RNA Delivery Function for Anticancer Therapeutics

Cover
Half Title
Series Page
Title Page
Copyright Page
Contents
Preface
Author
Chapter 1: Cancer Epigenetic Mechanisms: DNA Methylomes, Histone Codes, and MiRNAs
	1.1. Background
	1.2. Epigenetic Criterion Landscape
	1.3. Epigenetic Mechanisms
	1.4. DNA Methylation
	1.5. Histone Changes
	1.6. Posttranslational Histone Modifications
	1.7. Noncoding RNAs
	1.8. DNA Methyltransferase Enzymes
	1.9. The Role of DNA Methylation and Histone Acetylation in the Regulation of Gene Expression
	1.10. Relationship Between Gene Silencing and Disease
	1.11. Epigenetics in Normal Cells
		1.11.1. DNA Methylation
		1.11.2. Histone Changes
	1.12. Epigenetic Changes in Cancers
		1.12.1. DNA Methylation in Cancer
		1.12.2. Histone Modifications in Cancer
	1.13. Impacts of Epigenetic Changes on MiRNAs
	1.14. Epigenetic Biomarkers in Cancer
	1.15. Epigenetic Treatments
	1.16. MiRNAs’ Role in Cancer
	1.17. Epigenetic Alterations and MiRNAs
	1.18. MiRNA Genes Targeted by Epigenetic Modifications
	1.19. Epi-MiRNAs: A New Group of MiRNAs
	1.20. Controlling MiRNA Expression with Epigenetic Drugs
	1.21. MiRNAs: Regulators of Chromatin Structure?
	1.22. Clinical Applications: Epigenetic Tumor Markers
	1.23. Aberrant DNA Methylation in Cancer Risk Assessment and Prevention
	1.24. Aberrant DNA Methylation as a Diagnostic Tool
	1.25. Aberrant DNA Methylation and Assessment of Prognosis/Response to Therapeutics
	1.26. MiRNAs in Cancer Diagnosis, Classification, and Prognosis
	1.27. Clinical Applications: Epigenetic Therapy
	1.28. Conclusions
	References
Chapter 2: Circulating MiRNAs in Human Cancer: Cancer Biomarkers and Epigenetic Modifications
	2.1. Blood Cell Origin of Circulating MiRNAs
	2.2. Overview of Lung Cancer
	2.3. MiRNAs
		2.3.1. MiRNAs: Biogenesis
		2.3.2. MiRNAs: The Regulatory Role
		2.3.3. MiRNAs: Targets
		2.3.4. MiRNAs: Transports
	2.4. MiRNAs and Cancer
	2.5. Epigenetics
		2.5.1. DNA Methylation
		2.5.2. Histone Modification
	2.6. Epigenetics and Cancer
	2.7. Epigenetic Modifications and MiRNA Expression
		2.7.1. Epigenetic Modifications affect MiRNA Expression
			2.7.1.1. MiR-9 Family
			2.7.1.2. MiR-34 Family
			2.7.1.3. MiR-148a
			2.7.1.4. MiR-193a
			2.7.1.5. MiR-126
			2.7.1.6. MiR-124. Family
			2.7.1.7. MiR-152
			2.7.1.8. MiR-200. Family
			2.7.1.9. Let-7a-3
			2.7.1.10. MiR-127
			2.7.1.11. MiR-487b
			2.7.1.12. MiR-205
		2.7.2. MiRNAs that Target Epigenetic Machinery
			2.7.2.1. MiR-29 Family
			2.7.2.2. MiR-148a
			2.7.2.3. MiR-101
	2.8. Clinical Samples and Plasma Preparation
	2.9. MiRNA Limitations in Clinical Application and Plans for Introducing MiRNA as a Biomarker in Clinic
	2.10. Conclusion
	References
Chapter 3: The Role of Circulating MiRNAs in Diagnosis, Prognosis, and Treatment Targets of Cancer and Diseases
	3.1. General Considerations on Cellular MiRNAs
	3.2. Circulating MiRNAs: The New Frontier of Intercellular Communication
	3.3. Circulating MiRNAs in Health and Disease
	3.4. Circulating MiRNAs in Autoimmune Diseases, Inflammatory and Metabolic Disorders
	3.5. Cellular and Circulating MiRNAs in Neoplastic Diseases
		3.5.1. Cellular MiRNAs in Oncologic Patients
		3.5.2. Circulating MiRNAs and Cancer
	3.6. Specific Patterns of Circulating MiRNAs in Cancer Patients
		3.6.1. Lung Cancer
		3.6.2. Breast Cancer
