Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy

Our plain-English summary of Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy, by M. Tomasetti, S. Gaetani, F. Monaco, et al (Frontiers in Oncology, 2019).

The study

• Authors: M. Tomasetti, S. Gaetani, F. Monaco, J. Neuzil, L. Santarelli
• Journal: Frontiers in Oncology
• Published: 2019;9:1293
• Type of article: Review
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos exposure leads to epigenetic and epigenomic modifications that, in association with ROS-induced DNA damage, contribute to cancer onset. Few miRNAs epigenetically regulated in MM have been described in literature; miR-126, however, is one of them, and its expression is regulated by epigenetic mechanisms. Asbestos exposure induces early changes in the miRNAs, which are reversibly expressed as protective species, and their inability to reverse reflects the inability of the cells to restore the physiological miRNA levels despite the cessation of carcinogen exposure. Changes in miRNA expression, which results from genetic/epigenetic changes during tumor formation and evolution, can be detected in fluids and used as cancer biomarkers. This article has reviewed the epigenetic mechanisms involved in miRNA expression in MM, focusing on their role as biomarkers of early diagnosis and therapeutic effects.

Copyright © 2019 Tomasetti, Gaetani, Monaco, Neuzil and Santarelli.

In plain English

This article was a review, not a new study. The authors reviewed published research on epigenetic changes (chemical changes that switch genes on or off without altering the DNA code) that control small molecules called microRNAs (miRNAs) in malignant mesothelioma. They also reviewed whether miRNAs could help diagnose the disease early or treat it. They described asbestos as causing such changes partly through oxidative stress. They wrote that few miRNAs are known to be epigenetically regulated in mesothelioma, among them miR-34, miR-145 and miR-126. Summarizing earlier studies, they reported that miR-126 told healthy people apart from mesothelioma patients with a sensitivity of 71% (plus or minus 12%) and a low specificity of 54% (plus or minus 15%). They noted that an earlier study of blood taken before diagnosis found that candidate miRNAs failed to detect mesothelioma. They also described the only clinical trial of a miRNA-based treatment in mesothelioma patients, a phase I study of a drug designed to restore miR-16, in which 5% of patients had an objective response. The authors concluded that using these biomarkers for early detection of mesothelioma is questionable.

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: Narrative review of published research
• Who was studied: No study population of its own. The review covered published laboratory and clinical studies on miRNAs in malignant mesothelioma (MM).
• Exposure: Asbestos in general, with no particular fiber type specified. The authors described its effects as acting through oxidative stress and chronic inflammation.
• Main results:
  • Citing earlier studies, the review reported that hypermethylation of the promoter regions of miR-145 and miR-126 is responsible for low levels of these miRNAs in mesothelioma tissue and cell lines. It also reported that the miR-34 family was found downregulated in MM through promoter methylation.
  • Summarizing earlier studies (Table 2), the review reported that miR-126 distinguished healthy subjects from MM patients with a sensitivity of 71% (plus or minus 12%) and a low specificity of 54% (plus or minus 15%).
  • Citing an earlier study by Santarelli et al., the review reported increased miR-126 and miR-222 in people currently exposed to asbestos, such as workers maintaining and restoring buildings that contain asbestos.
  • In the same earlier study, people exposed to asbestos in the past showed no changes in miRNA expression. The authors interpreted this as suggesting a reversible mechanism.
  • Citing an earlier study, the review reported that three candidate miRNAs, including miR-126, failed to detect MM in samples taken before diagnosis, whether used alone or in combination.
  • In the review's section on miRNA-based therapy, the authors described the only clinical trial in human MM patients: a phase I, open-label, dose-escalation study of a drug designed to restore miR-16. In that trial, 5% of patients achieved an objective response, 68% had stable disease and 27% had progressive disease.
  • The authors cited their group's unpublished data suggesting that miR-126 expression in MM tissue was regulated by changes in chromatin structure rather than by DNA methylation.
• The authors' conclusion: The authors concluded that using miRNA biomarkers for early detection of MM is questionable, because significant changes in miRNA expression were detected only once the MM had become manifest.
• Limitations the authors state:
  • The authors stated that the quantification methods and sample types used in the miRNA studies limit their clinical application.
  • The authors stated that most candidate biomarkers have not been validated in samples taken before diagnosis.
  • The authors stated that miR-126 is not specific to cancer: it is also affected by conditions such as type 2 diabetes and coronary artery disease.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Biomarker, Asbestos Exposure.

Related studies

• Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy — M. Tomasetti, M. Amati, et al. (2017)
• ATG5 as biomarker for early detection of malignant mesothelioma — M. Tomasetti, F. Monaco, et al. (2023)
• Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies — L. Santarelli, S. Gaetani, et al. (2019)
• Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma — L. Santarelli, S. Staffolani, et al. (2015)
• Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy — S. Gaetani, F. Monaco, et al. (2020)
• Biomarkers for Early Diagnosis and Prognosis of Malignant Pleural Mesothelioma: The Quest Goes on — C. Ledda, P. Senia, et al. (2018)

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