Abstract

TGF-β-centered epithelial-mesenchymal transition (EMT) is a key process involved in radiation-induced pulmonary injury (RIPI) and pulmonary fibrosis. PIEZO1, a mechanosensitive calcium channel, is expressed in myeloid cell and has been found to play an important role in bleomycin-induced pulmonary fibrosis. Whether PIEZO1 is related with radiation-induced EMT remains elusive. Herein, we found that PIEZO1 is functional in rat primary type II epithelial cells and RLE-6TN cells. After irradiation, PIEZO1 expression was increased in rat lung alveolar type II epithelial cells and RLE-6TN cell line, which was accompanied with EMT changes evidenced by increased TGF-β1, N-cadherin, Vimentin, Fibronectin, and α-SMA expression and decreased E-cadherin expression. Addition of exogenous TGF-β1 further enhanced these phenomena in vitro. Knockdown of PIEZO1 partly reverses radiation-induced EMT in vitro. Mechanistically, we found that activation of PIEZO1 could upregulate TGF-β1 expression and promote EMT through Ca2+/HIF-1α signaling. Knockdown of HIF-1α partly reverses enhanced TGF-β1 expression caused by radiation. Meanwhile, the expression of PIEZO1 was up-regulated after TGF-β1 co-culture, and the mechanism could be traced to the inhibition of transcription factor C/EBPβ expression by TGF-β1. Irradiation also caused a decrease in C/EBPβ expression in RLE-6TN cells. Dual luciferase reporter assay and chromatin immunoprecipitation assay (ChIP) confirmed that C/EBPβ represses PIEZO1 expression by binding to the PIEZO1 promoter. Furthermore, overexpression of C/EBPβ by using the synonymous mutation to C/EBPβ siRNA could reverse siRNA-induced upregulation of PIEZO1. In summary, our research suggests a critical role of PIEZO1 signaling in radiation-induced EMT by forming positive feedback with TGF-β1.

Highlights

  • The human lung is sensitive to ionizing radiation (Ding et al, 2013)

  • We found that PIEZO1 expression was increased in rat alveolar type II epithelial cells after irradiation (IR)

  • The transcription factor C/EBPβ expression was inhibited by irradiation and exogenous TGF-β1

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Summary

Introduction

Radiation-induced pulmonary injury (RIPI) can be seen in patients with chest tumors radiotherapy, and in practitioners receiving long-term low-dose radiation (Dentesano et al, 2012; Kumar et al, 2013; Douguet and Honore, 2019; World Health Organization, 2020). 35% of lung and breast cancer patients will develop RIPI after receiving chest radiation therapy (Chen et al, 2019). RIPI was mainly divided into three stages, which are asymptomatic phase (He et al, 2019), radiation-induced pneumonitis (Hanania et al, 2019) and radiation-induced pulmonary fibrosis (Graves et al, 2010; Chen et al, 2019). Finding interventions to delay and reverse the development of RIPI remains a critical issue in current clinical practice

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