		3.6.3. Patients with Liver Damage and Hepatocellular Carcinoma
		3.6.4. Pancreatic Cancer
		3.6.5. Biliary Tract Cancer: MiRNA in Bodily Fluids
		3.6.6. Upper Digestive Tract: Esophageal Carcinoma and Gastric Cancer
		3.6.7. Colorectal Cancer
		3.6.8. Renal Cell Carcinoma and Prostate Cancer
		3.6.9. Salivary MiRNAs and Oral Cancer Detection
		3.6.10. Hematologic Neoplasias
		3.6.11. LLC
		3.6.12. Acute Leukemia, Myelodysplastic Syndrome, and Multiple Myeloma
	3.7. Advantages and Potential of MiRNAs as Blood-Based Cancer Biomarkers
	3.8. Limits and Challenges of Circulating MiRNAs
	3.9. Conclusions and Future Perspectives for Circulating MiRNAs
	References
Chapter 4: MicroRNA’s Potential in Human Cancer as Therapeutic Targets and Novel Biomarkers
	4.1. Cancer and MiRNA Overview
	4.2. MicroRNAs: Genomics, Biogenesis, and Mode of Action
	4.3. MiRNA Biogenesis and Mechanism of Action
	4.4. Methods for Studying MiRNA Genetics and Expression
		4.4.1. MiRNA Profiling
		4.4.2. MiRNA Databases and Validation
	4.5. Mechanisms of Alteration of MiRNA Levels in Malignancy
		4.5.1. General Principles of MiRNA Genomic Organization
		4.5.2. Alterations in Genomic MiRNA Copy Numbers and Location
		4.5.3. Alterations in MiRNA Transcriptional Regulation
		4.5.4. MiRNA Biogenesis Pathway in Tumorigenesis
			4.5.4.1. Alterations in RNASEN/DGCR8 and DICER1/TARBP2
			4.5.4.2. Alterations in Other Pathway-Related RBPs
	4.6. Dysregulation of MiRNA-MRNA Target Recognition
		4.6.1. MiRNA Function/Mechanism
		4.6.2. Organization of MiRNAs into Sequence Families
		4.6.3. MiRNA-MRNA Stoichiometry
	4.7. MiRNA Target Identification
		4.7.1. Changes in MiRNA Targets
	4.8. Distinct MiRNA Profiles of Cancer Tissues
		4.8.1. MicroRNAs and Cancer
		4.8.2. MiRNA Cancer Database
		4.8.3. Tissue Heterogeneity
		4.8.4. MicroRNAs as Tumor Suppressors
			4.8.4.1. MicroRNA-15a and MicroRNA-16-1
			4.8.4.2. let-7 MicroRNA Family
			4.8.4.3. MicroRNA-34 Family
		4.8.5. Tumor Suppressive MiRNAs and Oncomirs
			4.8.5.1. HCC Recurrence
			4.8.5.2. “MiRNA Perspective” in Liver Cancer
		4.8.6. MicroRNAs as Oncogenes
			4.8.6.1. MicroRNA-17-92-1. Cluster
			4.8.6.2. MicroRNA-372. and MicroRNA-373
			4.8.6.3. MicroRNA-21
			4.8.6.4. MicroRNA-155
		4.8.7. MiRNA-Regulated Pathways
	4.9. Cancer-Related MiRNAs and their Altered Expression in HCC
	4.10. MiRNA as a Diagnostic Tool
	4.11. Circulating MiRNAs
	4.12. Alterations of MiRNA Sequence
	4.13. MiRNAs as Therapeutics
	4.14. MicroRNAs and their Future use in the Clinic: Diagnosis, Prognosis, and Therapy
	4.15. Conclusion
	References
Chapter 5: Biological Function of miRNA and piRNA Targets in Cancer Tissues
	5.1. SncRNAs (Small Noncoding RNAs)
	5.2. The Role of piRNAs in Cancer
		5.2.1. Gastric Cancer
		5.2.2. Breast Cancer
		5.2.3. Bladder Cancer
		5.2.4. Lung Cancer
		5.2.5. Liver Cancer
		5.2.6. Colorectal Cancer
	5.3. Biological Function of MicroRNAs
	5.4. The Regulation of miR-193A-3P Expression
		5.4.1. Transcription Factors and Regulatory Proteins
		5.4.2. Epigenetic Regulation by DNA Methylation
		5.4.3. Competing Endogenous RNA (ceRNA)
	5.5. Expression Profile of Mir-193a in Normal Human Tissue
	5.6. Biological Function of Mir-193a-3p in Development and Cell Physiology
	5.7. miR-193a-3p Functions as Tumor Suppressor in Cancer
		5.7.1. miR-193a-3p Limits Cancer Cell Proliferation and Impairs Cell Cycle Progression
