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Pulmonary fibrosis (PF), which is characterized by excessive matrix formation, may ultimately lead to irreversible lung damage and thus death. Fibroblast activation has been regarded as a central event during PF pathogenesis. In our previous study, we confirmed that the miR-627/high-mobility group box protein 1 (HMGB1)/Nuclear factor kappa beta (NF-κB) axis modulates transforming growth factor beta 1 (TGFβ1)-induced pulmonary fibrosis. In the present study, we investigated the upstream factors leading to miR-627 dysregulation in the process of pulmonary fibroblast activation and PF. The lncRNA MIR155 host gene (MIR155HG) was found to be abnormally upregulated in pulmonary fibrosis tissues and TGFβ1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGFβ1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGFβ1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGFβ1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-κB activation; in NHLFs, NF-κB overexpression upregulated, whereas JSH-23 treatment downregulated MIR155HG expression. In tissue samples, HMGB1 protein levels and p65 phosphorylation were increased; MIR155HG was negatively correlated with miR-627 and positively correlated with HMGB1. In conclusion, we validated that the MIR155HG/miR-627/HMGB1/NF-κB axis formed a regulatory loop that modulates TGFβ1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-κB/MIR155HG/miR-627/HMGB1 regulatory loop could exert a vital effect on PF pathogenesis. Further in vivo and clinical investigations are required to confirm this model. Copyright © 2021. Published by Elsevier Inc.


Jie Li, Xueyu Zhang, Tao Wang, Jinghong Li, Qi Su, Cheng Zhong, Zhongshu Chen, Ying Liang. The MIR155 host gene/microRNA-627/HMGB1/NF-κB loop modulates fibroblast proliferation and extracellular matrix deposition. Life sciences. 2021 Mar 15;269:119085

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PMID: 33482190

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