EPR-Effect and Nano-medicine Backdoor or Bottleneck?

Abstract

MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules capable of negatively regulating the expression of target genes. This highly conserved method of gene regulation is accomplished via miRNA incorporation into a protein complex, mainly consisting of Argonaute proteins, where the miRNA binds a complementary region, typically within the 3’ UTR of an mRNA. Due to their critical gene regulatory function, miRNAs play an important role in many diseases, including cancer. Studies have shown that the majority of mammalian miRNAs are located within the introns of genes. These miRNAs are therefore referred to as intronic miRNAs [1]. Introns, although originally thought to be merely nonsense spacing elements in gene structure, have received extensive attention in recent years due to the discovery of important functions for these sequences. Further studies have demonstrated that intronic miRNAs are often co-expressed and therefore may share similar transcriptional regulatory mechanisms with their host genes in humans [2]. This correlation of expression suggests that these intronic miRNAs may have functions either similar, or opposite, to that of their host genes. Borchert and others have described how intronic miRNAs can be transcribed independently from the host gene, either by RNA polymerase II or III [3]. This independent transcription phenomenon is intriguing because miRNAs could then function and be regulated without any association with their protein-coding host genes. The questions of why these microRNAs are encoded within introns and how these intronic miRNAs relate to the function of their host genes beg to be answered by researchers. Certainly, there are intronic miRNAs that have functions completely unrelated to that of their host genes. Furthermore, there are some examples of intronic miRNAs that act in synergy with their host genes. Yet a third area of study is miRNAs which act in a way that is functionally opposed to the normal function of the host genes. Here we will highlight the role of those antagonistic intronic miRNAs, which are critical in the regulation of the expression and function of their host genes, and we will examine the implications of these intronic miRNAs in cancer development and progression.Bioinformatic studies have demonstrated that approximately 20% of intronic miRNAs are predicted to target their host genes [4]. Although target prediction methods are imperfect, this is a significantly greater percentage than can be attributed to mere chance. Additionally, one bioinformatic study utilized the GO Biological Process (GOBP) and KEGG ontologies, which associate genes with cellular processes and biochemical pathways, respectively, to survey for over representation of miRNA targets within host gene-associated pathways. In other words, this method examines how many of the predicted miRNA targets would be involved in the normal function of the host gene. This study demonstrated that host gene pathways were significantly over represented when analyzed for intronic miRNA targets. Interestingly, many malignancy-related pathways ranked high [4], supporting the importance of intronic miRNA regulation of cancer-associated pathways. At least two major mechanisms explain how a miRNA can negatively regulate its host gene or host gene function. First, the intronic miRNA can directly target the 3′ UTR of its host gene. This would lead to translational repression or direct mRNA degradation of the host gene and therefore, less of the total protein product will be expressed. One example of direct host gene targeting is miR-338-3p, which inhibits its host gene