MicroRNAome genome: a treasure for cancer diagnosis and therapy

Abstract

The interplay between abnormalities in genes coding for proteins and noncoding microRNAs (miRNAs) has been among the most exciting yet unexpected discoveries in oncology over the last decade. The complexity of this network has redefined cancer research as miRNAs, produced from what was once considered "genomic trash," have shown to be crucial for cancer initiation, progression, and dissemination. Naturally occurring miRNAs are very short transcripts that never produce a protein or amino acid chain, but act by regulating protein expression during cellular processes such as growth, development, and differentiation at the transcriptional, posttranscriptional, and/or translational level. In this review article, miRNAs are presented as ubiquitous players involved in all cancer hallmarks. The authors also describe the most used methods to detect their expression, which have revealed the identity of hundreds of miRNAs dysregulated in cancer cells or tumor microenvironment cells. Furthermore, the role of miRNAs as hormones and as reliable cancer biomarkers and predictors of treatment response is discussed. Along with this, the authors explore current strategies in designing miRNA-targeting therapeutics, as well as the associated challenges that research envisions to overcome. Finally, a new wave in molecular oncology translational research is introduced: the study of long noncoding RNAs.

Keywords: cancer.; diagnosis; microRNA; therapy.

© 2014 American Cancer Society.

Figures

Figure 1. miRNA processing

RNA polymerase II is responsible for the initial transcription of the miRNA gene into a long, capped and polyadenylated (poly-A) precursor, called primary (pri)-miRNA [13,14]. A dsRNA-specific ribonuclease, Drosha, in conjunction with its binding partner DGCR8 (DiGeorge syndrome critical region gene 8 or Pasha), further processes pri-miRNA into a 70 to 100 nucleotide hairpin RNA precursor (pre-miRNA) [15]. Pre-miRNA is translocated from the nucleus to the cytoplasm by Exportin 5/RanGTP, and cleaved into an 18- to 24-nucleotide duplex by a ribonucleoprotein complex composed of ribonuclease III (Dicer) and TRBP (HIV-1 transactivating response RNA-binding protein). Finally, the duplex interacts with the RNA-induced silencing complex (RISC), which includes proteins of the Argonaute family (Ago1 to Ago4 in humans). One strand of the miRNA duplex remains stably associated with RISC and becomes the mature miRNA, which primarily, but not exclusively, guides the RISC complex to the 3’-UTR (3’-untranslated region) of target mRNAs. Although the interaction between miRNA and mRNA usually results in translation inhibition, some cleavage of target mRNAs has also been observed

Figure 2. Mechanisms of action of microRNAs

miRNAs can work through a variety of mechanisms: (a) binding by direct complementarity to multiple regions at the mRNA including the 3’-UTRs, 5’-UTRs and coding regions and decreasing protein expression (majority of miRNAs); (b) positively regulation of translation (miR-369-3p) through increased recruitment of processing proteins; (c) direct interaction with promoter sequences (miR-373); (d) direct agonists of receptors such as Toll-like receptors (miR-21, miR-29a and let-7); (e) direct interaction with protein and enhancing protein expression through a decoy mechanism (miR-328). For gene abbreviations see text and http://www.ncbi.nlm.nih.gov/gene.

Figure 3. Examples of miRNA involved in the eight cancer hallmarks

The six biological capabilities acquired during the multistep development of human tumors include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism and evading immune destruction. For each one representative example of miRNA is presented. For more details see text.

Figure 4. MicroRNAs as targets for anticancer drug therapy

In order to restore tumor suppressor proteins levels, oncomiRs can be targeted with therapies such as antagomirs or LNAs anti-miRs. When aiming to target oncogenic proteins, the levels of tumor suppressor-miRNAs can be restored by using miRNA mimics, or alternatively through siRNA delivery against the oncogenic target. A direct messenger RNA inhibition of oncogenic proteins can be obtained also through a ribozyme-mediated translation inhibition.