MicroRNAs in Cancer Translational Research

Preface

Contents

Contributors

1 MicroRNAs in Cancer (An Overview)

1.1 Introduction

1.2 Mechanisms of MiRNA Deregulation in Human Cancer

1.3 Numerous MiRNAs are Deregulated in Human Cancer

1.4 MiRNAs and Their Targets

1.5 MiRNA Expression Profiles as Cancer Classifiers

1.6 MiRNAs as Prognostic Predictors

1.7 MiRNAs as Drug Response Predictors/Modulators

1.8 MiRNAs as Cancer Biomarkers

1.9 Conclusions and Future Perspectives

References

2 The Role of MicroRNAs in Lung Cancer Development, Progression, and Metastasis

2.1 Introduction

2.2 MiRNA Profiling of Lung Cancer and Clinical Application

2.3 Pathogenesis

2.4 Regulation of Known Oncogenes in Lung Cancer

2.4.1 Let-7, RAS, c-Myc and HMGA2

2.4.2 EGFR

2.4.3 p53 and MiR-34

2.4.4 Fus-1 and the 3p21.3 Deletion

2.4.5 MiR-17-92

2.4.6 MiR-155

2.5 Invasion and Metastasis Progression

2.6 Therapeutics

2.7 Conclusions

References

3 MicroRNAs in Breast Cancer

3.1 Deregulated Expression of MiRNAs in Breast Cancer

3.2 Biological Functions and Targets of MiRNAs in Breast Cancer

3.2.1 Tumor Suppressive Functions of MiRNAs

3.2.2 Oncogenic MiRNAs

3.2.3 MiRNAs in Estrogen Receptor Signalling

3.3 MiRNAs in Breast Cancer Invasion and Metastasis

3.4 MiRNAs in Breast Cancer Therapeutics

3.5 Conclusions and Future Perspectives

References

4 MicroRNAs in Colorectal Cancer

4.1 Introduction

4.2 MiRNAs in Colorectal Cancer Signaling

4.2.1 Wnt/-Catenin Pathway

4.2.2 EGFR Signaling (KRAS and PI3K Pathways)

4.2.3 p53 Pathway

4.2.4 IGF Signaling

4.2.5 E2F Family and Cell Cycle Regulation

4.2.6 MET Signaling

4.2.7 Cyclooxygenase-2

4.2.8 DNA Reparation

4.2.9 Extracellular Matrix Breakdown and Epithelial-mesenchymal Transition

4.2.10 Alterations in MiRNA Processing Machinery

4.2.11 Others

4.3 Single Nucleotide Polymorphisms (SNPs) and MiRNAs: Risk Factors for CRC

4.4 Plasma and Serum MiRNAs: Diagnosis and Monitoring of CRC

4.5 MiRNA Expression Profiles of CRC Tissue

4.6 MiRNAs in CRC Prognosis and Prediction

4.7 MiRNAs as Potential Therapeutic Targets in CRC

4.8 Perspectives and Challenges

References

5 MicroRNAs in Gastric Cancer

5.1 MicroRNAs

5.2 Target Genes of MiRNAs

5.3 Regulatory Mechanisms of MiRNA Expression

5.4 Aberrant Expression of MiRNAs in Gastric Cancer

5.5 MiRNA Profile as a Diagnostic Tool and a Predictor of the Prognosis of Patients with Gastric Cancer

5.6 A Novel MiRNA-mediated Therapeutic Strategy for Gastric Cancer

5.7 Conclusion and Perspectives

References

6 MicroRNAs in Prostate Cancer: A Possible Role as Novel Biomarkers and Therapeutic Targetsx003F;1539.1

6.1.1 Incidence and Screening

6.1.2 Diagnosis

