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

Our plain-English summary of microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma, by R.F. Walter, C. Vollbrecht, R. Werner, et al (Oncotarget, 2016).

The study

• Authors: R.F. Walter, C. Vollbrecht, R. Werner, J. Wohlschlaeger, D.C. Christoph, K.W. Schmid, F.D. Mairinger
• Journal: Oncotarget
• Published: 2016;7(14):18713-21
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This exploratory laboratory study measured small regulatory molecules called microRNAs in 24 stored tumour specimens of malignant pleural mesothelioma. The specimens came from patients treated at two centres in Essen, Germany, between 2006 and 2009. Twelve tumours were positive and twelve were negative for the protein MDM2, which can switch off the tumour-suppressor TP53. The authors measured 800 microRNAs. The study did not examine asbestos or any other exposure. They found 136 microRNAs that differed significantly between the two groups. Six microRNAs with p less than 0.01 were higher in MDM2-positive tumours, and the authors report the remaining ones as lower. Among the lower ones were 17 microRNAs acting on TP53, 18 on MDM2 and eleven on CDKN2A. Computer predictions gave scores of 11.67 for TP53, 8.02 for RB1, 4.50 for MDM2 and 1.27 for CDKN2A. The article is inconsistent about which group these scores describe. The authors concluded that MDM2 expression level noticeably affects microRNA expression in this cancer. They called the work a screening study, done without correction for multiple testing, that needs larger validation groups.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Exploratory retrospective laboratory study comparing microRNA expression in tumour tissue, with computer (in silico) target and pathway prediction
• Who was studied: 24 formalin-fixed paraffin-embedded tumour specimens of malignant pleural mesothelioma (12 MDM2-positive, 12 MDM2-negative). The specimens came from patients treated at the West German Cancer Centre or the West German Lung Centre (Essen, Germany) between 2006 and 2009
• Exposure: No asbestos or fiber exposure was studied. Tumours were compared by MDM2 protein expression on immunohistochemistry (score 0 versus score 1 or higher), and 800 cancer-related microRNAs were measured with the NanoString nCounter system
• Main results:
  • 136 microRNAs were significantly differentially regulated between MDM2-positive and MDM2-negative tumours. 39 had p less than 0.01, and six had p less than 0.001
  • Six microRNAs with p less than 0.01 were increased in MDM2-positive tumours. The authors report the remaining ones as decreased
  • In MDM2-expressing mesotheliomas, 17 microRNAs inhibiting TP53, 18 binding MDM2 and eleven suppressing CDKN2A were significantly decreased
  • In computer predictions, TP53 was predicted to be suppressed with a prediction score of 11.67, RB1 8.02, CDKN2A 1.27 and MDM2 4.50. The Results section says this applies to MDM2-negative tumours; the Discussion attributes the TP53 score to MDM2-positive tumours
  • The most affected predicted pathways between MDM2-positive and MDM2-negative tumours included Ribosome (eight targets, prediction score 36.24) and Wnt signaling pathway (122 targets, prediction score 29.45)
• The authors' conclusion: The authors concluded that MDM2 expression level noticeably affects overall microRNA expression, and through it cellular pathways such as ribosomal translation, in malignant pleural mesothelioma. They suggested this may lead to better understanding and possible new treatment approaches
• Limitations the authors state:
  • Because many targets were measured in a small number of cases, no correction for multiple testing (FDR or Bonferroni) was applied
  • The authors regard the work as a screening study that gives a first insight and needs larger validation cohorts

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), CDKN2A, Mesothelioma.

Related studies

• MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53 — R.F. Walter, F.D. Mairinger, et al. (2015)
• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)
• Are differentially expressed microRNAs useful in the diagnostics of malignant pleural mesothelioma? — M. Andersen, M. Grauslund, et al. (2012)
• Functional effects of differentially expressed microRNAs in A549 cells exposed to MWCNT-7 or crocidolite — C. Ventura, L. Vieira, et al. (2020)
• The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma — A. Chou, C.W. Toon, et al. (2018)
• Immunocytochemistry and DNA-image cytometry in diagnostic effusion cytology I. Prevalence of markers in tumour cell positive and negative smears — H. Motherby, M. Kube, et al. (1999)

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