نقش ریز آر ان ای (MicroRNAs) در تنظیم ترجمه و سرطان Role of microRNAs in translation regulation and cancer

INTRODUCTION Recent advances in transcriptome analysis and high throughput technologies highlighted an impressive complexity in the RNA world. The most studied RNA regions are protein-coding genes, mRNAs, accounting for around 1.5% of the human genome[1]. The importance of coding mRNAs is undisputable as they have been for years the building brick of experimental biology, culminating in the systematic deletion of coding genes in several species. Not less important are retrotransposons, specific genetic elements which are known to regulate gene expression[2,3]. Since RNA was identified as the crux of genetic regulation, the idea that it carries fundamental information has been extended to novel classes of RNA. More recently, the nonprotein coding portion of the genome gained attention due to its unexpected role in regulating development and disease[4]. Nowadays, most scientists agree in stating that transcription of the human genome is pervasive, therefore raising questions on the function of many uncharacterized RNAs. The discovery of non-coding RNAs (ncRNAs) has changed the way we look at the human genome and led the scientific world to characterize the different types of ncRNAs transcribed in human cells. Although there is not a clear delineation of ncRNA classes, they are usually classified, according to their nucleotides length, in three main groups: Short ncRNAs, mid-size ncRNAs and long ncRNAs[5]. Among short ncRNAs we can distinguish between microRNAs (miRNA) and piwiinteracting RNAs (piRNAs), respectively 19-25 base pairs (bp) and 26-31 bp long. miRNAs are involved in the regulation of gene expression at the translational and stability level[6-8], while piRNAs are involved in DNA methylation and transposon repression[9-11]. Small nucleolar RNAs (60-300 bp) are part of mid-size RNAs and act as guides for rRNA modifications[12], Promoter Associated RNAs (22-200 bp) belong to the same group but their function is obscure[13]. Last but not least, long non-coding RNAs (lncRNAs) comprise all ncRNAs longer than 200 nucleotides and include the largest portion of the non-coding transcriptome[4]. lncRNAs are involved in several biological and pathological processes, such as genomic imprinting, telomere regulation, X-chromosome inactivation, development, stem cell pluripotency, immune regulation, cancer progression and in metastatic potential[14,15]. In particular, a subset of lncRNAs, the T-UCR, themselves target specific miRNAs. The binding between these lncRNAs and miRNAs prevents target transcription degradation determining an intricate coregulation between lncRNAs and miRNAs[16-18] and strictly linking these two different types of ncRNAs. It should be however stressed out that the definition of ncRNA relies mainly on bioinformatic tools that are likely to be challenged in the next future. In particular, open reading frames (ORF) shorter than 100 nucleotides and/or lacking a strong ATG consensus sequence for translational start are considered noncoding. In view of the emergence of alternative translational start sites[19], we may discover that at least some ncRNAs are indeed “coding” for small peptides. The relevance of the non-coding transcriptome in the comprehension of human diseases is highlighted by the impressive number of ncRNAs that are abnormally expressed in cancer, in neurological and heart diseases or in immune disorders. In this context, short RNAs have attracted the attention of most researchers. Here, we focus on miRNA and on their role in translation regulation and cancer. In particular we zoom in the known mechanisms of miRNA-regulated translation, after a brief elucidation of their discovery and biogenesis. Finally, we account for the aberrant expression of miRNAs in cancer and for their therapeutical potential as new drugs. miRNA: DISCOVERY AND BIOGENESIS A brief history miRNAs are endogenous, non-coding single stranded RNAs of approximately 19-25 nucleotides in length, found both in animals and plants and involved in post transcriptional regulation[7,20]. Two decades ago the existence of miRNAs was obscure and the scientific community was focused largely on protein-coding genes. However in 1993 the discovery of the first small ncRNA lin-4, in C. elegans, has totally changed the scientists’ point of view[21]. At the time of the first discoveries, two main questions were raised: (1) what is the role of lin-4; and (2) what is its mechanism of action? Genetic studies showed that lin-4 is one of the most relevant genes involved in the control of temporal development of larval stages[22,23]. Almost simultaneously, Lee and collaborators discovered that null mutations of the lin-14 gene were able to cause an opposite phenotype to null lin-4 mutations, suggesting that lin-4 could regulate lin-14[23,24]. How was this regulation taking place? Several groups unequivocally demonstrated that the introduction of mutations in the putative ORF of the lin-4 gene, did not affect its function, concluding that lin-4 did not encode for a protein. Mature lin-4 was found to be present in two small transcripts with different lengths, 22 and 61 nucleotides[24]. Furthermore, mutations in the 3’UTR of lin-14 mRNA and gene fusion experiments showed that lin-14 was downregulated posttranscriptionally by lin-4, delineating the 3’UTR of lin-14 as necessary for the regulation of LIN-4 protein levels[25,26]. These data led to a unified conclusion: lin-4 transcripts were complementary to the 3’UTR of the lin-14 gene and regulated its expression by annealing to its 3’UTR. With a similar approach, seven years later another miRNA was discovered, let-7, which was able to regulate lin-41 expression by binding to its 3’UTR[27,28]. Further, the sequence of let-7 was found conserved among species, from flies to humans. A new era in transcriptomics was now open for study by the entire scientific world!