6.1.3 Current Therapies

6.2 MiRNA Expression Studies in Prostate Cancer: Towards MiRNA-based Diagnostic and Prognostic Biomarkers

6.2.1 Diagnostic Value of MiRNAs in Prostate Cancer

6.2.2 MiRNAs and Prostate Cancer Progression

6.2.3 Prognostic Value of MiRNAs in Prostate Cancer

6.2.4 MiRNAs in Circulating Blood

6.2.5 Are We Still Far from MiRNA-based Biomarkers for Prostate Cancer?

6.3 Functional Investigation of MiRNAs in Prostate Cancer: Towards the Development of MiRNA-based Therapies

6.4 Future Implications for Personalized Prostate Cancer Care

References

7 MicroRNAs in Hepatocellular Carcinoma

7.1 Introduction

7.1.1 Hepatocellular Carcinoma

7.1.2 MicroRNAs

7.1.2.1 Biogenesis of MiRNAs

7.1.2.2 Detection of MiRNA Expression and Function

7.2 Expression and Function of MiRNAs in HCC

7.2.1 MiRNAs are Aberrantly Expressed in HCCs

7.2.2 The Mechanism of the MiRNAs Deregulation in HCCs

7.2.2.1 Genomic Level

7.2.2.2 Transcriptional Level

7.2.2.3 Epigenetic Level and Others

7.2.3 Function of Aberrant-expressed MiRNAs in HCC

7.2.3.1 Promote HCC Tumorigenesis

7.2.3.2 Promote Tumor Progression

7.2.3.3 Multiple Functions of MiR-122 and Let-7

7.3 Biomarkers for Diagnosis, Prognosis, and Therapy of HCC

7.3.1 Biomarkers for Diagnosis

7.3.1.1 HCC Biomarkers

7.3.1.2 HCC Subtype Biomarkers

7.3.2 Biomarker for Prognosis

7.3.2.1 Metastasis and Recurrence

7.3.2.2 Survival

7.3.3 Biomarker for Therapy

7.3.3.1 Block Tumor Initiation

7.3.3.2 Block Tumor Progression

7.3.3.3 Drug Sensitivity

7.4 Conclusion and Prospective

References

8 MicroRNAs in Cervical Carcinoma

8.1 Introduction

8.2 MiRNA Expression in Cervical Carcinoma Cell Lines and Tissues

8.3 MiRNAs Functioning as Potential Oncogenes or Tumor Suppressors in Cervical Cancer

8.4 Interactions of HPV Infection and MiRNA in Cervical Carcinogenesis

8.5 MiRNA Predicting Cervical Cancer Prognosis

8.6 MiRNAs as Potential Cancer Therapeutics

8.7 Conclusions

References

9 MicroRNAs in Esophageal Cancer

9.1 Introduction

9.2 MiRNAs in BE and EAC Development

9.3 MiRNAs in ESCC Development

9.4 MiRNA as Prognostic Factors

9.5 Genes and Molecular Pathways Regulated by MiRNAs in Esophageal Cancer

9.5.1 MiRNAs Acting as Oncogenes in Esophageal Cancer

9.5.1.1 MiR-21

9.5.1.2 MiR-106-25 Polycistron (miR-25, miR-93, and miR-106b)

9.5.1.3 MiR-10b

9.5.1.4 MiR-196a

9.5.1.5 MiR -373

9.5.1.6 MiR-194

9.5.2 MiRNAs Acting as Tumor Suppressors in Esophageal Cancer

9.5.2.1 MiR-145

9.5.2.2 MiR-205

9.5.2.3 MiR-375

9.5.2.4 MiR-133a and MiR-133b

9.6 Germline Genetic Variations in MiRNA Genes, MiRNA Processing Genes, and MiRNA Binding Sites and the Risk of Esophageal Cancer

