MicroRNAs in Medicine E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1529

Veröffentlichungsjahr: 2013

Beschreibung

MicroRNAs in Medicine provides an access point into the current literature on microRNA for both scientists and clinicians, with an up-to-date look at what is happening in the emerging field of microRNAs and their relevance to medicine. Each chapter is a comprehensive review, with descriptions of the latest microRNA research written by international leaders in their field. Opening with an introduction to what microRNAs are and how they function, the book goes on to explore the role of microRNAs in normal physiological functions, infectious diseases, non-infectious diseases, cancer, circulating microRNAs as non-invasive biomarkers, and finally their potential as novel therapeutics. Including background information on the field as well as reviews of the latest research breakthroughs, MicroRNAs in Medicine is a one-stop source of information to satisfy the specialists and non-specialists alike, appealing to students, researchers, and clinicians interested in understanding the potential of microRNAs in medicine and research.

Leseprobe

Table of Contents

Title page

Copyright page

Foreword

Preface

Contributors

1: MicroRNAs: A Brief Introduction

I. A Short History of Small RNAs

II. Biogenesis of miRNAs

III. miRNA Function: Controlling mRNA Stability, Degradation, and/or Translation

IV. Regulating the Regulators: miRNA Control and Dysfunction in Disease

V. Present and Future Perspectives for miRNAs in Medicine

PART I: MicroRNAs as Physiological Regulators

2: MicroRNA Regulation of Stem Cell Fate and Reprogramming

I. Introduction

II. MicroRNAs in Pluripotency and Establishment of Different Lineages

III. MicroRNAs, Induced Pluripotency, and Transdifferentiation

IV. Conclusion

Acknowledgments

3: MicroRNAs as Regulators of Immunity

I. Introduction

II. Innate Immunity and miRNAs

III. Adaptive Immunity and miRNAs

IV. Conclusions and Future Directions

4: Regulation of Senescence by MicroRNAs

I. Introduction: Senescence

II. Posttranscriptional Regulation of Senescence by miRNAs

III. Impact of SA-miRNAs on In Vivo Senescence

IV. Concluding Remarks and Future Perspectives

Acknowledgments

5: The Emergence of GeroMIRs: A Group of MicroRNAs Implicated in Aging

I. Introduction

II. MiRNAs and Aging: Lessons from Invertebrates

III. Changes in miRNA Expression during Mammalian Aging

IV. MiRNA Modulation of Mammalian DNA Damage

V. Micromanaging of Other Aging-Associated Pathways in Mammals

VI. Conclusions and Future Perspectives

6: MicroRNAs and Hematopoiesis

I. Introduction

II. Lymphocyte Development

III. Monocyte and Granulocyte Development

IV. Erythrocyte and Megakaryocyte Development

V. Conclusions

7: MicroRNAs in Platelet Production and Activation

I. Introduction

II. miRNA Biogenesis and Function

III. miRNAs and Megakaryocytopoiesis

IV. Platelet miRNAs

V. Platelet miRNAs as Biomarkers

VI. Platelet Microparticles and miRNAs

VII. Summary and Future Directions

PART II: MicroRNAs in Infectious Disease: Host–Pathogen Interactions

8: MicroRNAs as Key Players in Host-Virus Interactions

I. Introduction

II. Host miRNAs and Virus Infection

III. Viral miRNAs

IV. Biological Roles of Viral miRNAs

V. Conclusions and Future Prospects

Acknowledgments

9: MicroRNA Expression in Avian Herpesviruses

I. Introduction

II. Avian Herpesviruses and Associated Diseases

III. Identification of miRNAs Encoded by Avian HerpesvirusES

IV. Viral Orthologues of Host miRNAs