		5.7.2. miR-193a-3p Induces Cell Death Mainly by Promoting Apoptosis
		5.7.3. miR-193a-3p Impairs Cancer Migration, Invasion, and Metastasis
		5.7.4. miR-193a-3p Modulates drug Resistance in Cancer Cells
	5.8. Gene Annotation Analysis on Predicted and Experimentally Validated Mir-193a-3p Targets
	5.9. miR-193a-3p as Diagnostic and Prognostic Biomarker
		5.9.1. Dysregulation of miR-193a-3p in Cancer Tissues
		5.9.2. Circulating miR-193a-3p Levels in Pathological Conditions
	5.10. Conclusions and Perspectives
	References
Chapter 6: Delivery Strategies for siRNA and Modifications Process of RNAi Therapeutics for Cancer Treatment
	6.1. Small Interfering RNA (siRNA) Therapeutics for Cancer Treatment
	6.2. Challenges in Clinical Applications of siRNA
		6.2.1. Inherent Properties of siRNA
		6.2.2. Barriers to siRNA Delivery
		6.2.3. Development of Efficient siRNA Delivery System
	6.3. Chemical Modification of siRNA
		6.3.1. Common Chemical Modification Strategies
		6.3.2. Applications of Chemically Modified siRNA
	6.4. siRNA Structural Variants
		6.4.1. RNAi Triggers with Increased Potency
		6.4.2. RNAi Triggers with Reduced Off-Target Effect
		6.4.3. RNAi Triggers with Increased Stability
	6.5. siRNA Conjugate System
		6.5.1. Lipophile–siRNA Conjugates
		6.5.2. Polymer–siRNA Conjugates
		6.5.3. Aptamer-siRNA Chimeras
	6.6. siRNA Polymerization
		6.6.1. Sticky siRNA
		6.6.2. Multi- siRNA and Poly-siRNA
		6.6.3. siRNA Microhydrogel
		6.6.4. RNAi Microsponge
	6.7. Advances and Hurdles to Clinical Translation of RNAi Therapeutics
	6.8. Conclusion
	References
Chapter 7: Clinical siRNA-Based Conjugate Systems for RNAi Cancer Cell Therapy
	7.1. Small Interfering RNAs (siRNAs)
	7.2. siRNA Conjugates: Pros and Cons as Therapeutics Compared with other Delivery Strategies
	7.3. siRNA-Based Conjugate Systems
		7.3.1. Aptamer–siRNA Conjugates
			7.3.1.1. Biologically Generated Aptamer–siRNA Chimeras
			7.3.1.2. Chemically Synthesized Aptamer–siRNA Conjugates
		7.3.2. Peptide–siRNA Conjugates
			7.3.2.1. Cell-Penetrating Peptides
			7.3.2.2. Targeting Peptides
			7.3.2.3. Lytic Peptides
		7.3.3. Carbohydrate–siRNA Conjugates
		7.3.4. Lipid–siRNA Conjugates
		7.3.5. Polymer–siRNA Conjugates
		7.3.6. Nanostructured Materials–siRNA Conjugates
	7.4. RNAi as Gene-Silencing Mechanism
	7.5. Current Status of Clinical Trials in RNAi-Based Cancer Therapy
	7.6. Immune Checkpoint Inhibitors in Clinical Trials
	7.7. Lessons from Previous SiRNA Conjugate Studies and Perspectives of Clinical Applications
	7.8. Conclusion and Perspectives
	References
Chapter 8: Potential for siRNA in Types of Genetic Disease, Cancer Therapeutics
	8.1. Lung Cancer
	8.2. Liver Cancer
	8.3. Prostate Cancer
	8.4. Breast Cancer
	8.5. Ovarian Cancer
	8.6. Delivery Challenge
	8.7. Targeting Challenge
	8.8. Conclusion
	References
Chapter 9: Recent Advances in miRNA Molecule Delivery as Anticancer Drugs
	9.1. Brief Introduction to miRNAs
	9.2. Therapeutic Applications and Challenges of Using miRNAs
		9.2.1. Brief Overview of miRNA Therapeutics
		9.2.2. Challenges of miRNA Therapy
	9.3. Nonviral miRNA Delivery Systems for Cancer Therapy
		9.3.1. Lipid-Based Nanocarriers
		9.3.2. Polymeric Vectors
			9.3.2.1. Polyethylenimine
			9.3.2.2. Atelocollagen
			9.3.2.3. Poly (Lactide-Co-Glycolide)
		9.3.3. Dendrimer-Based Vectors (Polyamidoamine Dendrimers)
