Role of the Key Gene LRP1 of Epithelial-mesenchymal Transition in the Progression of Silicosis Fibrosis

Tianhao HUANG; Yudi WANG; Xiaohui HAO

doi:10.12259/j.issn.2095-610X.S20250508

Volume 46 Issue 5

May 2025

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Tianhao HUANG, Yudi WANG, Xiaohui HAO. Role of the Key Gene LRP1 of Epithelial-mesenchymal Transition in the Progression of Silicosis Fibrosis[J]. Journal of Kunming Medical University, 2025, 46(5): 65-74. doi: 10.12259/j.issn.2095-610X.S20250508

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Tianhao HUANG, Yudi WANG, Xiaohui HAO. Role of the Key Gene LRP1 of Epithelial-mesenchymal Transition in the Progression of Silicosis Fibrosis[J]. Journal of Kunming Medical University, 2025, 46(5): 65-74. doi: 10.12259/j.issn.2095-610X.S20250508

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Role of the Key Gene LRP1 of Epithelial-mesenchymal Transition in the Progression of Silicosis Fibrosis

doi: 10.12259/j.issn.2095-610X.S20250508

1.
College of Stomatology
2.
School of Public Health，North China University of Science and Technology，Tangshan Hebei 063210
3.
Hebei Key Laboratory of Organ Fibrosis，Tangshan Hebei 063210，China

Received Date: 2025-02-25
Publish Date: 2025-05-30

Abstract

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.
- Silicosis,
- Epithelial-mesenchymal transition,
- Low-density lipoprotein receptor-related protein 1

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References(24)

References

[1]	Hoy R F,Chambers D C. Silica-related diseases in the modern world[J]. Allergy,2020,75(11):2805-2817. doi: 10.1111/all.14202
[2]	毛翎,彭莉君,王焕强,等. 尘肺病治疗中国专家共识(2024年版)[J]. 环境与职业医学,2024,41(1):1-21. doi: 10.11836/JEOM23379
[3]	Wang M,Zhang Z,Liu J,et al. Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis: A multi-omics study with drug exploration[J]. Signal Transduct Target Ther,2022,7(1):157. doi: 10.1038/s41392-022-00959-3
[4]	Dongre A,Weinberg R A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer[J]. Nat Rev Mol Cell Biol,2019,20(2):69-84.
[5]	Hao X,Jin Y,Zhang Y,et al. Inhibition of oncogenic src ameliorates silica-induced pulmonary fibrosis via PI3K/AKT pathway[J]. Int J Mol Sci,2023,24(1):774. doi: 10.3390/ijms24010774
[6]	李欣颖,郝小惠,张劲松,等. LPA在小鼠矽肺模型的表达及其对小鼠肺上皮细胞EMT影响[J]. 安徽医科大学学报,2022,57(5):771-775.
[7]	Tian Y,Xia J,Yang G,et al. A2aR inhibits fibrosis and the EMT process in silicosis by regulating Wnt/β-catenin pathway[J]. Ecotoxicol Environ Saf,2023,249:114410. doi: 10.1016/j.ecoenv.2022.114410
[8]	Zhao W,Wang L,Yang J,et al. Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration[J]. Cell Commun Signal,2023,21(1):56. doi: 10.1186/s12964-023-01040-4
[9]	Yamamoto K,Scilabra S D,Bonelli S,et al. Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1[J]. J Biol Chem,2024,300(8):107521. doi: 10.1016/j.jbc.2024.107521
[10]	Schnieder J,Mamazhakypov A,Birnhuber A,et al. Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-β1 from ECM stores[J]. Matrix Biol,2020,88:69-88. doi: 10.1016/j.matbio.2019.12.001
[11]	Chen C C,Hsu L W,Chen K D,et al. Extracellular calreticulin regulates fibrogenic and immunogenic properties of hepatic stellate cells[J]. Int Immunopharmacol,2025,148:114129. doi: 10.1016/j.intimp.2025.114129
[12]	Zhang J,Hu W,Liu K,et al. Integrated mRNA and microRNA profiling in lung tissue and blood from human silicosis[J]. J Gene Med,2023,25(8):e3518. doi: 10.1002/jgm.3518
[13]	Ye Z,Cheng M,Lian W,et al. GPX4 deficiency-induced ferroptosis drives endometrial epithelial fibrosis in polycystic ovary syndrome[J]. Redox Biol,2025,83:103615. doi: 10.1016/j.redox.2025.103615
[14]	Spottiswoode N,Tsitsiklis A,Chu V T,et al. Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia[J]. Nat Commun,2024,15(1):9339. doi: 10.1038/s41467-024-53566-x
[15]	Wu T,Hu E,Xu S,et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data[J]. Innovation (Camb),2021,2(3):100141.
[16]	Wang J,Tu W,Qiu J,et al. Predicting prognosis and immunotherapeutic response of clear cell renal cell carcinoma[J]. Front Pharmacol,2022,13:984080. doi: 10.3389/fphar.2022.984080
[17]	Phan T H G,Paliogiannis P,Nasrallah G K,et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis[J]. Cell Mol Life Sci,2021,78(5):2031-2057. doi: 10.1007/s00018-020-03693-7
[18]	Prasse A,Binder H,Schupp J C,et al. BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis[J]. Am J Respir Crit Care Med,2019,199(5):622-630. doi: 10.1164/rccm.201712-2551OC
[19]	Lee J,Lee H,Lee H,et al. ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells[J]. Nat Commun,2023,14(1):8463. doi: 10.1038/s41467-023-44319-3
[20]	Chen K,Martens Y A,Meneses A,et al. LRP1 is a neuronal receptor for α-synuclein uptake and spread[J]. Mol Neurodegener,2022,17(1):57. doi: 10.1186/s13024-022-00560-w
[21]	Sizova O,John L S,Ma Q,et al. Multi-faceted role of LRP1 in the immune system[J]. Front Immunol,2023,14:1166189. doi: 10.3389/fimmu.2023.1166189
[22]	Mishra A,Yao X,Saxena A,et al. Low-density lipoprotein receptor-related protein 1 attenuates house dust mite-induced eosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immune responses [J]. J Allergy Clin Immunol,2018,142(4): 1066-1079. e6.
[23]	Actis Dato V,Chiabrando G A. The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism,Glucose Homeostasis and Inflammation[J]. Int J Mol Sci,2018,19(6):1780.
[24]	Guo X,Pan Y,Xiong M,et al. Midkine activation of CD8(+) T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth[J]. Nat Commun,2020,11(1):2177. doi: 10.1038/s41467-020-15770-3

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