V. Target Identification of Avian Herpesvirus miRNAs

VI. Conclusions

Acknowledgment

10: Function of Human Cytomegalovirus MicroRNAs and Potential Roles in Latency

I. Introduction to Human Cytomegalovirus

II. Identification of Human Cytomegalovirus miRNAs

III. Human Cytomegalovirus miRNAs: Creating an Environment Conducive to Latency

IV. Conclusions

11: Involvement of Small Non-Coding RNA in HIV-1 Infection

I. Introduction

II. miRNAs, siRNAs, and tdsmRNAs

III. Regulation of miRNAs by HIV Infection

IV. Regulation of HIV-1 Infection by Host miRNAs

V. sncRNAs in Virally Infected Cells

VI. tRNA-Derived sncRNAs and HIV-1

VII. Concluding Remarks

Acknowledgment

12: MicroRNA in Malaria

I. Introduction: Malaria as a Disease

II. The Pathogenesis of Severe Malaria

III. miRNAs and Malaria

IV. Potential Roles for miRNAs in Regulating Host Response to Pathophysiological Mechanisms

V. Conclusions and Future Research Directions

PART III: Cancer

13: The MicroRNA Decalogue of Cancer Involvement

I. Introduction

II. The Decalogue of Principles of miRNA Involvement in Human Cancers

III. Conclusion

14: MicroRNAs as Oncogenes and Tumor Suppressors

I. Introduction

II. miRNA Targets

III. Role of miRNAs in Cancer

IV. miRNAs and Their Future Use in the Clinic: Diagnosis, Prognosis, and Therapy

15: Long Non-Coding RNAs and Their Roles in Cancer

I. Introduction

II. General Features of lncRNAs

III. Classifications of lncRNAs

IV. Functions and Mechanisms of lncRNAs

V. lncRNAs and Cancer

VI. Future Perspectives

Acknowledgments

16: Regulation of Hypoxia Responses by MicroRNA Expression

I. Hypoxia in Solid Tumors

II. Hypoxia-Inducible Factors (HIFs) and Transcriptional Regulation upon Hypoxia Response

III. MicroRNA (miRNA) Regulation under Hypoxia

IV. miR-210 as Key Player in Hypoxia

V. miRNA-Mediated Regulation of HIF

VI. Conclusions

17: Control of Receptor Function by MicroRNAs in Breast Cancer

I. Breast Cancer: Introduction

II. MicroRNAs (miRNAs) in Breast Cancer: Diagnostic, Prognostic, and Predictive Biomarkers

III. ER and miRNAs

IV. ErbB Receptor Signaling and miRNAs

V. Conclusions

Acknowledgments

18: MicroRNAs in Human Prostate Cancer: From Pathogenesis to Therapeutic Implications

I. Introduction

II. PCa Pathogenesis and miRNAs

III. miRNA Profiling in PCa

IV. miRNAs and Their Targets in PCa

V. miRNAs as Potential Markers for Diagnosis and Progression of PCa

VI. miRNAs Modulating Tumor Progression and Metastasis in PCa

VII. miRNAs that Play a Role in the Epigenetic Machinery of PCa Pathogenesis

VIII. miRNAs as Implicated in PCa Therapy and Their Future Potential

IX. Conclusion

Acknowledgment

19: MicroRNA Signatures as Biomarkers of Colorectal Cancer

I. Introduction

II. Circulating miRNAs in Plasma/Serum of CRC Patients

III. miRNAs in CRC Tumor Tissue

IV. Conclusion

20: Genetic Variations in MicroRNA-Encoding Sequences and MicroRNA Target Sites Alter Lung Cancer Susceptibility and Survival

I. Introduction

II. Genetic Variations in miR-Encoding Sequences and Lung Cancer

III. Genetic Polymorphisms in miRNA Target Sites and Lung Cancer

IV. Conclusions

21: MicroRNA in Myelopoiesis and Myeloid Disorders

I. Introduction

II. Significance of Myeloid Biology in the Earliest Mammalian miRNA Discoveries

III. Critical Requirements of miRNA Signaling to Instruct Proper Myeloid Cell Fate

IV. Diagnostic, Prognostic, Predictive, and Therapeutic Applications of miRNA in Myeloid Disorders and AML

Acknowledgments

22: MicroRNA Deregulation by Aberrant DNA Methylation in Acute Lymphoblastic Leukemia

