4.6 Article

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

Journal

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2020.105700

Keywords

miR-222; miR-126; Asbestos exposure; EGFR pathway; Epigenetic alterations

Funding

  1. INAIL (National Institute for Insurance against Workplace Accidents and Occupational Disease) [1/2011/5/n.1]
  2. Region Friuli Venezia Giulia (Italy) [1124/SPS/2016]
  3. Czech Health Research Council [1631704A]

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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 down regulated 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.

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