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

Abstract

BackgroundMalignant 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 Methods24 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.Results17 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.ConclusionMDM2 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.

Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy

“…Secondly, MTs might act as a negative regulator of the effect of the chemotherapy by sequestering zinc ions [ 60 , 61 ], thereby regulating proteins based on zinc ions as cofactor like p53. We also compared MT expression presented within this study with results on p53 and mdm2 from previous investigation from our group [ 16 , 18 , 62 – 64 ]. However, we could not define significant associations between the two pathways.…”

“…Notwithstanding this, p53 is an essential regulator for apoptosis in case of DNA damage repair and recognition [ 60 ] and plays an important role in tumorigenesis and response to alkylating chemotherapeutics [ 16 , 18 , 62 – 64 ]. Previously, possible correlations to clinic-pathological data with the tumor suppressors p53 and MTs were analyzed in MPM samples but revealed no statistical association as well as no correlation to each other [ 39 ].…”

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

“…Toward this aim, in the present study we screened the whole miRNA profile in a cohort of 26 MPM patients who did not undergo radical surgery, in order to identify novel prognostic markers. The analysis identified 46 miRNAs differentially expressed in MPM specimens, some of which had been previously reported in MPM, such as downregulation of let-7 in MDM2 positive MPM tumors [ 15 ], and low expression of miRNA23a-3p in a subgroup of MPM long survivors after surgery [ 13 ].…”

Targeting microRNA to improve diagnostic and therapeutic approaches for malignant mesothelioma

“…MiR-223 along with a number of other miRNA may also regulate tumour protein 53 (TP53) in MPM. These miRNA were identified as downregulated in tumours expressing the negative regulator of TP53 MDM2 [ 93 ]. Functional studies are required to validate these findings.…”