I. Introduction

II. miRNA Deregulation by DNA Methylation in ALL

III. Conclusion

23: Role of miRNAs in the Pathogenesis of Chronic Lymphocytic Leukemia

I. Introduction

II. miR-15a/16-1

III. miR-29

IV. miR-34b/c

V. miRNAs, Single-Nucleotide Polymorphisms (SNPs), and DNA Methylation

VI. Conclusions

Acknowledgments

24: MicroRNA in B-Cell Non-Hodgkin's Lymphoma: Diagnostic Markers and Therapeutic Targets

I. Introduction

II. The Process of B-Cell Differentiation

III. B-Cell Lymphomas and miRNAs

IV. miRNA-Targeted Therapy in B-Cell Lymphomas

V. Summary

25: MicroRNAs in Diffuse Large B-Cell Lymphoma

I. Introduction

II. Mature B-Cell Differentiation Stage-Specific MicroRNA Expression Patterns

III. MicroRNA Expression in DLBCL

IV. Potential Roles of MicroRNAs in Lymphomagenesis

V. MicroRNAs as Potential Biomarkers in DLBCL

VI. Conclusions

26: The Role of MicroRNAs in Hodgkin's Lymphoma

I. Introduction

II. miRNAs in Hodgkin's Lymphoma

III. miRNA Profiling Studies in Hodgkin's Lymphoma

IV. Functional miRNA Studies in HL

V. Clinical Value of miRNAs in HL

VI. Concluding Remarks and Future Perspectives

27: MicroRNA Expression in Cutaneous T-Cell Lymphomas

I. Introduction

II. The Pathology of Cutaneous Lymphoma

III. Aberrant Expression of Components of the MicroRNA Biogenesis Machinery in Cutaneous T-Cell Lymphoma

IV. miRNA Expression Profiling in Cutaneous T-Cell Lymphomas

V. Functional Consequences of (Aberrant) miRNA Expression in Cutaneous T-Cell Lymphoma

VI. Conclusions and Perspectives

Acknowledgments

PART IV: Hereditary and Other Non-Infectious Diseases

28: MicroRNAs and Hereditary Disorders

I. Introduction

II. MicroRNAs and Hereditary Disorders

III. Conclusion

29: MicroRNAs and Cardiovascular Diseases

I. Introduction

II. Cardiac Hypertrophy

III. Myocardial Ischemia and Cell Death

IV. Cardiac Fibrosis

V. Arrhythmia

VI. Angiogenesis and Vascular Diseases

VII. Heart Failure

VIII. Lipid Metabolism

IX. Conclusions

Acknowledgments

30: MicroRNAs and Diabetes

I. Introduction

II. Diabetes Mellitus Is Associated with Changes in Gene Expression in Many Organs

III. Role of miRNAs in the Regulation of β-Cell Functions

IV. Role of miRNAs in Insulin Target Tissues

V. Contribution of miRNAs to Diabetes Complications

VI. Circulating miRNAs as Diabetes Biomarkers

VII. Conclusion

31: MicroRNAs in Liver Diseases

I. Introduction

II. Viral Hepatitis

III. Alcoholic Liver Disease (ALD)

IV. Non-Alcoholic Fatty Liver Disease (NAFLD)

V. Drug-Induced Liver Injury (DILI)

VI. Hepatocellular Carcinoma (HCC)

VII. Biliary Diseases

VIII. Fibrosis

IX. miRNA-Based Therapeutic Approaches to Liver Disease

X. Conclusions and Future Directions

Acknowledgments

32: MicroRNA Regulation in Multiple Sclerosis

I. Introduction

II. miRNA Profiles in MS Patients

III. Involvement of miRNAs in the Pathophysiology of MS

IV. Concluding Remarks and Open Questions

Acknowledgments

33: The Role of MicroRNAs in Alzheimer's Disease

I. Introduction

II. miRNAs in Alzheimer's Disease and Other Neurodegenerative Diseases

III. Neuronal miRNAs

IV. miRNAs in Inflammatory Processes and Their Link to the Nervous System

V. miRNAs and AD Therapy

VI. Future Prospects and Concluding Remarks

Acknowledgments

34: Current Views on the Role of MicroRNAs in Psychosis

I. Introduction

