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MiRNA-21 functions in ionizing radiation-induced epithelium-to-mesenchymal transition (EMT) by downregulating PTEN

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Abstract

Radiation-induced pulmonary fibrosis (RIPF) results from thoracic radiotherapy and severely limits the use of radiotherapy. Recent studies suggest that epithelium-to-mesenchymal transition (EMT) contributes to pulmonary fibrosis. Although miRNA dysregulation participates in a variety of pathophysiologic processes, their roles in fibrotic lung diseases and EMT are unclear. In this study, we aimed to identify key miRNAs involved in this process using a mouse model of RIPF previously established by irradiation with a single dose (20 Gy) of 60Co γ-rays. At 2-weeks post-irradiation, a set of significantly upregulated miRNAs was identified in lung tissue by miRNA array analysis. This included miR-21, which has been reported to contribute to the pulmonary fibrotic response induced by stereotactic body radiotherapy. Here, we showed that miR-21 expression increased in parallel with EMT progression in the lungs of irradiated mice. Ectopic miR-21 expression promoted EMT progression in lung epithelial cells. Furthermore, downregulation of miR-21 expression by transfection of its inhibitor inhibited ionizing radiation (IR)-induced EMT. Knockdown of PTEN, which is the functional target of miR-21, reversed the attenuation of IR-induced EMT mediated by miR-21 downregulation. Radiation treatment decreased PTEN expression and increased Akt phosphorylation; these effects were abolished by the miR-21 inhibitor. MiR-21 overexpression in lung epithelial cell also downregulated PTEN expression and upregulated Akt phosphorylation. In conclusion, we have demonstrated that miR-21 functions as a key regulator of IR-induced EMT in lung epithelial cells via the PTEN/Akt pathway. Targeting miR-21 is implicated as a novel therapeutic strategy for the prevention of RIPF.

Graphical abstract: MiRNA-21 functions in ionizing radiation-induced epithelium-to-mesenchymal transition (EMT) by downregulating PTEN

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Publication details

The article was received on 21 Jan 2019, accepted on 26 Feb 2019 and first published on 28 Feb 2019


Article type: Paper
DOI: 10.1039/C9TX00019D
Citation: Toxicol. Res., 2019, Advance Article

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    MiRNA-21 functions in ionizing radiation-induced epithelium-to-mesenchymal transition (EMT) by downregulating PTEN

    Z. Liu, X. Liang, X. Li, X. Liu, M. Zhu, Y. Gu and P. Zhou, Toxicol. Res., 2019, Advance Article , DOI: 10.1039/C9TX00019D

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