MicroRNAs and cancer—new paradigms in molecular oncology

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The ‘classic’ view of molecular oncology indicates that cancer is a genetic disease involving tumor suppressor and oncogenic proteins. However, in the recent years, it has been demonstrated that small regulatory non-coding RNAs (ncRNAs) named microRNAs (miRNAs) are involved in human tumorigenesis, thus revealing a new layer in the molecular architecture of human cancer. Gene expression studies revealed that hundreds of miRNAs are deregulated in cancer cells and functional studies clarified that miRNAs are involved in all the molecular and biological processes that drive tumorigenesis. Here, we summarize the recent advances in miRNA involvement in human cancer and illustrate the benefits of using these knowledge for medical practice. New diagnostic classifiers based on miRNAs will soon be available for medical practitioners and, even more importantly, miRNAs may become novel anti-cancer tools.

Introduction

MicroRNAs (miRNAs) constitute a large class of philogenetically conserved single stranded RNA molecules of 19–25 nt, involved in post-transcriptional gene silencing. They arise from intergenic or intragenic (both exonic and intronic) genomic regions that are transcribed as long primary transcripts. Primary transcripts undergo two processing steps that produce the short ‘mature’ molecule. The mature miRNA binds to specific regions of target mRNA transcripts and either destabilizes the target mRNA transcript or blocks its translation or both (for detailed reviews, see [1, 2]).

Recent findings indicate that miRNAs are involved in the pathogenesis of all types of human cancers. Initially identified in B-cell chronic lymphocytic leukemia (CLL) [3•], miRNA alterations have since been detected in many types of human tumors (Table 1). The main mechanism of miRNome (defined as the full complement of miRNAs present in a genome) alterations in cancer cells is aberrant gene expression, which is characterized by abnormal expression levels of mature miRNAs.

In the present review we focus on the advances in understanding the roles of miRNAs in cancer reported in the past two years (for earlier studies, see these reviews [4, 5, 6]).

Section snippets

MicroRNAs as oncogenes and tumor suppressors

A growing amount of evidences proves that miRNAs can work as oncogenes (activating the malignant potential) or tumor suppressor genes (blocking the malignant potential) and they can affect all of the six hallmarks of malignant cells [7].

Sequence variations in microRNAs and microRNA targets as cancer predisposing factors

There are at least two lines of evidence indicating that miRNA genetic changes may increase cancer susceptibility.

Circulating microRNAs as novel diagnostic markers

As miRNAs are active players in human oncogenesis, an ever-growing number of reports are proving that miRNAs may represent novel diagnostic and prognostic tools for cancer stratification. For example, it was recently reported that high miR-21 expression is associated with poor survival and poor therapeutic outcome in colon adenocarcinoma [84], and a growing number of studies identified miRNA expression in human tumors as diagnostic or prognostic markers (for a review see [85]).

More recently,

MiRNA-based cancer gene therapy

RNA inhibition can be used to treat cancer patients in two ways: (a) by using RNA or DNA molecules as therapeutic drugs against messenger RNA of genes involved in the pathogenesis of cancers and (b) by directly targeting ncRNAs that participate in cancer pathogenesis. The specific tools used to accomplish these goals are presented in Table 3.

The use of miRNAs as potential drugs is still at preclinical stage, and no clinical or toxicological studies are published yet. miRNA mimics were shown to

Perspectives

There are no doubts that miRNAs are important cancer players. Main advances in this competitive field in next future will come from at least three areas: first, the identification of functional feedback and feed-forward loops involving transcription factors – microRNAs – gene targets, which will provide a wider picture of how cells become malignantly transformed, multiply, and invade patient's body; second, the identification of the clinical conditions in which miRNAs may become useful markers

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Negrini is supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Univerisità e Ricerca, Ministero della Sanità, and by project NOBEL from Fondazione Cariplo, Milan, Italy; Calin is supported as a Fellow of The University of Texas M. D. Anderson Research Trust, and as a Fellow of University of Texas System Regents Research Scholar and as a Ladjevardian Regents Research Scholar Fund. This study was funded also by an Institutional Research Grant (IRG) and

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