZCZEPANKIEWICZ1, P. KACZMAREK1, L. NOGOWSKI1, P. MAĆKOWIAK1, K. W. NOWAK1, H. KRAUSS4, M. Z. STROWSKI2,3 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Poznan, Poland, 2Department of Hepatology and Gastroenterology & The Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Berlin, Germany, 3Department of Internal Medicine, Park-Klinik Weissensee, Berlin, Germany, 4Department of Physiology, Karol Marcinkowski University of Medical Science, Poznan, Poland Received August 18, 2016 Accepted June 19, 2017 On-line November 10, 2017 Summary Corresponding author Spexin (SPX) and kisspeptin (KISS) are novel peptides relevant in P. A. Kolodziejski, Department of Animal Physiology and the context of regulation of metabolism, food intake, puberty and Biochemistry, Poznan University of Life Sciences, Wolynska Street reproduction. Here, we studied changes of serum SPX and KISS 28, 60-637 Poznan, Poland. E-mail: [email protected] levels in female non-obese volunteers (BMI<25 kg/m2) and obese patients (BMI>35 kg/m2). Correlations between SPX or Introduction KISS with BMI, McAuley index, QUICKI, HOMA IR, serum levels of insulin, glucagon, leptin, adiponectin, orexin-A, obestatin, Kisspeptin (KISS) and spexin (SPX) are peptides ghrelin and GLP-1 were assessed. Obese patients had lower SPX involved in regulation of body weight, metabolism and and KISS levels as compared to non-obese volunteers (SPX: sexual functions. In 2014, Kim and coworkers showed that 4.48±0.19 ng/ml vs.
    [Show full text]
  • An Amplified Fatty Acid-Binding Protein Gene Cluster In
    cancers Review An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis Rong-Zong Liu and Roseline Godbout * Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-780-432-8901 Received: 6 November 2020; Accepted: 16 December 2020; Published: 18 December 2020 Simple Summary: Prostate cancer is the second most common cancer in men. In many cases, prostate cancer grows very slowly and remains confined to the prostate. These localized cancers can usually be cured. However, prostate cancer can also metastasize to other organs of the body, which often results in death of the patient. We found that a cluster of genes involved in accumulation and utilization of fats exists in multiple copies and is expressed at much higher levels in metastatic prostate cancer compared to localized disease. These genes, called fatty acid-binding protein (or FABP) genes, individually and collectively, promote properties associated with prostate cancer metastasis. We propose that levels of these FABP genes may serve as an indicator of prostate cancer aggressiveness, and that inhibiting the action of FABP genes may provide a new approach to prevent and/or treat metastatic prostate cancer. Abstract: Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed.
    [Show full text]
  • Selectin Ligand Sialyl-Lewis X Antigen Drives Metastasis of Hormone-Dependent Breast Cancers
    Published OnlineFirst October 24, 2011; DOI: 10.1158/0008-5472.CAN-11-1139 Cancer Tumor and Stem Cell Biology Research Selectin Ligand Sialyl-Lewis x Antigen Drives Metastasis of Hormone-Dependent Breast Cancers Sylvain Julien1, Aleksandar Ivetic2, Anita Grigoriadis3, Ding QiZe1, Brian Burford1, Daisy Sproviero1, Gianfranco Picco1, Cheryl Gillett4, Suzanne L. Papp5, Lana Schaffer5, Andrew Tutt3, Joyce Taylor-Papadimitriou1, Sarah E. Pinder4, and Joy M. Burchell1 Abstract The glycome acts as an essential interface between cells and the surrounding microenvironment. However, changes in glycosylation occur in nearly all breast cancers, which can alter this interaction. Here, we report that profiles of glycosylation vary between ER-positive and ER-negative breast cancers. We found that genes involved in the synthesis of sialyl-Lewis x (sLex; FUT3, FUT4, and ST3GAL6) are significantly increased in estrogen receptor alpha-negative (ER-negative) tumors compared with ER-positive ones. SLex expression had no influence on the survival of patients whether they had ER-negative or ER-positive tumors. However, high expression of sLex in ER- positive tumors was correlated with metastasis to the bone where sLex receptor E-selectin is constitutively expressed. The ER-positive ZR-75-1 and the ER-negative BT20 cell lines both express sLex but only ZR-75-1 cells could adhere to activated endothelial cells under dynamic flow conditions in a sLex and E-selectin–dependent manner. Moreover, L/P-selectins bound strongly to ER-negative MDA-MB-231 and BT-20 cell lines in a heparan sulfate (HS)–dependent manner that was independent of sLex expression. Expression of glycosylation genes involved in heparan biosynthesis (EXT1 and HS3ST1) was increased in ER-negative tumors.
    [Show full text]
  • Polymerase Ribozyme with Promoter Recognition
    In vitro Evolution of a Processive Clamping RNA Polymerase Ribozyme with Promoter Recognition by Razvan Cojocaru BSc, Simon Fraser University, 2014 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Department of Molecular Biology and Biochemistry Faculty of Science © Razvan Cojocaru 2021 SIMON FRASER UNIVERSITY Summer 2021 Copyright in this work is held by the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Declaration of Committee Name: Razvan Cojocaru Degree: Doctor of Philosophy Title: In vitro Evolution of a Processive Clamping RNA Polymerase Ribozyme with Promoter Recognition Committee: Chair: Lisa Craig Professor, Molecular Biology and Biochemistry Peter Unrau Supervisor Professor, Molecular Biology and Biochemistry Dipankar Sen Committee Member Professor, Molecular Biology and Biochemistry Michel Leroux Committee Member Professor, Molecular Biology and Biochemistry Mani Larijani Internal Examiner Associate Professor, Molecular Biology and Biochemistry Gerald Joyce External Examiner Professor, Jack H. Skirball Center for Chemical Biology and Proteomics Salk Institute for Biological Studies Date Defended/Approved: August 12, 2021 ii Abstract The RNA World hypothesis proposes that the early evolution of life began with RNAs that can serve both as carriers of genetic information and as catalysts. Later in evolution, these functions were gradually replaced by DNA and enzymatic proteins in cellular biology. I start by reviewing the naturally occurring catalytic RNAs, ribozymes, as they play many important roles in biology today. These ribozymes are central to protein synthesis and the regulation of gene expression, creating a landscape that strongly supports an early RNA World.
    [Show full text]