9.7 Conclusions

References

10 MicroRNAs in Bladder Cancer

10.1 Introduction

10.2 Historical

10.2.1 Embryonic MiRNA Associations with Bladder Development

10.2.2 MiR-200 Family and Epithelial-mesenchymal Transition (EMT)

10.2.3 Other Identified MiRNAs

10.2.4 Genetic Variability in MiRNA Machinery

10.3 Prognostic Implications of MiRNAs

10.4 Perspective and Future Challenges

10.5 Conclusions

References

11 MicroRNAs in Lymphoma

11.1 MicroRNAs in the Normal Physiology of Lymphoid Cells

11.1.1 As Regulators of Lymphoid Cell Development in the Primary Lymphoid Organs

11.1.2 In B Cells

11.1.3 In T Cells

11.2 As Regulators of Immunologic Function of the Mature Lymphoid Cells

11.2.1 In B Cells

11.2.2 In T Cells

11.3 Oncomirs with Pathogenetic Implications in Lymphomas

11.3.1 Expression Deregulation as a Result of Genomic Instability

11.3.1.1 Involving Gains or Losses of MiRNA Chromosomal Loci

11.3.1.2 Involving Epigenetic Mechanisms Acting on MiRNA Genes

11.3.1.3 Involving Mutation of MiRNA Genes

11.3.2 Expression Deregulation as a Result of Virus Infection

11.4 As Regulators of Known Oncogenes and Tumor Suppressor Genes

11.4.1 Tumor Suppressor MiRNAs

11.4.2 Oncomirs

11.5 Oncomirs with Biomarker Implications in Lymphomas

11.5.1 Using MiRNA Expression for Lymphoma Diagnosis Improvement

11.5.1.1 In B/T Lymphomas

11.5.1.2 In Other Lymphomas

11.5.2 Using MiRNA Expression for Lymphoma Prognosis Stratification Improvement

11.5.2.1 In B/T Lymphomas

11.5.2.2 In Other Lymphomas

11.6 Oncomirs as Possible Candidates for Therapeutic Targeting: A Promise of More Specific Lymphoma Therapies

References

12 MicroRNAs in Leukemia

12.1 Introduction

12.2 Deregulated MiRNA Expression in AML

12.2.1 Profiling Deregulated MiRNA Expression in AML -- Association of MiRNA Profiles with Distinct AML Subtypes

12.2.2 Prognostic Impact of Altered MiRNA Expression in AML

12.2.3 MiRNAs of Pathogenic and Functional Relevance in AML

12.3 MiRNAs in CML

12.4 MiRNA in CLL

12.4.1 MiR-15a and MiR-16-1

12.4.2 MiRNA Microarray Screens Identifying Signatures and Subgroups for Prognostication

12.5 Summary

References

13 MicroRNAs in Pancreatic Cancer: Potential Interests as Biomarkers and Therapeutic Tools

13.1 Introduction

13.2 MiRNAs Differentially Expressed in PDAC

13.3 MiRNA Expression Profiles in PDAC Precursor Lesions

13.3.1 PanIN

13.3.2 Intraductal Papillary Mucinous Neoplasm (IPMN)

13.4 Molecular Mechanisms Responsible for Altered MiRNA Expression

13.4.1 Chromosomal Alterations

13.4.2 Transcription Factor Defects

13.4.3 Epigenetic Alterations

13.4.4 Exogenous Stimulation of MiRNA Expression

13.4.5 Hypoxia

13.4.6 Genetic Mutations in MiRNA Genes

13.5 Role of MiRNAs in Pancreatic Cancer Development and Metastasis

13.5.1 Cell Proliferation and Tumor Growth

13.5.2 Epithelial-mesenchymal Transition (EMT), Invasion, and Metastatic Behavior

13.5.2.1 Invasion

13.5.2.2 Metastatic Behavior

13.5.3 Apoptosis and Sensitivity to Anti-cancer Agents

13.6 Potential Interests in MiRNAs as Biomarkers for PDAC

13.6.1 MiRNAs as Diagnostic Marker

