Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future

Abstract

microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

Keywords: drug delivery; drug formulation; extracellular vesicles; malignant pleural mesothelioma; microRNA; oncomiR; tumor suppressor miRNA.

Figure 1

microRNA expression changes with disease course in MPM. The expression of most miRNAs is lower in MPM than normal mesothelium (NM) levels, and is shown schematically for three representative groups (levels are shown relative to NM, and are in arbitrary units for illustrative purposes). Some miRNAs are found at lower levels in tumors with poor prognosis (e.g., miR-215 and miR-193a) which may indicate a continuing gradual decrease in expression with tumor progression (indicated by decreasing levels in A). Others, such as miR-15/16 and the miR-34 family are consistently decreased in MPM samples but do not appear to have prognostic value, suggesting they do not change with advanced stage (B). Another group, exemplified by miR-31 and miR-17, exhibit lower levels in MPM compared with NM, but are also higher in patients with shorter survival, possibly indicating an increase in expression with tumor progression (C).

Figure 2

The key pathways most frequently mutated in MPM all contribute to global downregulation of microRNA levels. Tumor suppressor miRNAs are often downregulated in MPM, and several mechanisms appear to play a role in this observation. In addition to specific control of microRNA transcription, other pathways are involved in indirect control of microRNA levels via effects on processing. In mesothelial cells (left panel), the p53 pathway (1) is intact, and cell stress induces microRNA levels via direct transcription as well as by p53-induced pri-miR processing. Similarly, normal signaling of the Hippo pathway (2) through NF2 and LATS2 phosphorylates YAP1 which is retained in the cytoplasm. BAP1 deubiquitinase activity (3) destabilizes EZH2, a key component of the polycomb repressor complex 2. In mesothelioma (right panel), frequent mutation or deletion of the CDKN2A locus leads to loss of p14ARF and increased MDM2-mediated p53 degradation. Loss of function mutations of NF2/Merlin or LATS2 (or gain-of-function mutations of YAP) dysregulate Hippo signaling leading to accumulation of YAP in the nucleus where it can inhibit the microprocessor complex via interaction with Drosha. Inactivating BAP1 mutations prevent control of EZH2 which can alter miRNA levels. Additionally, MYC amplification or mutation can lead to transcriptional suppression of multiple miRNA genes. Whether these changes are also involved in the upregulation of oncogenic miRNAs in MPM remains to be determined.