microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism.

Material and methods: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed.

Results: 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27.

Conclusion: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome.

Keywords: MDM2; NanoString nCounter; microRNA; pleural mesothelioma.

Figure 1. In silico prediction of miRNAs affecting TP53 pathway members in MDM2-negativ tumours compared to MDM2-positive ones is shown

TP53 is downregulated with a prediction score (PS) of 11.67, RB1 with a PS of 8.02, CDKN2A with a PS 1.27 and MDM2 with a PS of 4.50.

Figure 2. In silico prediction of the most affected KEGG-pathways between MDM2-positive and negative tumours is shown

Most likely affected are Ribosome, Wnt signaling pathway, Metabolism of xenobiotics by cytochrome P450, MAPK signaling pathway, focal adhesion, regulation of actin cytoskeleton, Axon guidance, Colorectal cancer, Oxidative phosphorylation as well as TGF-beta signaling pathway.

Figure 3. The heatmap presents miRNAs directing TP53 pathway members

miRNAs regulating either MDM2, TP53 or RB1 are downregulated in MDM2-positiv tumours. CDKN2A seems to be unaffected.

Figure 4. The schematic illustrations describes the role of TP53 in miRNA processing and regulation

TP53 acts as transcription factor for some miRNAs. Additionally, TP53 plays a role in miRNA processing by directly interacting with P68 (DROSHA-complex), P63 (DICER-complex) as well as RBM38. The figure is adapted from Rokavec et al. Clin Exp Gastroenterol, 2014 [44].