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Dr. Saura C. Sahu, Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of Hepatotoxicity (Wiley, 2007), Toxicogenomics (Wiley, 2008), Nanotoxicity (Wiley, 2009), Handbook of Systems Toxicology (Wiley, 2011), and Toxicology and Epigenetics (Wiley, 2012).
List of Contributors xix
Preface xxiii
Acknowledgments xxv
PART I microRNAs AND TOXICOLOGY 1
1 Introduction 3
Saura C. Sahu
References 4
2 Environmental Toxicants and Perturbation of miRNA Signaling 5
Kathryn A. Bailey and Rebecca C. Fry
2.1 Introduction 5
2.2 miRNAs: Description and Biological Significance 8
2.2.1 miRNA Biosynthesis and Processing 8
2.2.2 Interaction of miRNAs with mRNA Targets 9
2.3 Environmental Toxicant-Associated miRNA Perturbations 10
2.3.1 Toxicant Class 1: Carcinogenic Metals (Arsenic and Cadmium) 10
2.3.1.1 Arsenic 10
2.3.1.2 Cadmium 12
2.3.2 Toxicant Class 2: Air Toxicants (Formaldehyde, Diesel Exhaust Particles, Cigarette Smoke) 13
2.3.2.1 Formaldehyde 13
2.3.2.2 Diesel Exhaust Particles (DEPs) 14
2.3.2.3 Cigarette Smoke 14
2.3.3 Toxicant Class 3: Polycyclic Aromatic Hydrocarbon (B(a)P) 17
2.3.4 Toxicant Class 4: Endocrine Disruptors (BPA, DDT, Fludioxonil, Fenhexamid, and Nonylphenol) 19
2.3.4.1 BPA, DDT, Fludioxonil, Fenhexamid 19
2.3.4.2 Nonylphenol (NP) 20
2.4 Conclusions and Future Directions 22
Acknowledgments 22
References 22
3 microRNAs in Drug-Induced Liver Toxicity 33
Si Chen, Jiekun Xuan and Lei Guo
3.1 Introduction 33
3.2 miRNA Tissue Distribution and Abundance 34
3.2.1 miRNA in Solid Tissues 34
3.2.2 microRNA in Body Fluids 35
3.3 miRNA and Drug-Induced Liver Toxicity 35
3.3.1 Acetaminophen 36
3.3.2 Carbon Tetrachloride (CCl4) 37
3.3.3 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) 37
3.3.4 Benzo[a]pyrene 37
3.3.5 Tamoxifen 38
3.3.6 Others 38
3.4 Circulating miRNAs as Potential Biomarkers for Drug-Induced Liver Toxicity 38
3.4.1 Introduction of Circulating miRNAs 38
3.4.1.1 Exosomes 39
3.4.1.2 HDL 39
3.4.1.3 Ago2 39
3.4.2 Blood miRNAs in Drug-Induced Liver Toxicity 39
3.4.3 Urine miRNAs in Drug-Induced Liver Toxicity 41
3.4.4 Technique Challenges 42
3.5 Mechanistic Studies and Perspectives 42
Disclaimer 44
References 44
4 Fishing for microRNAs in Toxicology 49
Jennifer L. Freeman, Gregory J. Weber and Maria S. Sepulveda
4.1 microRNAs in Toxicology 49
4.2 Fish Models in Toxicology 49
4.2.1 Small Fish Models in Toxicology 50
4.2.2 Large Fish Models in Toxicology 51
4.3 Fish as Models for Studying miRNA Function 51
4.3.1 miRNA Studies in Zebrafish 51
4.3.2 miRNA Studies in Other Fish Models 52
4.4 Application of Fish Models in Toxicity Studies of miRNA Alterations 52
4.4.1 Zebrafish in Toxicity Studies of miRNA Alterations 52
4.4.2 Other Fish Models in Toxicity Studies of miRNA Alterations 68
4.5 Summary 68
Acknowledgments 68
References 68
PART II microRNAs AND DISEASE STATES 77
5 microRNAs and Inflammation 79
Yan Huang, Samir N. Ghadiali and S. Patrick Nana-Sinkam
5.1 Introduction 79
5.2 miRNA Biogenesis and Functions 80
5.3 miRNAs in Hematopoietic Systems 80
5.4 miRNA and Inflammatory Diseases 81
5.5 Regulation of the Immune System 86
5.5.1 Acquired Immunity 86
5.5.2 Innate Immunity 86
5.6 Regulation of miRNA Expression 87
5.6.1 Regulation of miRNA by Cytokines and Bacterial Toxins 87
5.6.2 Regulation of miRNA by Mechanical Stimuli 88
5.7 Select miRNA Regulation of Inflammation 89
5.7.1 miR-146a: Negative Regulator of Immune Response 89
