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Silencing of Long Non-Coding RNA X Inactive Specific Transcript (Xist) Contributes to Suppression of Bronchopulmonary Dysplasia Induced by Hyperoxia in Newborn Mice via microRNA-101-3p and the transforming growth factor-beta 1 (TGF-β1)/Smad3 Axis

Wenhao Yuan, Xiaoyan Liu, Lingkong Zeng, Hanchu Liu, Baohuan Cai, Yanping Huang, Xuwei Tao, Luxia Mo, Lingxia Zhao, Chunfang Gao

Department of Neonatology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)

Med Sci Monit 2020; 26:e922424

DOI: 10.12659/MSM.922424

Available online: 2020-05-15

Published: 2020-10-18

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly affecting premature infants. Long non-coding RNA (lncRNA) X inactive specific transcript (Xist) is actively involved in pulmonary disease development. The present study explored the potential mechanism of Xist in BPD development.
MATERIAL AND METHODS: First, newborn BPD mouse models were successfully established. lncRNAs and genes with differential expression were identified using microarray analysis. Various injuries and radial alveolar counts of lung tissues of BPD mice were detected by hematoxylin-eosin staining. Functional assays were utilized to detect alterations of superoxide dismutase (SOD), malondialdehyde (MDA), vascular endothelial growth factor, collagen I, alpha-smooth muscle Actin, TGF-ß1, and Smad3. Then, dual-luciferase reporter gene assay and RNA pull-down assay were performed to clarify the targeting relationship between Xist and miR-101-3p and between miR-101-3p and high-mobility group protein B3 (HMGB3).
RESULTS: In BPD mice, radial alveolar counts value and SOD activity declined while MDA level increased. Results of microarray analysis found that Xist and HMGB3 were highly expressed in BPD mice. Next, silenced Xist alleviated lung damage in BPD mice. Xist competitively bound to miR-101-3p to activate HMGB3, and overexpressed miR-101-3p mitigated lung damage in BPD mice. Additionally, silenced Xist downregulated the TGF-ß1/Smad3 axis.
CONCLUSIONS: Our study demonstrated that silencing of Xist suppressed BPD development by binding to miR-101-3p and downregulating HMGB3 and the TGF-b1/Smad3 axis. Our results may provide novel insights for BPD treatment.

Keywords: Bronchopulmonary Dysplasia, HMGB3 Protein, MicroRNAs, RNA, Long Noncoding