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首页> 外文期刊>Life sciences >The MIR155 host gene/microRNA-627/HMGB1/NF-kappa B loop modulates fibroblast proliferation and extracellular matrix deposition
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The MIR155 host gene/microRNA-627/HMGB1/NF-kappa B loop modulates fibroblast proliferation and extracellular matrix deposition

机译：miR155宿主基因/ microRNA-627 / HMGB1 / NF-Kappa B Loop调节成纤维细胞增殖和细胞外基质沉积

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摘要

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-kappa B) axis modulates transforming growth factor beta 1 (TGF beta 1)-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 TGF beta 1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGF beta 1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGF beta 1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGF beta 1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-kappa B activation; in NHLFs, NF-kappa B 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-kappa B axis formed a regulatory loop that modulates TGF beta 1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-kappa B/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.
机译：以基质形成过多为特征的肺纤维化（PF）最终可能导致不可逆转的肺损伤，从而导致死亡。成纤维细胞活化被认为是PF发病过程中的中心事件。在我们之前的研究中，我们证实miR-627/高迁移率族盒蛋白1（HMGB1）/核因子-κ-β（NF-κB）轴调节转化生长因子-β1（TGF-β1）诱导的肺纤维化。在本研究中，我们研究了肺成纤维细胞激活和PF过程中导致miR-627失调的上游因素。在肺纤维化组织和TGFβ1刺激的正常人原发性肺成纤维细胞（NHLFs）中发现lncRNA MIR155宿主基因（MIR155HG）异常上调。通过直接结合miR-627，MIR155HG抑制了miR-627的表达。MIR155HG过表达增强了TGF-β1诱导的HMGB1蛋白表达和p65磷酸化、NHLF增殖和细胞外基质（ECM）沉积的增加。相反，miR-627的过度表达减弱了TGFβ1诱导的NHLFs变化，并显著逆转了miR-155Hg过度表达的影响。在TGF-β1刺激下，miR-627抑制作用增强，而JSH-23治疗抑制NF-κB激活；在NHLFs中，NF-κB过度表达上调，而JSH-23治疗下调MIR155HG表达。在组织样本中，HMGB1蛋白水平和p65磷酸化增加；MIR155HG与miR-627呈负相关，与HMGB1呈正相关。总之，我们验证了MIR155HG/miR-627/HMGB1/NF-κB轴形成了调节TGF-β1诱导的NHLF激活的调节环。考虑到NHLF激活在PF发病机制中的关键作用，NF-κB/MIR155HG/miR-627/HMGB1调节环可能在PF发病机制中发挥重要作用。需要进一步的体内和临床研究来确认该模型。

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