5.7.2 Role of miR-155 in Mediating Inflammatory Responses 91
5.7.3 miR-125a/b 92
5.7.4 miR-181a 93
5.8 Conclusion 94
References 94
6 Regulatory Role of microRNAs in Mutagenesis 101
Fanxue Meng, Yang Luan, Jian Yan and Tao Chen
6.1 Introduction 101
6.2 miRNA Roles in Xenobiotic Metabolism 102
6.3 miRNA Roles in the Cell Cycle 105
6.4 miRNA Roles in DNA Repair 106
6.5 Apoptosis 107
6.6 miRNA Regulation and Mutation Formation 108
6.7 Conclusions 109
Disclaimer 109
References 110
7 microRNAs and Cancer 113
Dongsheng Yan and Geir Skogerbø
7.1 Introduction 113
7.2 miRNAs are Deregulated in Cancer 114
7.3 miRNAs Function as Oncogenes and Tumor Suppressor Genes 116
7.4 miRNAs in Cancer Metastasis 117
7.5 miRNAs in Cancer Stem Cells 119
7.6 Mutations in miRNA Loci 119
7.7 Mutations in miRNA Target Genes 120
7.8 Prospective: miRNA as Biomarkers and Therapeutics 121
References 121
8 miRNAs in Cancer Invasion and Metastasis 133
Brock Humphries and Chengfeng Yang
8.1 Introduction 133
8.2 miRNAs and Cancer Invasion and Metastasis 136
8.2.1 miRNAs Involved in Angiogenesis 136
8.2.2 miRNAs Involved in Cancer Cell Detachment, Migration, and Invasion 138
8.2.3 miRNAs Involved in Cancer Cell Intravasation 140
8.2.4 miRNAs Involved in Circulating Cancer Cell Survival 142
8.2.5 miRNAs Involved in Cancer Cell Extravasation 143
8.2.6 miRNAs Involved in Metastatic Colonization 144
8.3 miRNAs as Useful Cancer Prognostic Markers 146
8.4 Future Perspectives 147
References 148
9 The Role of microRNAs in Tumor Progression and Therapy 153
Azfur S. Ali, Aamir Ahmad, Shadan Ali, Philip A. Philip and Fazlul H. Sarkar
9.1 Introduction 153
9.2 Tumor Progression 154
9.3 Key Signaling Pathways 154
9.3.1 Angiogenesis 154
9.3.2 The Ras Pathway 155
9.3.3 The Epidermal Growth Factor Receptor Pathway 155
9.3.4 The PI3K/Akt Pathway 156
9.4 The miRNAs as Regulators of Tumor Progression 156
9.4.1 Current Therapies to Control Tumor Progression 157
9.4.2 Tumor Promoter miRNAs 158
9.4.2.1 miR-21 158
9.4.2.2 miR-155 159
9.4.3 Tumor Suppressor miRNAs 159
9.4.3.1 The miR-200 Family 159
9.4.3.2 miR-146a 160
9.4.3.3 The let-7 Family 160
9.5 Regulation of miRNAs by Novel Anticancer Compounds 160
9.6 Conclusions and Perspectives 161
References 162
10 Current Understanding of microRNAs as Therapeutic Targets in Cancer 167
Marion Gayral, Jérome Torrisani and Pierre Cordelier
10.1 Introduction on the Rationale of Using miRNAs as Therapeutics in Cancer 167
10.2 Current Approaches to Target miRNAs 167
10.3 Evidence of Successful miRNA Targeting in Experimental Cancer Models 168
10.4 Open Question: Targeting miRNA Processing in Cancer Cells 170
10.5 Concluding Remarks 170
References 170
11 microRNAs, New Players in Cancer Chemoprevention 173
Bin Yi and Yaguang Xi
11.1 Introduction 173
11.2 miRNA and the Natural Products 175
11.2.1 Vitamin A 175
11.2.2 Vitamin B 176
11.2.3 Vitamin D 176
11.2.4 Vitamin E 176
11.2.5 Fatty Acids 176
11.2.6 Curcumin 177
11.2.7 Resveratrol 177
11.2.8 Ellagitannin 177
11.2.9 Genistein 177
11.2.10 Catechins 178
11.2.11 Indoles 178
11.3 miRNA and Pharmaceuticals 178
11.3.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 178
11.3.2 Estrogen Receptor Antagonist 181
11.4 Perspectives 182
Acknowledgments 183
References 183
12 microRNA and Neurodegenerative Diseases 189
Josephine Malmevik, Malin Ákerblom and Johan Jakobsson
12.1 Introduction 189
12.2 miRNAs and Parkinson's Disease 191
12.3 miRNAs and Alzheimer's Disease 193
