Malignant pleural mesothelioma (MPM) is a very aggressive malignancy affecting the pleural linings. MPM has a notoriously poor prognosis, and most therapeutic options are limited to palliative care due to frequent resistance to chemo- and radiotherapy. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression, and have shown therapeutic potential in recent years. The miR-137 has been shown to have a tumour suppressor function in several tumours, but its role in MPM is still unclear. One known target of miR-137 is YB-1, a multifunctional oncoprotein often up-regulated in cancers and associated with aggressiveness and poor patient outcome.
The aim of this study was to characterise the expression and biological roles of miR-137 and YB1 in MPM and evaluate their potential as novel therapeutic targets.
Expression of miR-137 was highly variable among MPM cell lines and tissue specimen. The disparity of miR-137 expression in MPM cells compared to normal mesothelial cells can be explained by copy number variation and, more prominently, promotor hyper-methylation. Ectopic re-expression of miR-137 resulted in decreased MPM cell growth and colony formation as well as impaired cell migration and invasion. Besides other target genes such as MAPK8, AKT2 and CDK6, which are frequently dysregulated in cancer, miR-137 downregulates YB1, a highly expressed oncoprotein in MPM cell lines and tissues. A direct interaction between miR-137 and YB1 was confirmed by luciferase reporter assays. YB1 knock down also significantly inhibited MPM cell growth, colony formation, migration and invasion, recapitulating the effects of increasing miR-137 levels.
Our results show that miR-137 achieves a tumour-suppressor function in MPM, at least in part, due to the downregulation of YB1, which is involved in cell growth and malignant behaviour. Therefore, both YB1 and miR-137 have important roles in several aspects of MPM biology and represent potential targets for the development of novel MPM treatment strategies.