13.6.2 MiRNAs as Prognostic Markers

13.7 Potential Interests in MiRNAs as Therapeutic Tool for PDAC

13.8 Perspectives and Challenges

References

14 MicroRNAs in Epithelial Ovarian Cancer

14.1 Introduction

14.2 Overview of Epithelial Ovarian Cancer

14.2.1 Pathological Complexity of Ovarian Cancers

14.2.2 The Origin of EOC

14.2.3 Biomarkers of EOC

14.3 MiRNA Biology

14.3.1 MiRNA Biogenesis

14.3.2 MiRNA Directed Gene Silencing

14.3.3 Regulating MiRNA Function

14.4 MiRNA in Human Cancer

14.4.1 MiRNA as a Tumor Suppressor and Oncogene

14.4.2 Mechanism of MiRNA Deregulation in Cancer

14.4.3 MiRNA as Prognostic Marker and Therapeutic Agent in Cancer

14.5 MiRNA Deregulation in Epithelial Ovarian Cancer

14.5.1 Genomic Alteration of MiRNA in Ovarian Cancer

14.5.2 Epigenetic Alteration of MiRNA in Ovarian Cancer

14.5.3 Alteration of MiRNA Biogenesis in Ovarian Cancer

14.5.4 Subtype Specific MiRNA Deregulation

14.5.5 Factors Contributing to the Inter-study Conflicts

14.6 MiRNA Function in Epithelial Ovarian Cancer

14.6.1 Tumor Suppressive MiRNA in Ovarian Cancer

14.6.2 Oncogenic MiRNA in Ovarian Cancer

14.6.3 Epithelial-mesenchymal Transition (EMT) Associated MiRNA in Ovarian Cancer

14.7 MiRNAs as Biomarkers and Prognostic Tools in Ovarian Cancer

14.7.1 Serum MiRNA as Biomarker in Ovarian Cancer

14.7.2 MiRNA as Tools to Classify Ovarian Cancer Subtypes

14.7.3 MiRNA as Prognostic Marker

14.7.4 MiRNA as Predictor for Therapy Response

14.8 MiRNA as Therapeutic Agents in Ovarian Cancer

References

15 MicroRNAs in Brain Tumors

15.1 Introduction

15.1.1 MiRNAs in Normal and Neoplastic Brain Growth

15.2 Malignant Gliomas

15.2.1 Genetic and Molecular Features of Malignant Gliomas

15.2.2 MiRNAs in GBM Pathogenesis

15.2.2.1 Cell Cycle/Proliferative/Survival Defects

15.2.2.2 Cell Migration and Invasion

15.2.2.3 Angiogenesis and Tumor Metabolism

15.2.2.4 Differentiation and Self-renewal

15.3 Embryonal Brain Tumors

15.3.1 Medulloblastoma

15.3.2 MiRNAs in Medulloblastoma

15.3.2.1 MB MiRNAs, MYC, and SHH Signaling

15.3.2.2 MB MiRNAs and NOTCH Signaling

15.3.2.3 MB-associated MiRNAs and Neuronal Differentiation

15.3.3 CNS-PNETs

15.3.3.1 MiRNAs in CNS-PNET

15.4 Prospects for Translation into the Clinic

15.4.1 MiRNAs as Brain Tumor Diagnostic and Predictive Tools

15.4.2 MiRNAs as Biomarkers

15.4.3 MiRNAs as Targets for Brain Tumor Treatment

15.4.3.1 Antisense MiRNA Treatment

15.4.3.2 Selecting Candidate MiRNAs to Target for Treatment

15.4.3.3 Challenges to Brain Tumor Treatment Using Anti-miRNA Oligonucleotides

15.5 Conclusion

References

16 MicroRNAs and Cancer Stem Cells

16.1 Introduction

16.1.1 Definition of the Stem Cell and Cancer Stem Cell

16.1.2 Discovery of the Cancer Stem Cell

16.2 MicroRNA

16.2.1 MiRNA and the Stem Cell

16.2.2 MiRNA Expression Profile in ES Cells

16.2.3 MiRNA Expression in Cancer Stem Cells

16.3 Individual MiRNAs

16.3.1 MiR-302

16.3.2 MiR-17 Cluster

16.3.3 MiR-181

16.3.4 Let-7

16.3.5 MiR-145

16.3.6 MiR-203

16.3.7 MiR-34

16.3.8 MiR-199b

16.3.9 MiR-128

16.3.10 MiR-200