12.4 miRNAs and Huntington's Disease 195
12.5 Outlook 195
Acknowledgements 196
References 196
13 Sleep and microRNAs (miRNAs) in Neurodegenerative Diseases 201
Daniel B. Kay and Christopher J. Davis
13.1 Sleep and microRNAs (miRNAs) in Neurodegenerative Diseases 201
13.2 miRNAs and Sleep 202
13.3 Aging 203
13.4 Alzheimer's Disease 204
13.5 Parkinson's Disease 205
13.6 Creutzfeldt-Jakob Disease 206
13.7 Huntington's Disease 207
13.8 Multiple Sclerosis 208
13.9 Fronto-Temporal Dementia 208
13.10 Summary 208
Acknowledgments 209
References 209
14 Role of microRNA in Autism Spectrum Disorder 215
Tewarit Sarachana and Valerie W. Hu
14.1 Introduction 215
14.2 Epidemiology of ASD 216
14.3 Etiology of ASD: Genetic Associations 216
14.4 ASD as Multigenic Systemic Disorders 217
14.5 Evidence for Epigenetic Contributions 218
14.6 The Role of microRNAs in Neurodevelopment 218
14.7 microRNAs in Neurodevelopmental and Psychiatric Disorders: An Overview 219
14.8 microRNA Expression Profiles in Autism Spectrum Disorder 220
14.8.1 Evidence for Dysregulated miRNAs in Brain and Blood 220
14.8.2 Identification of Novel Gene Targets of Differentially Expressed miRNAs in ASD 220
14.8.3 Brain-Related miRNAs are Differentially Expressed in LCLs from Individuals with ASD 222
14.8.4 Functional Associations of Confirmed Differentially Expressed miRNAs 225
14.9 Conclusions 226
Acknowledgments 227
References 227
15 The Emerging Function of Natural Products as Regulators of miRNAs in Human Diseases 237
Keitaro Hagiwara, Luc Gailhouste, Nobuyoshi Kosaka and Takahiro Ochiya
15.1 Introduction 237
15.2 History of Natural Products as Drugs 238
15.3 Functions of miRNAs in Human Diseases 238
15.4 Regulation of miRNAs using Natural Products 239
15.5 Resveratrol and miRNAs 239
15.6 EGCG and miRNAs 241
15.7 Curcumin and miRNAs 242
15.8 Isoflavone and miRNAs 242
15.9 Metformin miRNA 242
15.10 Traditional Herbs and miRNAs 243
15.11 Polyphenol and miRNAs 243
15.12 Rice and miRNA 243
15.13 Human Breast Milk and miRNAs 244
15.14 Conclusion 245
Acknowledgments 245
References 245
PART III microRNAs AND STEM CELLS 249
16 Pluripotency and Early Cell Fate Decisions are Orchestrated by microRNAs 251
Matthias Jung and Insa S. Schroeder
16.1 Importance of microRNAs in ES and iPS Cells 251
16.2 Biogenesis and Function of microRNAs 252
16.3 microRNAs Mark ES Cell Identity 253
16.3.1 ES Cell Identity is Characterized by Distinct miRs 253
16.3.2 Mouse ES Cell-Specific miRs 254
16.3.3 Human ES Cell-Specific miRs 255
16.3.4 Self-Renewal of ES Cells is Regulated by Cell Cycle Regulating miRs 255
16.3.5 Differentiation Capacity of ES Cells is Maintained by miRs 256
16.3.6 Isoforms and 3 Variability in ES Cell-Specific miRs 256
16.4 microRNAs Guide Induced Pluripotency 257
16.4.1 Reprogramming Factors Regulate ES Cell-Associated miRs 257
16.4.2 Differentiation of ES and iPS Cells is Prevented by miRs 258
16.4.3 Reprogramming Requires ES Cell-Specific miRs 258
16.5 microRNAs Manipulate Cell Fate Decision 259
16.5.1 Induction of Early Differentiation is Regulated by miRs 259
16.5.2 Major Signaling Pathways in ES Cells Regulated by miRs 260
16.5.3 Differentiation of ES Cells Can be Manipulated by miRs 260
16.5.4 Cell Fate Decisions are Influenced by miRs and RNA Binding Proteins (RBPs) 261
References 262
17 microRNAs in Cancer Stem Cells: Micromanagers of Malignancy 269
Arun Bhardwaj, Sumit Arora, Seema Singh, and Ajay P. Singh
17.1 Introduction 269
17.2 Cancer Stem Cells 270