II. Phenotypic Expression of Schizophrenia: The Role of Neurotransmitters

III. Etiology of Psychosis

IV. MicroRNA and Schizophrenia

V. Bipolar Affective Disorder

VI. miRNAs as Drug Targets for Treatment of Psychosis

VII. Future MicroRNA-Based Therapies

VIII. Conclusions

Acknowledgments

PART V: Circulating MicroRNAs as Cellular Messengers and Novel Biomarkers

35: Circulating MicroRNAs as Non-Invasive Biomarkers

I. Introduction

II. Characteristics of MicroRNAs

III. Biological Role of Circulating MicroRNAs

IV. Quantification of Circulating MicroRNAs

V. MicroRNAs in Cancer

VI. Circulating MicroRNAs in Cancer

VII. Circulating MicroRNAs in Pregnancy and Benign Diseases

VIII. Conclusion

36: Circulating MicroRNAs as Cellular Messengers

I. Introduction

II. Extracellular miRNA

III. Intercellular Communication

IV. Cellular Export of Extracellular miRNA

V. Lipid-Based miRNA Carriers

VI. Protein miRNA Carriers

VII. Delivery of Circulating miRNA to Recipient Cells

VIII. Functional Roles of Extracellular miRNA

IX. Summary

37: Release of MicroRNA-Containing Vesicles Can Stimulate Angiogenesis and Metastasis in Renal Carcinoma

I. Introduction

II. Extracellular Vesicles in Cell Communication

III. Interplay between Tumor and Their Surrounding Cells

IV. Renal Carcinomas

V. Tumor Angiogenesis and miRNAs

VI. Tumor Metastasis and miRNAs

VII. Cancer Stem Cells

VIII. Conclusions

PART VI: Therapeutic Uses of MicroRNAs: Current Perspectives and Future Directions

38: MicroRNA Regulation of Cancer Stem Cells and MicroRNAs as Potential Cancer Stem Cell Therapeutics

I. Introduction

II. miRNA Regulation of Cancer Stem Cells

III. miRNAs in Cancer Diagnosis, Prognosis, and Therapy

IV. Conclusions and Perspectives

Acknowledgments

39: Therapeutic Modulation of MicroRNAs

I. Introduction: Physiological and Pathophysiological Roles of MicroRNAs

II. General Approaches for Therapeutic MicroRNA-Based Intervention

III. Therapeutic MicroRNA Replacement

IV. Therapeutic Studies in MicroRNA Inhibition

V. Perspectives, Issues, and Future Directions

Acknowledgments

40: Locked Nucleic Acids as MicroRNA Therapeutics

I. Introduction

II. Design of LNA-Based Inhibitors of miRNAs

III. Activity in Experimental Animals

IV. LNA-antimiRs/tiny LNAs in Pre-Clinical Development

V. LNA-antimiR in Clinical Development

VI. Discussion

Conflict of Interest

Acknowledgment

Index

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

MicroRNAs in medicine / edited by Charles H. Lawrie.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-30039-8 (cloth : alk. paper)

I. Lawrie, Charles H., editor of compilation.

[DNLM: 1. MicroRNAs. QU 58.7]

QP623.5.S63

572.8'8–dc23

2013038052

Foreword

The history of microRNA (miRNA) starts with an elegant genetic analysis by Ambros and Ruvkun that led to the discovery of a small non-coding RNA regulator of developmental timing. Eventually these two collaborators realised, during a late night phone conversation, that their RNA regulator binds, by Watson-Crick base pairing, to its target mRNA. Later work in the 1990s identified a second similar regulatory RNA, but I do not think that anyone would have predicted at that time that these RNA regulators would be the pioneers of a large class of RNA—the miRNAs—that affects the expression of a very large number of mRNAs.

