Open Accessβ-Catenin/Lin28/let-7 regulatory network determines type II alveolar epithelial stem cell differentiation phenotypes following thoracic irradiation
Author(s) -
Xiaozhuan Liu,
Tingting Zhang,
Jianwei Zhou,
Ziting Xiao,
Yanjun Li,
Yuwei Zhang,
Haodi Yue,
Zhitao Li,
Jing Tian
Publication year - 2020
Publication title -
journal of radiation research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.643
H-Index - 60
eISSN - 1349-9157
pISSN - 0449-3060
DOI - 10.1093/jrr/rraa119
Subject(s) - lin28 , downregulation and upregulation , stem cell , biology , microrna , cancer research , phenotype , catenin , cellular differentiation , vimentin , microbiology and biotechnology , pathology , andrology , wnt signaling pathway , immunology , medicine , immunohistochemistry , gene , signal transduction , biochemistry , transcription factor , sox2
The contribution of type II alveolar epithelial stem cells (AEC II) to radiation-induced lung fibrosis (RILF) is largely unknown. Cell differentiation phenotypes are determined by the balance between Lin28 and lethal-7 microRNA (let-7 miRNA). Lin28 is activated by β-catenin. The aim of this study was to track AEC II phenotypes at different phases of injury following thoracic irradiation and examine the expression of β-catenin, Lin28 and let-7 to identify their role in AEC II differentiation. Results showed that coexpression of prosurfactant protein C (proSP-C, an AEC II biomarker) and HOPX (homeobox only protein X, an AEC I biomarker) or vimentin (a differentiation marker) was detected in AEC II post-irradiation. The protein expression levels of HOPX and proSP-C were significantly downregulated, but vimentin was significantly upregulated following irradiation. The expression of E-cadherin, which prevents β-catenin from translocating to the nucleus, was downregulated, and the expression of β-catenin and Lin28 was upregulated after irradiation (P < 0.05 to P < 0.001). Four let-7 miRNA members (a, b, c and d) were upregulated in irradiated lungs (P < 0.05 to P < 0.001), but let-7d was significantly downregulated at 5 and 6 months (P < 0.001). The ratios of Lin28 to four let-7 members were low during the early phase of injury and were slightly higher after 2 months. Intriguingly, the Lin28/let-7d ratio was strikingly increased after 4 months. We concluded that β-catenin contributed to RILF by promoting Lin28 expression, which increased the number of AEC II and the transcription of profibrotic molecules. In this study, the downregulation of let-7d miRNA by Lin28 resulted in the inability of AEC II to differentiate into type I alveolar epithelial cells (AEC I).