17.2.1 Origin of Cancer Stem Cells 270
17.2.2 Characteristics and Pathological Significance of Cancer Stem Cells 271
17.3 microRNAs: Biology and Mechanism 273
17.4 Role of microRNAs in the Regulation of Genes and Signaling Pathways Associated with Cancer Stem Cells 273
17.4.1 HMGA2 275
17.4.2 Bcl-2 275
17.4.3 Bmi-1 276
17.4.4 Wnt/ß-Catenin 276
17.4.5 Notch 277
17.4.6 Hedgehog 277
17.4.7 TGF-ß 278
17.5 Translational Implications and Future Perspectives 279
References 279
PART IV microRNAs AND GENOMICS 285
18 microRNAs: Tiny Regulators of Great Potential for Gene Regulation 287
Nahid Akhtar and Tariq M. Haqqi
18.1 Introduction 287
18.2 microRNAs: Biogenesis and Expression Criteria 288
18.3 Mechanism of miRNA Mediated Regulation of Genes 288
18.4 Complexities of miRNA Regulation 290
18.5 microRNA and Epigenetics 291
18.6 Role of miRNAs in Biological Processes 295
18.7 microRNAs: Association with Disease Pathogenesis 296
18.8 microRNAs: Another Way to Unravel Disease Pathogenesis 297
18.9 microRNAs as Novel Therapeutic Targets 298
18.10 Concluding Remarks 299
Competing Interests 300
Conflict of interest statement 300
Acknowledgments 300
References 300
19 Exploration of microRNA Genomic Variation Associated with Common Human Diseases 309
Joel Fontanarosa and Yang Dai
19.1 Introduction 309
19.2 Methods 310
19.3 Results 311
19.4 Discussion 313
Acknowledgment 315
References 315
PART V microRNAs AND EPIGENOMICS 317
20 Crosstalk between microRNAs and Epigenetics: From the Nutritional Perspective 319
Zhenhua Liu, Stephanie A Tammen, Simonetta Friso and Sang-Woon Choi
20.1 Introduction 319
20.2 Epigenetic Regulation of microRNA Expression 321
20.2.1 microRNA Biogenesis and Epigenetic Regulation 321
20.2.2 Epigenetically-Regulated microRNAs 323
20.2.2.1 microRNAs Controlled by Promoter Methylation 323
20.2.2.2 microRNAs Controlled by Histone Modification 324
20.3 Regulation of Epigenetic Machinery by microRNAs 326
20.3.1 Epigenetic Machinery and its Regulation by microRNA 326
20.3.2 epi-miRNAs 327
20.4 microRNA and Epigenetics: Regulation by Nutrition 329
20.4.1 Nutrition and Epigenetics 329
20.4.1.1 One-Carbon Nutrients 329
20.4.1.2 Dietary Bioactive Components 329
20.4.2 Nutrition and microRNA 331
20.4.2.1 One-Carbon Nutrients 331
20.4.2.2 Dietary Bioactive Components 331
20.4.3 Nutritional Modulation of the Epigenetics-microRNA Inter-Regulatory Network 332
20.5 Summary 333
References 334
PART VI microRNAs AND BIOMARKERS 341
21 Body Fluid microRNAs as Toxicological Biomarkers 343
Zhishan Wang and Chengfeng Yang
21.1 microRNA History, Biogenesis and Functions 343
21.2 Differential Expression of miRNAs During Development and Diseases 344
21.3 Alterations of miRNA Expressions by Toxicant Exposures 345
21.4 Discovery of Body Fluid miRNAs 346
21.5 Body Fluid miRNAs as Toxicological Biomarkers 347
21.5.1 Plasma or Serum miRNAs as Toxicological Biomarkers 347
21.5.1.1 Plasma or Serum miRNAs as Biomarkers for Liver Injuries 347
21.5.1.2 Plasma or Serum miRNAs as Biomarkers for Heart Injuries 349
21.5.1.3 Plasma or Serum miRNAs as Biomarkers for Kidney Injuries 350
21.5.1.4 Plasma or Serum miRNAs as Biomarkers for Radiation Exposure 351
21.5.1.5 Plasma or Serum miRNAs as Biomarkers for Drug Abuse 353
21.5.2 Urinary miRNAs as Toxicological Biomarkers 353
21.5.2.1 Urinary miRNAs as Biomarkers for Kidney Injuries 353
21.5.2.2 Urinary miRNAs as Biomarkers for Liver Injuries 354
21.5.3 Other Body Fluid miRNAs as Toxicological Biomarkers 355
