MicroRNAs in cancer: small molecules with a huge impact

Abstract

Every cellular process is likely to be regulated by microRNAs, and an aberrant microRNA expression signature is a hallmark of several diseases, including cancer. MicroRNA expression profiling has indeed provided evidence of the association of these tiny molecules with tumor development and progression. An increasing number of studies have then demonstrated that microRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. Here we review our current knowledge about the involvement of microRNAs in cancer and their potential as diagnostic, prognostic, and therapeutic tools.

Fig 1.

Biogenesis, processing, and maturation of microRNAs (miRs). miRs are transcribed mainly by RNA polymerase II as long primary transcripts characterized by hairpin structures (pri-miRs) and processed in the nucleus by RNAse III Drosha in a 70-nucleotide-long pre-miR. This precursor molecule is exported by the Exportin 5 to the cytoplasm, where RNAse III Dicer generates a dsRNA of approximately 22 nucleotides, named miR/miR*. The mature miR product is then incorporated in the complex known as miRISC, whereas the other strand is likely subjected to degradation. As part of this complex, the mature miR is able to regulate gene expression binding through partial homology the 3′UTR of target mRNAs and leading to mRNA degradation in case of perfect matching or translation inhibition. RISC, RNA-induced silencing complex.

Fig 2.

Molecular alterations in chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). Deletion or downregulation of microRNA (miR)-15a/miR-16-1 cluster, located at chromosome 13q14.3 and directly involved in the regulation of BCL2 and MCL1 expression, represent an early event in the pathogenesis of CLL. During the evolution of malignant clones, other microRNAs (miRs) can be deleted (such as miR-29) or overexpressed (such as miR-155), contributing to the aggressiveness of B-cell CLL. Such abnormalities can influence the expression of other protein-coding genes (PCGs), as TCL1 oncogene, directly regulated by miR-29 and miR-181, or affect other noncoding RNAs (ncRNAs). The consequences of this steady accumulation of abnormalities are represented by the reduction of apoptosis and the induction of survival and proliferation of malignant B cells, leading to the evolution of more aggressive clones. Members of the miR-29 family, lost in AML and in other tumor types as lung cancer, have also been shown to directly target MCL1 and DNMT3A and B.

Fig 3.

Mechanisms of microRNA (miR) regulation. The deregulated microRNA expression observed in cancer can be caused by chromosomal abnormalities, mutations, polymorphisms (SNPs), transcriptional deregulation, defects in the microRNA biogenesis machinery, and epigenetic changes.

Fig 4.

MicroRNAs (miRs) as therapeutic tools. The reintroduction by transfection of synthetic miRs lost during cancer development or progression or the inhibition of oncogenic miRs by using anti-miR oligonucleotides could contribute to counteract tumor proliferation, extended survival, and the acquisition of a metastatic potential, thus representing potential therapeutic tools.