In my laboratory, we work on plants and, in 1997, we tried to make a connection with the work of Ambros and Ruvkun. We had discovered small RNA that has a role in posttranscriptional gene silencing of transgenic and virus-infected plants. Like most biologists, we are always keen to make connections between different branches of the tree of life, and we hoped that our plant RNA would be similar to the regulatory RNA of worms. However, our silencing phenomena clearly operated at the level of RNA turnover, whereas the Ambros and Ruvkun RNAs mediated translational suppression. Our initial reluctant conclusion was that the worm RNAs and transgene silencing are separate phenomena.

Two later developments caused us, and others, to change our minds. First, there was use of sequencing to characterize the small RNA populations in several animals. This analysis revealed that the original Ambros and Ruvkun miRNAs are highly conserved from worms to man and that there are many similar RNAs that also bind to the 3′-UTR of their target RNA. Second, from genetic analyses, it was clear that the enzymes involved in the biogenesis and the effector activity of these regulatory RNAs—Dicer and Slicer—are implicated in many regulatory processes throughout development, as well as with gene silencing in transgenic and virus-infected plants. It was clear that the RNAs of Ambros and Ruvkun do not represent a specialized regulatory mechanism of early development in worms: they are part of a large family of silencing RNAs that includes the short RNAs that we had seen in plants. RNA silencing is common to both animal and plant kingdoms, and it can have many different biological effects.

The diversity of RNA silencing is indicated by the multiplicity of effector mechanisms involving RNA turnover and chromatin modification in addition to translational effects. This diversification is manifested even among miRNAs. They can act on target RNA stability, as well as on translation and they can both block and activate translation. Adding to the complexity of miRNA regulation there are “sponge” RNAs that are decoys of the natural miRNA target and miRNAs feature in regulatory systems with negative feedback loops. Some miRNAs are found in circulating blood, and they may act both outside and inside the cell. Clearly, there is the potential for great diversity and complexity in miRNA-mediated regulation.

Given this diversity and complexity, it is not surprising that there is great interest in clinical application of miRNAs. There is a good prospect that, even with the present level of understanding, miRNAs will feature in novel diagnostic tools, and that they will help identify targets for pharmaceutical and other inventions. Key areas for research include the targeting specificity of miRNAs and their place in networks of genetic regulation. New analytic methods based on next-generation sequencing will accelerate this research, and computational approaches for data analysis and systems modeling will be important drivers of progress.

The other, as yet relatively underexplored potential of miRNA, is as a therapeutic agent. A set of artificial miRNAs could be designed that would target one or more motifs in disease genes, and these RNAs could then be delivered so that they are taken up and have an effect in cells. In plants, the use of artificial miRNAs is a routine tool, although the targeting mechanism is simpler than in animals and delivery can be via transgenes rather than through uptake of RNA molecules into cells. Delivery is the major challenge for this therapeutic application of miRNAs, but there are early indications that it can be overcome for liver and possibly superficial tissues.

The translation pathway from basic research to the clinic and patient care is always complicated. Practical requirements often thwart the good intentions or clever ideas of the researchers. However, in the case of miRNAs, as with other applications related to RNA silencing, we can be more than usually optimistic for two reasons. The first reason is because a single set of miRNA mechanisms are involved in many aspects of growth, development, and responses to external stimuli. There is, therefore, a good prospect that miRNA research findings will have general relevance to many clinical applications. The second reason follows from the finding that miRNAs interact with their target through Watson-Crick base pairing. Such interactions are more predictable and computable than processes involving, for example, proteins or lipids or small molecules. Over the next decade, I anticipate that miRNAs will feature in many different clinical applications.

Prof. Sir David Baulcombe

University of Cambridge

Corecipient (along with Victor Ambros and Gary Ruvkun)

of the 2008 Lasker Award for work on siRNA and miRNA

Preface

Since their formal recognition just over 10 years ago, microRNAs (miRNAs) have become one of the hottest topics in biology, not least of all because during this short time they have been found to act as crucial regulators of many, if not all, physiological and pathological processes. Nowhere has this increasing interest in miRNAs been more pronounced than within the medical field. Yet surprisingly, until now, there has been no book that attempts to cover this subject in any significant depth. Therefore, the primary aim of this project was to fill this gap by putting together a comprehensive collection of reviews from some of the leading lights in the miRNA world; for the first time, combining areas of medicine as diverse as stem cells, immunology, aging, infectious disease, cancer, psychiatric disease, and hereditary disorders are united by the central theme of miRNA involvement.

