Role of microRNAs in translation regulation and cancer

Abstract

MicroRNAs (miRNAs) are pervasively expressed and regulate most biological functions. They function by modulating transcriptional and translational programs and therefore they orchestrate both physiological and pathological processes, such as development, cell differentiation, proliferation, apoptosis and tumor growth. miRNAs work as small guide molecules in RNA silencing, by negatively regulating the expression of several genes both at mRNA and protein level, by degrading their mRNA target and/or by silencing translation. One of the most recent advances in the field is the comprehension of their role in oncogenesis. The number of miRNA genes is increasing and an alteration in the level of miRNAs is involved in the initiation, progression and metastases formation of several tumors. Some tumor types show a distinct miRNA signature that distinguishes them from normal tissues and from other cancer types. Genetic and biochemical evidence supports the essential role of miRNAs in tumor development. Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the cause of this dysregulation is still unknown. Here, we discuss the biogenesis of miRNAs, focusing on the mechanisms by which they regulate protein synthesis. In addition we debate on their role in cancer, highlighting their potential to become therapeutic targets.

Keywords: Cancer; MicroRNA; OncomiR; Translation; Tumor suppressor.

Figure 1

Mechanisms of action of microRNAs. A: miRNAs bind the 3’UTR of a target gene by base pairing. The binding between the miRNA seed sequence (nucleotides 2-8 at the 5’end of the miRNA sequence) and the miRNA regulatory element (MRE) at the 3’UTR of a target gene determines the specific type of regulation; B: miRNAs act as inhibitors of translation when the binding at the 3’UTR of target genes is only partially complementary. Instead, when the binding complementarity is perfect, miRNAs induce mRNA degradation; C: miRNAs can also function in an unconventional manner: Under specific conditions, particularly during quiescence, they can activate translation by binding non canonical sites in the 5’UTR of target genes. ORF: Open reading frames.

Figure 2

Schematic representation of microRNAs role in translation. miRNAs can inhibit protein synthesis at three different stages of translation: Initiation, the rate limiting step, post initiation and elongation. For details refer to text.

Figure 3

Roles of microRNAs in cancer. miRNAs suppress the expression of their target genes. An oncogenic miRNA, termed oncomiR, can repress the translation of a tumor suppressor gene, stimulating tumorigenesis and leading to tumor formation. Conversely, a tumor suppressor miRNA is able to inhibit the expression of oncogenes, blocking the tumorigenesis process and consequently the development of cancer.