16.4 MiRNA, Cancer Stem Cell, EMT, and Cancer Metastasis

16.5 MiRNA, Cancer Stem Cell, and Cancer Therapy

16.6 MiRNA-mediated Heterotypic Signals in Tumorigenesis

16.7 The Challenges of MiRNA-based Therapeutic

16.7.1 How to Alter the MiRNA Level in Tumors?

16.7.2 How to Deliver MiRNA to Patients?

16.7.3 How to Locate MiRNA to the Tumor Tissue?

References

17 MicroRNAs in Cancer Invasion and Metastasis

17.1 Introduction

17.2 The Role of MiRNAs in the Regulation of Tumor Cell Invasion

17.2.1 Cell Invasion as the 1st Step of Cancer Progression

17.2.2 The Role of MiR-1 Down-regulation in Lung Cancer

17.2.3 The Role of MiR-21: A Major MiRNA in Tumor Cell Invasion

17.2.4 The Role of MiR-29 Family in Cancer

17.2.5 Down-regulation of MiR-205 in Several Cancers

17.3 The Functional Role of MiRNA in the Regulation of Cancer Cell Migration, Invasion, and Metastasis

17.3.1 Epithelial-mesenchymal Transition (EMT) as a Prerequisite for Cancer Metastasis

17.3.2 Role of MiR-101 in Modulating E-cadherin Expression

17.3.3 Role of MiR-520h in EMT

17.3.4 Elevation of MiR-155 Correlates with Invasive Breast Cancer

17.3.5 The Role of MiR-200, MiR-205, and Modulation of ZEB Expression

17.4 Metastatic MiRNAs

17.4.1 Over-expression of MiR-10b in Metastatic Tumors

17.4.2 The Role of MiR-9 and MiR-10a in Pancreatic and Other Cancers

17.4.3 The Role of MiR-211 in Oral Carcinoma

17.4.4 The Role of MiR-373 and MiR-520c Expressions in Promoting Metastasis Through Suppression of CD44

17.5 Anti-metastatic MiRNA

17.5.1 The Emerging Role of Let-7 Family Members in Malignancies

17.5.2 The Role of MiR-17/20 Cluster in Human Malignancies

17.5.3 The Role of MiR-31 as an Anti-metastatic Human MiRNA

17.5.4 The Regulatory Role of MiR-34a Expression

17.5.5 The Role of MiR-122 in Liver Cancer

17.5.6 The Role of MiR-138 in Head and Neck Squamous Cell Carcinoma

17.5.7 The Role of MiR-145 and MiR-146a/146b

17.5.8 Over-expression of MiR-335, MiR-206, and MiR-126 Inhibits Metastasis

17.6 The Role of MiRNAs in Angiogenesis

17.7 Conclusions and Perspectives

17.7.1 Critical Role of MiRNA in Tumor Cell Invasion, Migration, and Metastases

17.7.2 The Role of MiRNAs as Diagnostic/Prognostic Markers

17.7.3 Development of MiRNA Targeted Therapies for Cancers

References

18 MicroRNAs in Predicting Radiotherapy andINTtie

18.1 Introduction

18.1.1 Current Classification of Malignancies

18.1.2 Biomarkers in Sensitization and Resistance to Radiotherapy (RT) and Chemotherapy (CT)

18.1.2.1 RT

18.1.2.2 CT

18.2 MiRNAs in Cancer: Tumor Suppressors and Oncogenes

18.2.1 Tumor Suppressive MiRNAs

18.2.2 Oncogenic MiRNAs

18.2.3 MiRNAs Involved in Cell Cycle and Apoptosis

18.2.4 MiRNAs in Metastasis and EMT

18.3 MiRNAs as Biomarkers of Cancer

18.3.1 MiRNAs in Determining Cancer Prognosis

18.3.2 Circulating MiRNAs

18.3.3 MiRNA Biomarkers in Clinical Trials

18.4 MiRNAs in Altering Sensitivity to RT and CT

18.4.1 MiRNAs in Predicting Response to RT

18.4.1.1 Radiosensitivity

18.4.1.2 Radioresistance

18.4.2 MiRNAs in Predicting Response to CT

18.4.2.1 Breast Cancer

