吸烟通过 PIK3CA 过表达激活 COPD 支气管上皮细胞的 EMT

IF 1 Q4 GENETICS & HEREDITY
Lin Chen , Hui Chen , Hui Zhang , Guang Zhou , Xuejiao Sun
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引用次数: 0

摘要

背景吸烟导致的气道重塑是慢性阻塞性肺疾病(COPD)的重要病理变化,而上皮-间质转化(EMT)是气道重塑的核心机制之一。然而,慢性阻塞性肺病诱导 EMT 的确切分子和途径机制在很大程度上仍不为人所知。以往的大量研究阐明,PIK3CA 的过表达可通过诱导 EMT 促进各类肿瘤的增殖和转移,而抑制 PIK3CA 则可抑制肿瘤的侵袭和增殖。方法从接受肺组织切除术的慢性阻塞性肺疾病吸烟者(9 人)和无慢性阻塞性肺疾病的非吸烟者对照组(9 人)中采集远离肿瘤部位的新鲜肺标本,对肺组织 mRNA 进行深度测序。通过生物信息学研究发现,PIK3CA 和 EMT 通路在慢性阻塞性肺病的发病中起着重要作用。因此,研究人员构建了一个暴露于香烟烟雾(CS)的肺气肿小鼠模型,通过免疫组化和免疫荧光,该模型显示支气管上皮细胞中 PIK3CA 表达和 EMT 激活增加,凋亡增加。在体外,香烟烟雾提取物(CSE)诱导的 BEAS-2B 细胞进一步证实了 PIK3CA 的表达和 EMT 的激活。通过 PIK3CA 基因敲除,证明了 PIK3CA 在 EMT 过程中起着重要作用。结果通过分析 COPD 吸烟者和非 COPD 非吸烟者新鲜肺标本的 mRNA 测序数据,我们发现 EMT 在 COPD 中起着核心作用。通过 GSEA 和 PPI 分析,我们发现 PIK3CA 是慢性阻塞性肺病的关键基因。通过研究已建立的慢性阻塞性肺病小鼠模型和用 CSE 培养的 BEAS-2B 细胞,我们发现暴露于 CS 会增加 PIK3CA 的表达和相关的 EMT 激活。结论香烟烟雾通过上调 PIK3CA 的表达诱导支气管上皮细胞的 EMT。PIK3CA敲除可逆转CSE诱导的EMT。EMT和PIK3CA可能是未来治疗慢性阻塞性肺病的潜在新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Smoking activates EMT in COPD bronchial epithelial cells through PIK3CA overexpression

Background

Airway remodeling caused by smoking is an important pathological change in chronic obstructive pulmonary disease (COPD), and epithelial-mesenchymal transition (EMT) is one of the core mechanisms involved in airway remodeling. However, the exact molecules and pathway mechanisms involved in the induction of EMT in COPD remain largely unknown. Numerous previous studies have elucidated that overexpression of PIK3CA promotes the proliferation and metastasis in various types of tumors by inducing EMT, while inhibition of PIK3CA can inhibit the invasion and proliferation of tumors. However, the relationship between PIK3CA and EMT has not been reported in COPD.

Methods

Fresh pulmonary specimens were collected away from the tumor site from the smoker with COPD (n = 9) and non-smokers without COPD control group (n = 9) who underwent lung tissue resection, and conducted deep sequencing of lung tissue mRNA. It was found that the PIK3CA and EMT pathways play a significant role in the development of COPD using bioinformatics. Therefore a mouse model of emphysema exposed to cigarette smoke(CS) was constructed which demonstrated increased PIK3CA expression and EMT activation in bronchial epithelial cells with increased apoptosis by immunohistochemical and immunofluorescence. In vitro, it was further confirmed the expression of PIK3CA and the activation of EMT by cigarette smoke extract (CSE)-incubated BEAS-2B cells. By PIK3CA knockout, it was proved that PIK3CA plays an important role in the EMT process.

Results

Through the analysis of mRNA sequencing data of fresh pulmonary specimens from smokers with COPD and non-smokers without COPD, we found that EMT plays a core role in COPD. Through analysis of GSEA and PPI, we found that PIK3CA is a key gene in COPD. By studying the established mouse model of COPD and BEAS-2B cells incubated with CSE, we found that CS exposure increased PIK3CA expression and associated EMT activation. CSE can induce EMT in vitro by increasing PIK3CA expression, and knockout PIK3CA can reverse CSE-induced EMT.

Conclusion

Cigarette smoke induces EMT in bronchial epithelial cells by up-regulating PIK3CA expression. PIK3CA knockdown reversed CSE-induced EMT. EMT and PIK3CA may be potential new targets for the treatment of COPD in the future.

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来源期刊
Gene Reports
Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.30
自引率
7.70%
发文量
246
审稿时长
49 days
期刊介绍: Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.
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