Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy.
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.
['Gaetani|Simona|S|', 'Monaco|Federica|F|', 'Alessandrini|Federica|F|', 'Tagliabracci|Adriano|A|', 'Sabbatini|Armando|A|', 'Bracci|Massimo|M|', 'Valentino|Matteo|M|', 'Neuzil|Jiri|J|', 'Amati|Monica|M|', 'Santarelli|Lory|L|', 'Tomasetti|Marco|M|']
D000368:Aged D001194:Asbestos D002273:Carcinogens D006801:Humans D008175:Lung Neoplasms D008297:Male D008654:Mesothelioma D000086002:Mesothelioma, Malignant D035683:MicroRNAs
miR-222 miR-126 Asbestos exposure EGFR pathway Epigenetic alterations