[Frontiers in Bioscience 17, 2508-2540, June 1, 2012]

MicroRNAs: molecular features and role in cancer

Elodie Lages1,2, Helene Ipas1,2, Audrey Guttin1,2,3, Houssam Nesr1,2, Francois Berger1,2, Jean-Paul Issartel1,2,3,4

1INSERM, U836, Team7 Nanomedicine and Brain, BP 170, Grenoble Cedex 9, F-38042, France, 2Universite Joseph Fourier, Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France, 3Clinical Transcriptomics and Proteomics Facilities, Institut de Biologie et Pathologie, Centre Hospitalier Universitaire and Grenoble Institut des Neurosciences, Grenoble, France, 4CNRS, 25 rue des Martyrs, Grenoble Cedex 9, F-38042, France

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. miRNA: nomenclature, biogenesis and functions
3.1. miRNA nomenclature
3.2. Interfering RNAs: similarities and differences
3.3. miRNA biogenesis
3.3.1. Localization and structure of miRNA coding genes
3.3.2. Transcription of primary miRNA transcript
3.3.3. Maturation of pri-miRNAs into miRNAs
3.3.3.1. Formation of the pre-miRNA in the nucleus
3.3.3.2. Pre-miRNAs export from the nucleus to the cytoplasm
3.3.3.3. Mature miRNA production in the cytoplasm
3.4. Gene expression regulation by miRNAs
3.4.1. miRISC (miRNA-induced silencing complex) formation
3.4.2. Interaction between miRNAs and mRNA targets
3.4.2.1. Mechanisms of interaction
3.4.2.2. Categories of target sites
3.4.2.3. Biocomputational tools for the prediction of target sites
3.4.3. Molecular mechanisms of translation regulation of mRNA targets by miRNAs
3.4.3.1. mRNA maturation, stability, and translation: basic features
3.4.3.2. Translation initiation repression by miRNAs
3.4.3.3. Repression of the postinitiation step of translation by miRNAs
3.4.3.4. Regulation by degradation of the mRNA targets
3.4.4. Translation activation by miRNAs
4. miRNAs in tumorigenesis and tumor development processes
4.1. Modifications of miRNA expression levels in cancer
4.1.1. miRNA expression profiles in tumors
4.1.2. Deregulation of miRNA expression by defects in the biogenesis mechanism
4.1.3. Deregulation of miRNA expression by chromosomal rearrangements
4.1.4. Deregulation of miRNA expression due to point mutations in coding genes
4.1.5. Modifications of miRNA expression due to transcriptional regulation
4.2. Modifications of the interactions between miRNAs and their mRNA targets
4.2.1. Deregulation by chromosomal modification
4.2.2. Deregulation by point mutations
4.3. Oncogene and tumor suppressor miRNAs involved in molecular pathways of tumor development
4.3.1. Apoptosis and cellular proliferation processes
4.3.2. Angiogenesis process
4.4. Exosomal miRNAs: new potential tumor biomarkers
4.5. miRNAs in cancer therapy
5. Conclusion
6. Acknowledgements
7. References

1. ABSTRACT

microRNAs (miRNAs) are small noncoding endogenously produced RNAs that play key roles in controlling the expression of many cellular proteins. Once they are recruited and incorporated into a ribonucleoprotein complex miRISC, they can target specific mRNAs in a miRNA sequence-dependent process and interfere in the translation into proteins of the targeted mRNAs via several mechanisms. Consequently, miRNAs can regulate many cellular pathways and processes. Dysregulation of their physiological roles may largely contribute to disease. In particular, in cancer, miRNAs can be involved in the deregulation of the expression of important genes that play key roles in tumorigenesis, tumor development, and angiogenesis and have oncogenic or tumor suppressor roles. This review focuses on the biogenesis and maturation of miRNAs, their mechanisms of gene regulation, and the way their expression is deregulated in cancer. The involvement of miRNAs in several oncogenic pathways such as angiogenesis and apoptosis, and in the inter-cellular dialog mediated by miRNA-loaded exosomes as well as the development of new therapeutical strategies based on miRNAs will be discussed.