A criticism often leveled at a project like this is that it covers such a fast-moving subject that the book is out of date before it even hits the shelf. Had the aim of the book been solely to provide a collection of up-to-date reviews, then this criticism would indeed have been well founded; instead, we have tried to highlight general concepts of miRNA involvement as applied to well-established areas within medicine. While the specific roles for miRNAs described within these chapters will surely change and expand in the future, it is believed that the field is now sufficiently mature that these central concepts will stand the test of time and consequently this book will provide an invaluable resource for many years to come. Moreover, although specialist scientific journals can provide the reader with the very latest developments in the miRNA arena, in general, these texts are presented within a very narrow context and are not readily accessible to non-experts. A central goal of this endeavor was to provide each chapter with sufficient background context in order to open it up to readers outside of their specialist field, and in doing so, allow the reader to draw comparisons of the role of miRNAs between differing disciplines. For example, the hematologist may recognize the central role of miR-181 in lymphoid differentiation and malignancy, but may not yet realize its importance to other pathologies, such as breast cancer, colorectal carcinoma, or even schizophrenia. This book attempts to offer a “one-stop shop” for information related to miRNA involvement in differing areas of medicine, and it is hoped that this cross-fertilization of ideas will stimulate novel research directions as a consequence. Another important role for this book was to serve as a preparatory text to the world of miRNAs for the uninitiated. With this in mind, an introductory chapter that aims to cover the FAQs of miRNAs has been included in order to provide a general framework for appreciating the subsequent chapters.

In summary, MicroRNAs in Medicine aspires to provide experts and non-experts alike with an understanding of the excitement, importance, breadth, and potential of miRNAs to modern medicine, and is aimed to appeal to clinicians, researchers, students, and journalists, as well as the interested public. It is hoped that this book marks the beginning (or continuation) of the readers journey into the miRNA world, and although comprehensive, the book makes no claim to be an exhaustive authority on the subject; rather, it is intended to serve as a foundation for further investigation.

I am indebted to the many contributing authors who have given so much of their valuable time to make this project a success. The involvement of such a high caliber of contributors, including some of the true pioneers of the field, have made the editorial role a pleasure, and it has been a great honor to work alongside many of the people that inspired my original foray into the miRNA world.

Special thanks should be given to Dr. Chris Hatton (Director of Clinical Medicine at the John Radcliffe Hospital, Oxford) for his inspiration and continual support over the years. This book is dedicated to my two beautiful children, Julia and Carlos, and my wonderful and understanding wife, María.

Charles H. Lawrie

Biodonostia Research Institute, San Sebastián, Spain

Contributors

Xabier Agirre, Oncology Division, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

Achim Aigner, Rudolf-Boehm-Institute for Pharmacology and Toxicology Clinical Pharmacology, University of Leipzig, Leipzig, Germany

Alvaro J. Alencar, Department of Medicine, Division of Hematology-Oncology and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

Veronica Balatti, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and the Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Jesus M. Banales, Division of Hepatology and Gastroenterology, Biodonostia Research Institute, San Sebastián, Spain; and IKERBASQUE, Basque Foundation of Science, Bilbao, Spain

Shahar Barbash, Department of Biological Chemistry and The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

Javier A. Bravo, Department of Psychiatry, University College Cork, Cork, Ireland

Paul F. Bray, The Cardeza Foundation for Hematologic Research and the Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Luis Bujanda, Division of Hepatology and Gastroenterology, Biodonostia Research Institute, San Sebastián, Spain

Barbara Burwinkel, Molecular Epidemiology (C080), German Cancer Research Center, Heidelberg, Germany; and Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany

George A. Calin, Experimental Therapeutics Department and Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Carme Camps, Genomics Research Group, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