		9.3.4. Amphiphilic Star-Branched Copolymers
		9.3.5. Inorganic Materials
	9.4. Targeted Delivery of miRNA
		9.4.1. Passive Targeted Delivery
		9.4.2. Active Targeted Delivery
			9.4.2.1. Peptides or Protein Ligands
			9.4.2.2. Antibodies
			9.4.2.3. Aptamers
			9.4.2.4. Other Ligands
			9.4.2.5. Magnetic Nanoparticles
	9.5. miRNA Molecules and miRNA-Regulating Machinery Associated with Clinical Features
	9.6. Genesis of Mature miRNA Molecules
		9.6.1. miRNA-Regulating Machinery
		9.6.2. Primer on miRNA Nomenclature
	9.7. Clinical Implications
		9.7.1. Aberrant Expression of miRNA-Biogenesis Machinery Components in EOC
		9.7.2. Aberrant miRNA-Regulating Machinery Expression in Mouse Models
		9.7.3. Genetic Alterations of miRNA Machinery Genes
	9.8. miRNA Molecules as Clinical Biomarkers for EOC
		9.8.1. miRNA Molecules with Clinical Associations
		9.8.2. miRNA Molecules in Rare Histotypes of EOC
		9.8.3. miRNA Molecules in Bodily Fluids as Biomarkers
		9.8.4. miRNA Molecules as Markers of Treatment Specificity
		9.8.5. Hypoxia-Regulated miRNA Molecules in EOC
	9.9. miRNA Molecules as Therapy for EOC
	9.10. Challenges to Clinical use of miRNA Molecules and miRNA Regulatory Machinery in EOC
	9.11. Conclusions
	References
Chapter 10: DNA-Damaging Cancer Therapies and FDA Novel Drug Approvals
	10.1. Defects in Signaling and Repair of DNA Damage
	10.2. Clinical-Translational Advances
	10.3. Sonodynamic Activities of Porphyrins
	10.4. FDA Novel Drug Approvals for 2019
	10.5. Conclusions
	References
Chapter 11: Therapeutic Potential Role of miRNAs in Pancreatic and Prostate Cancer Cells
	11.1. Epigenetic Contributions to Cancer
		11.1.1. An Epigenetic Basis for Prostate Cancer
		11.1.2. An Emergent Understanding on the Role of miRNA in Prostate Cancer
	11.2. Interplay Between Histone Modifications, DNA Methylation, and miRNA
		11.2.1. Regulation of DNA and Histone Modifications Under the Control of miRNAs in Prostate Cancer
		11.2.2. Regulation of miRNAs by DNA and Histone Modification in Prostate Cancer
	11.3. Pancreatic Cancer
		11.3.1. Deregulated miRNAs in Pancreatic Cancer
	11.4. MiRNA and KRAS in Pancreatic Cancer
	11.5. MiRNA and the p53 Pathway
		11.5.1. p53-Mediated Regulation of miRNAs
		11.5.2. miRNAs Regulating p53 Expression
	11.6. p16 and MiRNA in Pancreatic Cancer
	11.7. TGF-β/SMAD Signaling Regulates MiRNAs in PC
	11.8. Sonic Hedgehog Signaling and MiRNA in Pancreatic Cancer
	11.9. The Impact of MiRNAs on Cell Cycle and Proliferation of Pancreatic Cancer Cells
	11.10. Potential Role of MiRNAs in Pancreatic Cancer Diagnosis
	11.11. MiRNAs as Therapeutic Agents in Pancreatic Cancer
		11.11.1. Targeting of miRNAs in Pancreatic Cancer
	11.12. Clinical Exploitation of Epigenetic States in Prostate Cancer
		11.12.1. Epigenetic Modifications as Biomarkers in Prostate Cancer
		11.12.2. Diagnostic and Prognostic miRNA Expression Patterns
		11.12.3. Insights from the Cancer Genome Atlas (TCGA) and ENCODE
	11.13. Conclusions
	References
Chapter 12: Regulation of miRNAs and Their Role in Regeneration and Cancer Diseases
	12.1. Introduction
	12.2. MiRNA
	12.3. Liver Development
		12.3.1. MiRNAs in Liver Development
	12.4. MiRNAs in Liver Regeneration
	12.5. Transcriptional Regulation of MiRNA
	12.6. Posttranscriptional Regulation of MiRNA
	12.7. Epigenetic Alterations of MiRNA
	12.8. Single-Nucleotide Polymorphism and Genetic Alterations
