Front Cover

miRNA and Cancer

Copyright

Contents

Contributors

Preface

Chapter One: MicroRNAs and Cancer: A Long Story for Short RNAs

References

Chapter Two: The Enigma of miRNA Regulation in Cancer

1. Introduction

2. Tumor Suppressor miRs and OncomiRs

3. Factors Regulating miRNAs

4. Regulation of the miRNA Biogenesis Pathway

4.1. AGO Proteins

4.2. Drosha Proteins

4.3. DGCR8 Proteins

4.4. DICER Proteins

5. Direct (Transcriptional) Regulation

5.1. c-MYC

5.2. E2F1

5.3. p53

6. Indirect Regulation

6.1. Nuclear Receptors

6.2. Epigenetic Control

6.3. TGF-β Signaling

6.4. MDA-7/IL-24

6.5. hPNPase

6.6. hnRNPA1

6.7. ADARs

6.8. Stress

6.9. Diet and Natural Products

7. Conclusions and Future Perspectives

Acknowledgments

References

Chapter Three: Animal Models to Study MicroRNA Function

1. Introduction

1.1. MicroRNA Biogenesis, Mechanism of Action and Function

1.1.1. Biogenesis

1.1.1.1. Expression of MiRNA Genes

1.1.1.1.1. Regulation Mediated by Availability of Transcription Factors

1.1.1.1.2. Regulation Mediated by Genomic Location of MiRNA Genes

1.1.1.1.2.1. Location in the Epigenome

1.1.1.1.2.2. Location Relative to Host Genes

1.1.1.1.2.3. Regulation by MiRNA Copy Number

1.1.1.1.2.4. Cancer-Associated Genomic Regions

1.1.1.2. Process of Biogenesis

1.1.2. Mechanisms of Action and Functions of MiRNAs

1.1.2.1. Incorporation Into miRISC and Targeting

1.1.2.2. The Role of Family Members in Expression and Targeting

1.1.2.3. The Role of MiRNA Clusters and Paralogous in Targeting

1.1.2.4. Use of Bioinformatics to Elucidate MiRNA Function

1.2. MiRNA Function and Relevance in Cancer

1.2.1. OncomiRs

1.2.2. Tumor-Suppressive MiRNA

1.3. Tools That Advanced MiRNA Research

2. Generation of Model Organisms and Their Use in MiRNA Functional Studies

2.1. Caenorhabditis elegans

2.1.1. Generation of Transgenic C. elegans for Use in MiRNA Functional Studies

2.1.2. C. elegans as a Model System for Studying the Function of MiRNAs in Cancer

2.2. Drosophila melanogaster (Fruit Flies)

2.2.1. Generation of Transgenic D. melanogaster to Model Cancer Phenotypes

2.2.2. D. melanogaster as a Model for Studying the Functions of MiRNAs in Cancer

2.3. Danio rerio (Zebrafish)

2.3.1. Generation of Transgenic D. rerio for Use in MiRNA Functional Research

2.3.2. D. rerio as a Model for Studying the Function of MiRNA in Cancer

2.4. Mus musculus (Mouse)

2.4.1. Generation of Transgenic M. musculus for Use in MiRNA Functional Research

2.4.1.1. Genetically Engineered Mouse Models Generated via Transgenesis

2.4.1.2. GEMMs Generated via Homologous Recombination

2.4.2. Strategies Utilized to Generate Gene-Targeting Vectors

2.4.2.1. Cre–LoxP System

2.4.2.2. Flp–FRT System

2.4.2.3. Inducible Systems

2.4.2.3.1. Tetracycline ON/OFF System

2.4.2.3.2. Cre-ER(T) System

2.4.3. Using M. musculus for MiRNA Functional Studies in Cancer

3. Conclusion

References

Chapter Four: Cancer Hallmarks and MicroRNAs: The Therapeutic Connection

1. Introduction

2. Regulation of Cell Proliferation and Cell Growth

3. Regulation of Apoptosis and Induction of Genomic Instability and Mutations

4. Regulation of Angiogenesis

5. Regulation of Invasion and Metastasis

6. Regulation of Immune Response

7. Conclusion

References

Chapter Five: microRNAs in Cancer Susceptibility

1. Introduction

2. Functional Consequences of miRNA SNPs

2.1. SNPs in miRNA Genes

2.2. SNPs in miRNA-Binding Sites

2.3. SNPs in the Processing Machinery

3. Emerging and Unresolved Concepts in miR-SNP Biology

3.1. Viral miRNA SNPs

3.2. IsomiRs

3.3. Methylation

3.4. Alternative Polyadenylation

3.5. SNPs in Coding Regions and 5'UTR

4. Conclusions

References

Chapter Six: Role of the tRNA-Derived Small RNAs in Cancer: New Potential Biomarkers and Target for Therapy

1. Regulatory Noncoding RNAs: Long ncRNAs, Small ncRNAs, and tRNA-Derived ncRNAs

2. tRNA-Derived ncRNAs: tRFs, tsRNAs, and tiRNA and the Differences in Their Biogenesis, Structures, and Nomenclature

2.1. tRFs

2.2. tsRNAs

2.3. tiRNAs

3. tsRNA in Cancer: Signatures, Functions, and Mutations

3.1. tsRNA Signatures in Cancer

3.2. tsRNA Functions in Cancer

3.3. tsRNA Mutations in Cancer

4. Concluding Remarks

References

Chapter Seven: MicroRNAs and Epigenetics

1. Introduction

2. Epigenetics and Its Mechanisms

2.1. DNA Methylation

2.2. Histones Modifications

3. Epigenetic Regulation of miRNAs in Cancer

3.1. DNA Methylation of miRNAs and Functional Consequences

3.2. Control of miRNAs Expression by Histone Modifiers

3.3. miRNAs Epigenetic Regulation Through Transcription Factors

4. miRNAs Control of the Epigenetic Machinery

4.1. Epi-miRNAs

4.2. Transcriptional Epigenetic Modulation by miRNAs

5. Exploiting miRNAs Epigenetics to Fight Cancer

6. Conclusion

References

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