Giovanni Camussi, Department of Internal Medicine, Molecular Biotechnology Center (MBC) and Centre for Research in Experimental Medicine (CeRMS), Torino, Italy

Xurde M. Caravia, Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

Daniela Castanotto, Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

Federica Collino, Department of Internal Medicine, Molecular Biotechnology Center (MBC) and Centre for Research in Experimental Medicine (CeRMS), Torino, Italy

Carlo M. Croce, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and the Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Hannelore Dassow, Rudolf-Boehm-Institute for Pharmacology and Toxicology Clinical Pharmacology, University of Leipzig, Leipzig, Germany

Arjan Diepstra, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Lorena Di Lisio, Cancer Genomics Laboratory, IFIMAV, Santander, Spain

Timothy G. Dinan, Department of Psychiatry, University College Cork, Cork, Ireland

Leonard C. Edelstein, The Cardeza Foundation for Hematologic Research and the Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Aurélie Fender, Architecture et Réactivité de l'ARN, Institut de biologie moléculaire et cellulaire du CNRS, Université de Strasbourg, Strasbourg, France

Ramiro Garzon, Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Irena Godnic, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domzale, Slovenia

Myriam Gorospe, Laboratory of Genetics, NIA-IRP, NIH, Baltimore, MD, USA

Donald T. Gracias, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA

Ioannis Grammatikakis, Laboratory of Genetics, NIA-IRP, NIH, Baltimore, MD, USA

Cristina Grange, Department of Internal Medicine, Molecular Biotechnology Center (MBC) and Centre for Research in Experimental Medicine (CeRMS), Torino, Italy

Finn E. Grey, Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK

H. Leighton Grimes, Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; and Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Adrian L. Harris, Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

Elizabeth Hijona, Division of Hepatology and Gastroenterology, Biodonostia Research Institute, San Sebastián, Spain

Simon Horvat, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domzale, Slovenia; and Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia

Maite Huarte, Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Pamplona, Spain

Marilena V. Iorio, Start Up Unit, Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy

Juan Carlos Izpisua Belmonte, Centre for Regenerative Medicine in Barcelona, Barcelona, Spain; and Salk Institute for Biological Studies, La Jolla, CA, USA

Andreas Junker, Department of Neuropathology, University Medical Center Goettingen, Georg-August University, Gottingen, Germany

Omer Faruk Karatas, Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey

Peter D. Katsikis, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA

Aoife Kearney, Department of Psychiatry, University College Cork, Cork, Ireland

Joost Kluiver, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands

Tanja Kunej, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domzale, Slovenia

Agnieszka Kwarciak, Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

Charles H. Lawrie, Biodonostia Research Institute, San Sebastián, Spain; and Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

Dongxin Lin, State Key Laboratory of Molecular Oncology and Beijing Key Laboratory of Carcinogenesis and Cancer Prevention, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Can Liu, Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

Carlos López-Otín, Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

Erika Lorenzo Vivas, Centre for Regenerative Medicine in Barcelona, Barcelona, Spain

Izidore S. Lossos, Department of Medicine, Division of Hematology-Oncology and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

Xiaoya Luo, Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center, Heidelberg, Germany

Jose Antonio Lupiáñez, Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain

Nerea Martínez, Cancer Genomics Laboratory, IFIMAV, Santander, Spain

Marco Marzioni, Department of Gastroenterology, “Università Politecnica delle Marche,” Ancona, Italy

Pedro P. Medina, Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain; and Centre for Genomics and Oncological Research (GENYO), Granada, Spain

Sara E. Meyer, Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Miguel A. Moreno-Pelayo, Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain

Matías Morín, Unidad de Genética Molecular, Ramón y Cajal Institute of Health Research (IRYCIS) and Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain

Patricia Munoz-Garrido, Division of Hepatology and Gastroenterology, Biodonostia Research Institute, San Sebastián, Spain

Srikanth Nagalla, The Cardeza Foundation for Hematologic Research and the Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Venugopal Nair, Avian Viral Diseases Programme, The Pirbright Institute, Compton Laboratory, Compton, Berkshire, UK

Koh Ono, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Henrik Ørum, Santaris Pharma, Hørsholm, Denmark

