Blocking MSI2 alleviated radiation-induced pulmonary fibrosis through inhibiting epithelial-mesenchymal transition.

Abstract

Purpose: Ionizing radiation (IR) has been shown to induce epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs), which is a critical cause of radiation-induced pulmonary fibrosis (RIPF). In this study, we investigated the role and molecular mechanisms of musashi2 (MSI2), an RNA-binding protein, in IR-induced EMT of AECs for aiming at potential therapeutic strategies to prevent RIPF.

Materials and methods: Changes in the expression levels of MSI2 and EMT markers (E-cadherin, N-cadherin, and Vimentin) induced by IR in AECs were detected by western blot (WB). Then, the effect of MSI2 on IR-induced EMT of AECs was investigated by observing morphological changes and detecting expression of MSI2 and EMT markers by WB and immunofluorescence (IF). RNA-Seq analysis, WB and RT-qPCR were used to identify the targets of MSI2.

Results: We observed that IR could cause a significant increase of MSI2 protein expression, a down-regulation of E-cadherin and an up-regulation of Vimentin and N-cadherin in AECs (MLE-12 and RLE-6TN cells). We also revealed that MSI2 was involved in regulating the alteration of morphology and EMT-related markers in AECs after irradiation, suggesting the occurrence of EMT regulated by MSI2. Moreover, we found the mechanism of MSI2 participating in EMT by regulating the expression of transcription factor ZEB1, acting as a downstream target of MSI2 in IR-induced EMT of AECs.

Conclusions: Our study unveils the critical role of MSI2 in IR-induced EMT of AECs and preliminarily elucidates its molecular mechanisms, providing new insights into the process of IR-induced pulmonary fibrosis.