	12.9. Deregulation of MiRNA in HCC
	12.10. Suppression of Apoptosis
	12.11. Alteration of Signaling Pathways
	12.12. Epithelial–Mesenchymal Transition and Metastasis
	12.13. MiRNAs as Diagnostic Markers in HCC
	12.14. Predictive Prognostic Value of MiRNAs in HCC
	12.15. MiRNAs and Liver Disease
		12.15.1. Alcoholic Liver Disease
		12.15.2. Nonalcoholic Fatty Liver Disease
		12.15.3. Viral Hepatitis
		12.15.4. Primary Liver Cancer
	12.16. MiRNAs in HCC Therapy
	12.17. Conclusions and Future Directions
	References
Chapter 13: Novel Classes of Noncoding RNAs and Cancer Biology Therapeutic Targets
	13.1. Introduction
	13.2. Noncoding RNAs: Classification
		13.2.1. Small Noncoding RNAs
		13.2.2. MiRNAs
		13.2.3. piRNAs
		13.2.4. snoRNAs
		13.2.5. lncRNAs
		13.2.6. Small Interfering RNAs
	13.3. Piwi Protein–Associated RNAs
	13.4. Small Nucleolar RNAs
	13.5. Promoter-Associated RNAs
	13.6. Centromere Repeat Associated Small Interacting RNAs
	13.7. Telomere-Specific Small RNAs
	13.8. Pyknons
	13.9. Long Noncoding RNAs
	13.10. Long Intergenic Noncoding RNAs
	13.11. Long Intronic Noncoding RNAs
	13.12. Telomere-Associated ncRNAs
	13.13. Long NcRNAs with Dual Functions
	13.14. Pseudogene RNAs
	13.15. Transcribed Ultraconserved Regions
	13.16. Deregulated Expression of ncRNAs in MM
		13.16.1. miRNAs
			13.16.1.1. Genomic Alterations
			13.16.1.2. Transcriptional Regulation
			13.16.1.3. Epigenetic Regulation
		13.16.2. Other ncRNAs
	13.17. ncRNAs as Potential Clinical Biomarkers in MM
	13.18. ncRNA-Based Therapeutic Strategies in MM
	13.19. Expert Opinion
	13.20. Conclusions and Future Perspectives
	References
Chapter 14: Advances in the Inhibition and Optimization of Checkpoint Kinases by Small Molecules for the Treatment of Cancer
	14.1. DNA-Targeting Therapies
	14.2. Overview of CHK1 Inhibitors in the Clinic
		14.2.1. XL-844
		14.2.2. AZD-7762
		14.2.3. PF-477736
	14.3. Drug Design and SAR of CHK1 Inhibitors from Preclinical Research Programs
		14.3.1. ICOS Corp CHK1 Inhibitors
		14.3.2. Millennium Pharmaceuticals Inc. CHK1 Inhibitors
		14.3.3. Abbott Laboratories CHK1 Inhibitors
		14.3.4. Chiron Corp. CHK1 inhibitors
		14.3.5. Merck and Co. Inc. CHK1 Inhibitors
		14.3.6. Vernalis plc CHK1 Inhibitors
		14.3.7. Other CHK1 Inhibitors
	14.4. Preclinical Overview of Suggested siRNA Delivery Systems and Pros/Concern of DNA-Based Gene Delivery Carriers
	14.5. Conclusion and Future Perspectives
	References
Chapter 15: Recent Therapeutic Prospects of miRNAs and siRNA Delivery Systems in Cancer Treatment Nanobiotechnology
	15.1. Role of MiRNAs in Regulating Disease
	15.2. Description of MiRNA Biogenesis and Regulation
	15.3. MiRNA and SiRNA Delivery Systems for Applications in Cancer Therapy
	15.4. MiRNA Delivery Through Nanoparticles in Cancer Therapy
	15.5. Role of Nanoparticles in MiRNA Biosensor Chemotherapeutic Delivery Technology
	15.6. MiRNAs are Important Regulators of Cancer Multidrug Resistance and Metastatic Capacity
	15.7. MiRNA Detection
	15.8. Delivery Systems used in Cancer Research
		15.8.1. Viral Delivery Systems
		15.8.2. Nonviral Delivery Systems
		15.8.3. Gold Nanoparticles
		15.8.4. Liposomes
		15.8.5. Hybrid Systems
		15.8.6. Dendrimers
		15.8.7. Carbon Nanotubes
	15.9. Nanoscale Immunotherapy
	15.10. Conclusions and Future Prospects
	References
List of Abbreviations
Index