Mustafa Ozen, Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; Bezmialem Vakif University, Istanbul, Turkey; and Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA

Klaus Pantel, Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Jon A. Pavelin, Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK

Yuri Pekarsky, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and the Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Sébastien Pfeffer, Architecture et Réactivité de l'ARN, Institut de biologie moléculaire et cellulaire du CNRS, Université de Strasbourg, Strasbourg, France

Katrin Pfütze, Molecular Epidemiology (C080), German Cancer Research Center, Heidelberg, Germany; and Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany

Claudia Piovan, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA; and Start Up Unit, Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy

Miguel Angel Piris, Cancer Genomics Laboratory, IFIMAV, Santander, Spain; and Department of Pathology, Hospital U. Marqués de Valdecilla, Santander, Spain

Wouter Plattel, Department of Pathology and Medical Biology, Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Panote Prapansilp, Department of Laboratory Medicine and WHO Collaborating Center for Research and Training on Viral Zoonoses, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Felipe Prósper, Oncology Division, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; and Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain

Jiannis Ragoussis, Genomics Research Group, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

Andrew J. Ramsay, Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

Romano Regazzi, Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland

Fernando J. Reyes-Zurita, Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain

Natalie L. Reynolds, Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK

Lara Rizzotto, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and the Wexner Medical Center, The Ohio State University, Columbus, OH, USA

John J. Rossi, Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

Eva E. Rufino-Palomares, Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain

Yolanda Sánchez, Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Pamplona, Spain

Sukhinder K. Sandhu, Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Heidi Schwarzenbach, Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Hermona Soreq, Department of Biological Chemistry and The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

Guihua Sun, Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA

Dean G. Tang, Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

Cornelis P. Tensen, Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands

Gustavo Tiscornia, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal

Gareth D.H. Turner, Mahidol-Oxford Tropical Medicine Research Unit and Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK

Alejandro P. Ugalde, Departamento de Bioquímica y Biología Molecular, Instituto Uni­versitario de Oncología-IUOPA, Universidad de Oviedo, Oviedo, Spain

Anke van den Berg, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Kasey C. Vickers, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

Lydia Visser, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Ming Yang, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

Yongxiu Yao, Avian Viral Diseases Programme, The Pirbright Institute, Compton Laboratory, Compton, Berkshire, UK

Minja Zorc, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domzale, Slovenia

1

MicroRNAs: A Brief Introduction

Charles H. Lawrie

Biodonostia Research Institute, San Sebastián, Spain

Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

I. A Short History of Small RNAs

II. Biogenesis of miRNAs

A. miRNA Nomenclature: What's in a Name?

III. miRNA Function: Controlling mRNA Stability, Degradation, and/or Translation

IV. Regulating the Regulators: miRNA Control and Dysfunction in Disease

A. Genetic Dysregulation of miRNA Expression

B. Epigenetic Regulation

C. Transcription Factors and miRNA Regulatory Networks

D. Regulating miRNA Synthesis and Processing

E. Control of miRNA Function

V. Present and Future Perspectives for miRNAs in Medicine

A. Deciphering the miRNA Targetome: Understanding the Functional Consequences of miRNA Dysregulation in Disease

B. Tip of the Non-Coding RNA Iceberg

C. Are miRNAs Clinically Useful Molecules?

References

Abbreviations

ADARadenosine deaminases that act on RNAAgoArgonauteALLacute lymphoblastic leukemiaCLLchronic lymphocytic leukemiaDGCR8DiGeorge critical region 8dsRNAdouble-stranded RNAExp-5exportin 5HITS-CLIPhigh-throughput sequencing of RNA isolated by cross-linking immunoprecipitationIPimmunoprecipitationlncRNAlong non-coding RNAmiRISCmiRNA RNA interference silencing complexmiRNAmicroRNAmRNA messenger RNAncRNAnon-coding RNAntnucleotidePACTprotein activator of the interferon-induced protein kinasePAR-CLIPphotoactivatable-ribonucleoside-enhanced cross-linking and immunoprecipitationPASRpromoter-associated small RNAs