Abstract
Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.
Highlights
Malignant pleural mesothelioma (MPM), a disease of the serosal surfaces of the thoracic cavity induced by asbestos, exhibits significant changes in gene expression
In MPM, as in other cancer types, there is a trend towards global downregulation of microRNA expression, and a number have been shown to act as tumor suppressors which are in many cases predicted to regulate the protein coding genes typically overexpressed in MPM [5,6,7,8]
Previous studies comparing MPM with adeno carcinomas identified differentially expressed microRNAs with diagnostic value, but the expression of these diagnostic microRNAs has not been assessed in normal mesothelium
Summary
Malignant pleural mesothelioma (MPM), a disease of the serosal surfaces of the thoracic cavity induced by asbestos, exhibits significant changes in gene expression. The changes in microRNA expression found in MPM have been exploited in the search for new diagnostic [9, 10] and prognostic markers [11,12,13], and therapeutic targets [8, 14]. Two early reports identified a subset of microRNAs with differential expression in MPM and lung adenocarcinoma. In the study by Gee et al, miR-200c-3p, miR-141-3p, miR-200b-3p, miR-200a-5p, miR-429, miR203 and miR-205 were all found to be expressed at lower levels in MPM than in lung adenocarcinoma [10]. MiR-193a-3p was expressed at higher levels in MPM With this combination, the authors devised a scoring system to discriminate MPM from other tumors, and this forms the basis of a clinically used diagnostic test. As the intention was to identify markers to differentiate between MPM and adenocarcinoma, a comparison between MPM and normal mesothelium was not made in either study
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