昆明医科大学学报2025，Vol.46Issue(5)：65-74,10.DOI:10.12259/j.issn.2095-610X.S20250508
上皮间充质转换关键基因LRP1在矽肺中的作用
Role of the Key Gene LRP1 of Epithelial-mesenchymal Transition in the Progression of Silicosis Fibrosis
摘要
Abstract
Objective To investigate the role of low-density lipoprotein receptor-related protein 1(LRP1),the key gene of epithelial-mesenchymal transition,in silicosis fibrosis progression,and to preliminarily explore its regulatory mechanisms.Methods Gene set variation analysis(GSVA)was employed on GSE70866 and GSE49072 from Gene Expression Omnibus(GEO)database to assess the activity of the epithelial-mesenchymal transition gene set.LRP1 was screened via Venn diagram intersection.A multivariable Cox proportional hazards regression model(adjusted for age and sex)was constructed to validate the independent prognostic value of LRP1.Patients were grouped based on LRP1 expression,and its function mechanisms in pulmonary were explored through differential analysis,enrichment analysis,correlation analysis,and immune infiltration analysis.The silicosis model was established by a single intratracheal injection of 10 mg SiO2 suspension in C57BL/6J mice,with 100 μL of 0.9%saline administered as the control group.Pathological changes were assessed by hematoxylin-eosin staining in lung tissues.EMT model was induced in A549 cells by TGF-β1 at varying time points.LRP1 mRNA levels were measured by qPCR in lung tissues and A549 cells of TGF-β1-induced EMT model.Protein expression of LRP1,E-Cadherin,α-SMA,collagen I,p-PI3K,PI3K,p-mTOR and mTOR were detected by Western blot in lung tissues and A549 cells.Results The epithelial-mesenchymal transition gene set score was significantly higher in patients than in healthy control,with high-score patients showing reduced survival time(P<0.01).Bioinformatics analysis revealed that LRP1 primarily acts through the mTOR signaling pathway.Immune infiltration analysis demonstrated enhanced activities of activated dendritic cells,effector memory CD4+T cells,and Th17/Th2 cells in LRP1 high-expression patients,suggesting its potential regulatory role in adaptive immune responses.Histopathological observation confirmed obvious silica nodule formation in lung tissues of mouse silicosis model.RT-qPCR and Western blot analyses showed that the expression levels of LRP1 mRNA and protein were significantly downregulated in both silicosis mouse lungs and A549 cells(P<0.05).E-cadherin protein expression was downregulated,while α-SMA and collagen I expression were upregulated(P<0.05).Furthermore,the phosphorylation ratios of PI3K(p-PI3K/PI3K)and mTOR(p-mTOR/mTOR)were significantly increased(P<0.05).Conclusion LRP1 downregulation may activate the PI3K/mTOR signaling pathway,promoting the EMT process and fibrosis in silicosis.Targeting LRP1 regulation might become a new therapeutic strategy for silicosis.关键词
矽肺/上皮-间质转化/低密度脂蛋白受体相关蛋白1Key words
Silicosis/Epithelial-mesenchymal transition/Low-density lipoprotein receptor-related protein 1分类
预防医学引用本文复制引用
黄天浩,王渝迪,郝小惠..上皮间充质转换关键基因LRP1在矽肺中的作用[J].昆明医科大学学报,2025,46(5):65-74,10.基金项目
河北省大学生创新创业训练计划项目(X2022116) （X2022116）
河北省自然科学基金(H2024209025) （H2024209025）
