microRNAs in Toxicology and Medicine

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/β-Catenin 276

17.4.5 Notch 277

17.4.6 Hedgehog 277

17.4.7 TGF-β 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