21.6 Challenges and the Future of Body Fluid miRNAs as Biomarkers 356
References 358
22 Cell-free microRNAs as Biomarkers in Human Diseases 363
Xi Yang, William B. Mattes, Qiang Shi, Zuquan Weng and William F. Salminen
22.1 Introduction 363
22.2 Secretion and Transportation of Cell-Free miRNAs in Body Fluids 365
22.3 Technical Challenges in the Analysis of Cell-Free miRNAs 367
22.4 Cell-Free miRNAs as Novel Potential Biomarkers for Cancers and Tissue Injuries 369
22.4.1 Acute Myeloid Leukemia and B-Cell Lymphoma 370
22.4.2 Bladder Cancer 370
22.4.3 Breast Cancer 370
22.4.4 Colorectal Cancer 373
22.4.5 Gastric Cancer 373
22.4.6 Hepatocellular Carcinoma 374
22.4.7 Lung Cancer 374
22.4.8 Melanoma 375
22.4.9 Oral and Squamous Cell Carcinoma 375
22.4.10 Ovarian Cancer 376
22.4.11 Pancreatic Cancer 376
22.4.12 Prostate Cancer 377
22.4.13 Cardiovascular Diseases 377
22.4.14 Drug-Induced Liver Injury 379
22.4.15 Kidney Injury 380
22.5 Conclusion and Perspectives 380
Disclaimer 380
References 381
23 Plasma microRNAs as Biomarkers of Human Diseases 389
Katarina Cuk, Dharanija Madhavan, Andrey Turchinovich and Barbara Burwinkel
23.1 Introduction 389
23.2 Cancer 390
23.2.1 Breast Cancer 390
23.2.2 Prostate Cancer 391
23.2.3 Lung Cancer 406
23.2.4 Colorectal Cancer 407
23.3 Cardiovascular Diseases and Disorders 408
23.3.1 Acute Myocardial Infarction 408
23.3.2 Other Cardiovascular Diseases 410
23.4 Neurological Diseases and Disorders 411
23.5 Diabetes Mellitus 412
23.6 Infectious Diseases 413
23.7 Standardization of Circulating miRNA Analysis 413
23.7.1 Sample Processing and Handling 413
23.7.2 Data Normalization 415
23.8 Discovery, Origins and Functions of Circulating miRNAs 416
References 418
24 Circulating microRNAs as Biomarkers of Drug-Induced Pancreatitis 425
Rodney Rouse, Barry A. Rosenzweig and Karol L. Thompson
24.1 Introduction 425
24.2 Pancreatic Injury and Serum Biomarkers 426
24.3 Amylase and Lipase: Sensitivity and Specificity as Biomarkers of Pancreatic Injury 427
24.4 Pancreas Selective microRNAs as Circulating Biomarkers 428
24.4.1 Pancreas Selective Expression of microRNAs in Tissue 428
24.4.2 Circulating microRNAs in Models of Pancreatitis 429
24.4.3 Mouse Model of Acute Pancreatic Injury 430
24.4.4 Time Course of Pancreas-Selective microRNAs in the Serum of Mice Treated with Caerulein 430
24.4.5 Dose Response of Pancreas-Selective microRNAs in the Serum of Mice Treated with Caerulein 432
24.4.6 Serum Lipase and Amylase in Mice Treated with Caerulein 433
24.4.7 Receiver Operating Characteristic (ROC) Analysis of Serum microRNAs, Lipase, and Amylase 433
24.5 Conclusions 433
24.6 Future Directions 434
Acknowledgments 434
Disclaimer 434
References 435
25 microRNA Profiling: Strategies and Challenges 437
Jiekun Xuan, Leming Shi and Lei Guo
25.1 miRNA Biogenesis 437
25.2 Challenges of miRNA Profiling 437
25.3 miRNA Profiling Methodologies 438
25.3.1 Northern Blotting 438
25.3.2 Quantitative Reverse Transcription PCR 440
25.3.3 Microarray 441
25.3.4 Next Generation Sequencing 441
25.3.4.1 Roche/454 441
25.3.4.2 Illumina/Solexa 442
25.3.4.3 Life Technologies/SOLiD 442
25.3.4.4 cDNA Library Construction 443
25.3.4.5 Multiplexing 443
25.3.4.6 Bioinformatics Tools 444
25.4 Technical Challenges of Circulating miRNA Profiling 446
25.5 Quality Assessment and Data Normalization 446
Disclaimer 448
References 448
Index 455
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