MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

Abstract

Uveal melanoma (UM) is a rare tumour of the eye, characterised by a high propensity to metastasise in half of all patients, most frequently to the liver. Although there are effective treatment options for the primary tumour, once metastasis has occurred prognosis is poor, with overall survival limited to months. Currently, there are no effective treatments for metastatic UM, despite the tumour having a well-defined signalling pathway to which many therapies have been directed. In an effort to develop novel treatment approaches, understanding the role of other signalling molecules, such as microRNAs, is fundamental. MicroRNAs (miRNAs) are small non-coding RNA molecules involved in posttranscriptional gene regulation, resulting in reduced target gene expression and subsequent protein translation. In UM, several dysregulated miRNAs have been proposed to play a functional role in disease progression, whereas others have been put forward as clinical biomarkers of high-risk disease following isolation from blood, plasma and exosomes. Most recently, analyses of large datasets have identified promising prognostic miRNA signatures and panels. This review navigates the plethora of aberrant miRNAs disclosed so far in UM, and maps these to signalling pathways, which could be targeted in future therapies for the disseminated disease.

Keywords: biomarkers; miRNA; uveal melanoma (UM).

Figure 1

MicroRNAs (miRNAs) associated with an increased metastatic risk in uveal melanoma (UM). Evaluation of miRNA commonality was undertaken between three studies examining miRNA expression de novo in large well-defined UM sample sets. (A) Venn diagram of upregulated miRNAs associated with an increased metastatic risk. (B) Venn diagram of downregulated miRNAs associated with an increased metastatic risk. The miRNAs included in this analysis were obtained from Worley et al. (only upregulated miRNAs reported), Robertson et al. (miRNAs comparing cluster 3 + 4 with 1 + 2, fold change >2) and Smit et al. (all miRNAs found in high and low/intermediate metastatic risk comparisons). Overlapping miRNAs are in bold font and commonalities are identified for the upregulated miRNAs et-7b, 199a, 143, 155 and 21, and for the downregulated miRNA 181a. Only the mature miRNA identifiers were used within this comparative analysis.

Figure 2

Selected miRNAs reported in uveal melanoma (UM) studies that have been examined functionally and are associated with disease progression or increased metastatic risk. These data include all functional miRNAs examined in Table 1 and Table 2, miRNAs identified as fluid biomarkers of disease progression or metastasis as well as miRNAs identified as associated with increased metastatic risk from both UM tissue samples and in silico data-mining studies. All data presented are significantly changed miRNAs in the study setting and have been cross-compared between studies to identify important miRNAs. Common miRNAs identified in the different study settings are in bold.