18.4.2.2 Lung Cancer

18.4.2.3 Hematological Malignancies

18.4.2.4 Pancreatic Cancer

18.4.2.5 Ovarian Cancer

18.4.2.6 Other Cancers

18.4.2.7 MiRNA Predictors in Clinical Trials

18.4.3 Targeting MiRNAs for More Effective Treatment

18.4.4 MiRNA Diagnostics

18.5 Conclusions

References

19 Role of MicroRNAs in Anti-cancer Drug Resistance

19.1 Drug Resistance

19.2 MicroRNAs: Biogenesis, Targets, and Function

19.3 MiRNAs and Cancer

19.4 Anti-cancer Drugs Affect MiRNA Expression

19.5 MiRNAs Capable of Modulating Sensitivity to Anti-cancer Drugs

19.5.1 MiR-21

19.5.2 MiR-214

19.5.3 MiR-200 Family

19.5.4 MiR-221 and 222

19.6 Future Prospects

References

20 MicroRNAs and Cancer Metabolism

20.1 Introduction

20.2 Aerobic Glycolysis, or Warburg Effect, Is the Central Hallmark of Cancer Metabolism

20.3 Genetic Alteration of Oncogenes and Tumor Suppressors and Its Interplay with MiRNAs in Cancer Metabolism

20.3.1 c-Myc

20.3.2 HIF-1

20.3.3 LKB1/AMPK

20.3.4 P53

20.4 Conclusion and Future Outlook

References

21 MicroRNAs as Blood-based Biomarkers of Cancer

21.1 Introduction

21.2 Detection and Characterization of Circulating MiRNAs in Serum and Plasma

21.2.1 MiRNAs and Human Cancer

21.2.2 Existence of MiRNAs in Serum and Plasma

21.2.3 Circulating MiRNAs as a Biomarker for Cancer Diagnosis

21.2.4 Circulating MiRNAs as a Biomarker for Tumor Classification and Prognostication

21.2.5 Circulating MiRNAs as an Indicator to Reflect Other Diseases

21.3 Detection and Characterization of Circulating MiRNAs in Other Body Fluids

21.4 Experimental Techniques and Issues in Analysis of Circulating MiRNAs

21.5 Circulating MiRNAs Serving as Novel Potential Biomarkers for Early Tumor Detection, Diagnosis, and Prognosis

21.5.1 A Panel of Circulating MiRNAs Instead of Individual Circulating MiRNA as a Biomarker for Tumor Detection

21.5.2 A Working Model for Identifying Circulating MiRNA-based Biomarkers for Diseases

21.6 Some Key Issues Regarding the Sources and Biological Functions of Circulating MiRNAs

21.6.1 Sources of Circulating MiRNAs

21.6.2 Molecular Basis of the High Stability of Circulating MiRNAs

21.6.3 Correlation Between Tissue MiRNAs and Circulating MiRNAs

21.6.4 Potential Biological Functions of Circulating MiRNAs

21.7 Concluding Remarks and Future Directions

References

22 RNAi-based Approaches to the Treatment of Brain Tumors

22.1 Introduction

22.1.1 RNA Interference (RNAi)

22.1.2 Non-coding RNAs that Impart RNAi

22.1.3 MiRNA

22.2 Mechanisms of Interference

22.3 Rational Design of siRNA for Pre-clinical and Clinical Studies

22.4 Pre-clinical Experimental Strategies

22.5 siRNA Targets in Glioma Pre-clinical Studies

22.5.1 Targeting Cell Surface Receptors

22.5.2 Targeting Invasive Nature of Glioma

22.5.3 Induction of Glioma Apoptosis

22.5.4 Targeting Hypoxia-induced Glioma Angiogenesis Cascades via RNAi

22.5.5 Modulation of Immuno-activity Against Glioma

22.6 MiRNA Targets in Glioma

22.7 Systemic Delivery of RNAi to Brain Tumors

22.8 RNAi-mediated Glioma Therapy Clinical Trials

22.9 Conclusions

References

Index