Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy

Our plain-English summary of Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy, by S. Gaetani, F. Monaco, F. Alessandrini, et al (The International Journal of Biochemistry & Cell Biology, 2020).

The study

• Authors: S. Gaetani, F. Monaco, F. Alessandrini, A. Tagliabracci, A. Sabbatini, M. Bracci, M. Valentino, J. Neuzil, M. Amati, L. Santarelli, M. Tomasetti
• Journal: The International Journal of Biochemistry & Cell Biology
• Published: 2020;121:105700
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

MiR-222 and miR-126 are associated with asbestos exposure and the ensuing malignancy, but the mechanism(s) of their regulation remain unclear. We evaluated the mechanism by which asbestos regulates miR-222 and miR-126 expression in the context of cancer etiology. An 'in vitro' model of carcinogen-induced cell transformation was used based on exposing bronchial epithelium BEAS-2B cells to three different carcinogens including asbestos. Involvement of the EGFR pathway and the role of epigenetics have been investigated in carcinogen-transformed cells and in malignant mesothelioma, a neoplastic disease associated with asbestos exposure. Increased expression of miR-222 and miR-126 were found in asbestos-transformed cells, but not in cells exposed to arsenic and chrome. Asbestos-mediated activation of the EGFR pathway and macrophages-induced inflammation resulted in miR-222 upregulation, which was reversed by EGFR inhibition. Conversely, asbestos-induced miR-126 expression was affected neither by EGFR modulation nor inflammation. Rather than methylation of the miR-126 host gene EGFL7, epigenetic mechanism involving DNMT1- and PARP1-mediated chromatin remodeling was found to upregulate of miR-126 in asbestos-exposed cells, while miR-126 was downregulated in malignant cells. Analysis of MM tissue supported the role of PARP1 in miR-126 regulation. Therefore, activation of the EGFR pathway and the PARP1-mediated epigenetic regulation both play a role in asbestos-induced miRNA expression, associated with in asbestos-induced carcinogenesis and tumor progression.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

This laboratory study examined how asbestos may change the levels of two small regulatory RNA molecules, miR-222 and miR-126. The authors exposed human bronchial lining cells (BEAS-2B) to crocidolite asbestos, arsenic or hexavalent chromium. They also exposed non-malignant mesothelial cells to asbestos for one month, and they studied a malignant mesothelioma cell line and biopsies from 6 male mesothelioma patients. Of the three carcinogens, asbestos raised both molecules over time, peaking on day 14. Blocking the EGFR signaling pathway reduced the asbestos-induced rise in miR-222. The asbestos-induced rise in miR-126 was not affected by inflammation and did not depend on EGFR. That rise was not explained by methylation of miR-126's host gene, EGFL7, but blocking the enzymes DNMT1 or PARP1 reduced it. Mesothelioma tissue showed lower miR-126 and EGFL7 and higher PARP1 and DNMT1 than adjacent non-malignant tissue. The authors concluded that EGFR activation and PARP1-driven epigenetic regulation are two mechanisms, not mutually exclusive, that likely play an important role in asbestos-induced carcinogenesis and tumor growth.

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: Laboratory (in vitro) cell experiments, plus analysis of tumor biopsies and matched non-malignant tissue from mesothelioma patients
• Who was studied: Laboratory cells: immortalized human bronchial epithelial cells (BEAS-2B), non-malignant mesothelial cells (Met-5A) and malignant mesothelioma cells (H28). Also diagnostic biopsies from 6 male malignant mesothelioma patients diagnosed at Ancona University Hospital, Italy, in 2011 to 2017 (5 epithelioid, 1 sarcomatoid), with patient-matched non-malignant tissue.
• Exposure: Crocidolite asbestos fibers at 5 μg/cm2, compared with arsenic (sodium arsenite, 1 μM) and hexavalent chrome (potassium chromate, 0.5 μM). BEAS-2B cells were exposed for 4 weeks and then grown in soft agar for 3 months. Met-5A cells had one month of continuous asbestos exposure.
• Main results:
  • Among the three carcinogens tested on BEAS-2B cells, asbestos raised miR-222 and miR-126 over time, with the peak on day 14.
  • In asbestos-transformed BEAS-2B cells, levels of both miRNAs rose further when the cells were grown with fibroblasts and blood-vessel cells (a cancer stroma model).
  • In asbestos-transformed BEAS-2B cells, blocking EGFR significantly reduced the asbestos-induced rise in miR-222.
  • In asbestos-transformed BEAS-2B cells, asbestos-induced miR-126 was not affected by inflammation and did not depend on EGFR.
  • Asbestos-transformed BEAS-2B cells showed no change in DNA methylation of the EGFL7 gene compared with control cells.
  • In asbestos-transformed BEAS-2B cells, blocking DNMT1 or PARP1 markedly reduced miR-126.
  • In non-malignant mesothelial cells (Met-5A), one month of asbestos exposure increased miR-222 through EGFR signaling, with no change in miR-126.
  • Malignant mesothelioma cells (H28) had low miR-126 compared with non-malignant mesothelial cells (Met-5A).
  • The authors reported a positive correlation between miR-222 and PARP1 levels (r = 0.723, p = 0.032). The article does not clearly state which samples this correlation was based on.
  • In the mesothelioma biopsies, lower miR-126 and EGFL7 were not linked to methylation changes in the EGFL7 promoter.
  • PARP1 and DNMT1 levels were higher in malignant mesothelioma tissue than in non-malignant tissue.
  • In the tissue samples, EGFL7 and miR-126 levels rose together and were negatively related to PARP1 and DNMT1 levels.
• The authors' conclusion: The authors proposed two mechanisms of asbestos-induced miRNA regulation: EGFR activation, and epigenetic regulation in which PARP1 directs miRNA expression. In their view, the two are not mutually exclusive and likely play an important role in asbestos-induced carcinogenesis and tumor growth.

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: Asbestos Exposure, Etiology, Epithelium, EGFR, Mesothelioma, Macrophage, Inflammation, Carcinogenesis.

Related studies

• Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies — L. Santarelli, S. Gaetani, et al. (2019)
• Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients — M. Tomasetti, S. Staffolani, et al. (2012)
• Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma — L. Santarelli, E. Strafella, et al. (2011)
• Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma — L. Santarelli, S. Staffolani, et al. (2015)
• ATG5 as biomarker for early detection of malignant mesothelioma — M. Tomasetti, F. Monaco, et al. (2023)
• Asbestos exposure affects poly(ADP-ribose) polymerase-1 activity: role in asbestos-induced carcinogenesis — M. Tomasetti, M. Amati, et al. (2011)

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