SPP1 induces idiopathic pulmonary fibrosis and NSCLC progression via the PI3K/Akt/mTOR pathway.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-05 DOI:10.1186/s12931-024-02989-7
Bingqing Yue, Dian Xiong, Juan Chen, Xiucheng Yang, Jin Zhao, Jingbo Shao, Dong Wei, Fei Gao, Man Huang, Jingyu Chen
{"title":"SPP1 induces idiopathic pulmonary fibrosis and NSCLC progression via the PI3K/Akt/mTOR pathway.","authors":"Bingqing Yue, Dian Xiong, Juan Chen, Xiucheng Yang, Jin Zhao, Jingbo Shao, Dong Wei, Fei Gao, Man Huang, Jingyu Chen","doi":"10.1186/s12931-024-02989-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.</p><p><strong>Methods: </strong>Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.</p><p><strong>Results: </strong>Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.</p><p><strong>Conclusions: </strong>Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8000,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456247/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12931-024-02989-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

Abstract

Background: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.

Methods: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.

Results: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.

Conclusions: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
SPP1 通过 PI3K/Akt/mTOR 通路诱导特发性肺纤维化和 NSCLC 进展。
背景:在被诊断患有特发性肺纤维化(IPF)的患者中,非小细胞肺癌(NSCLC)的发病率明显升高。分泌磷蛋白1(SPP1)因参与多种生理过程(包括肿瘤发生和器官纤维化)而闻名,但它在特发性肺纤维化和非小细胞肺癌之间的作用却不明确。我们的研究试图阐明 SPP1 在 IPF 发病机制中的功能及其随后对 NSCLC 进展的影响:方法:分析了四个 GEO 数据集中的常见差异基因,并使用 TCGA 数据库分析预后。TIMER数据库分析了免疫浸润。在人类肺组织、IPF成纤维细胞和BLM诱导的小鼠肺纤维化模型中检测了SPP1的表达。结合 SPP1 基因增益和功能缺失、qRT-PCR、Western blot、EdU 和 CCK-8 实验,评估 SPP1 在 IPF 进展中的作用和机制。通过共培养 IPF 成纤维细胞和 NSCLC 细胞,检测了 SPP1 对 NSCLC 的影响:通过生物信息学分析,我们在 IPF 和 NSCLC 患者数据集中观察到 SPP1 的显著过表达,这与 NSCLC 中癌症相关成纤维细胞的免疫浸润增强有关。在 IPF 患者和博莱霉素诱导的小鼠模型的肺组织样本中检测到 SPP1 水平升高,并与α-平滑肌肌动蛋白部分共定位。敲除 SPP1 可抑制 TGF-β1 诱导的成纤维细胞向肌成纤维细胞的分化以及 IPF 成纤维细胞的增殖。相反,SPP1的过表达可通过PI3K/Akt/mTOR途径促进IPF成纤维细胞的增殖。此外,IPF成纤维细胞还能促进NSCLC细胞增殖并激活PI3K/Akt/mTOR通路;IPF成纤维细胞中的SPP1基因敲除可减轻这些影响:我们的研究结果表明,SPP1 是一种同时促进纤维化和肿瘤发生的分子,因此有望成为治疗 IPF 和 NSCLC 并发症的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
期刊最新文献
Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats. Loss of interferon regulatory factor-1 prevents lung fibrosis by upregulation of pon1 expression. Patient-centered care in pulmonary fibrosis: access, anticipate, and act. Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3. Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1