An emerging role for microRNAs in NF1 tumorigenesis

Abstract

MicroRNAs (miRNAs) are a class of non-coding RNA, which have recently been shown to have a wide variety of regulatory functions in relation to gene expression. Since their identification nearly 20 years ago, miRNAs have been found to play an important role in cancer, including in neurofibromatosis type 1 (NF1)-associated tumours. NF1 is the most commonly inherited tumour predisposition syndrome and can lead to malignancy via the development of malignant peripheral nerve sheath tumours (MPNSTs). Although the mechanisms by which benign neurofibromas develop into MPNSTs still remain to be elucidated, it is becoming increasingly clear that miRNAs play a key role in this process and have the potential to be used as both diagnostic and prognostic markers of tumorigenesis.

Figure 1

The flowchart highlights the processes involved in the following miRNA biogenesis: (1) The process begins inside the nucleus, where RNA polymerase II or III initiates the transcription of miRNA-coding genes to produce ‘pri-microRNA’s[10,11]. (2) A microprocessor complex comprising both Drosha, an RNase III class enzyme, and Pasha, identifies and cleaves pre-microRNAs generating pre-microRNAs [12-14]. (3) Pre-microRNA molecules are transferred to the cytoplasm through exportin-5-mediated transport, which uses GTP that is bound to the Ran protein. The function of exportin-5 is dependent upon the GTP-bound form of the Ran co-factor for specific binding to the corresponding substrates. Therefore, this process comprises the hydrolysis of Ran-GTP to Ran-GDP, via the Ran GTPase-activating protein in the cytoplasm [15,16]. (4) In the cytoplasm, Dicer acts to cleave pre-miRNA molecules and, with the action of Argonaute 2 which is required for miRNA-induced silencing, forms an RNA-induced silencing complex (RISC) leading to the creation of a miRNA-induced silencing complex (miRISC). (5) Interaction between the miRNA and its target mRNA in the miRISC can cause either translational repression or miRNA degradation depending upon the degree of complementarity.