Aberrant MicroRNA Expression in Malignant Pleural Mesothelioma

Abstract

Malignant Pleural Mesothelioma (MPM) is an aggressive asbestos related malignancy. The global downregulation of microRNA (miRNA) expression is common in MPM, however, the mechanisms driving the downregulation of some tumour suppressor miRNAs, including the miR-15 family, are yet to be clarified. In this study, multiple mechanisms, including a combination of genomic deletion, DNA methylation and transcriptional repression, were demonstrated to lead to downregulation of miR-15a/16-1, miR-15b/16-2, miR-193a-3p, and miR-34c. The c-Myc oncogene was evidenced to transcriptionally repress expression of miR-15/16, predominately via association with the miR-15b/16-2 locus. The majority of MPM patients become refractory to the first-line treatment of pemetrexed and cisplatin chemotherapy due to chemo-resistance. MiRNAs belonging to the miR-15/16 and -34 families have been previously implicated in the development of drug resistance in other malignancies but their role in MPM chemo-resistance is largely unexplored. The expression of miR-15a/16-1 and miR-34a was downregulated in cell lines with acquired resistance to chemotherapy. Restoration of miRNA expression by mimic transfection led to the sensitisation of MPM cell lines to chemotherapy induced cytotoxicity and apoptosis, partly via repression of BCL2. Immune checkpoint inhibition of the PD-1/PD-L1 axis is an emerging therapeutic field in MPM. PD-L1 expression is upregulated and associated with poor prognosis in MPM, but the molecular mechanisms causing its dysregulation are poorly understood. In this study, reduced miRNA expression was related to elevated PD-L1 levels in the MPM patient panel. Restoration of miRNA expression led to downregulation of PD-L1 mRNA and protein expression via association with the 3’UTR region of the PD-L1 mRNA in MPM cell lines. Results from this study, and others, suggests that restoration of aberrant miRNA expression has the potential to improve, or lead to new targets for MPM therapy.