成纤维细胞衍生的细胞外囊泡在特发性肺纤维化微环境中诱导肺癌进展
Fibroblast-derived Extracellular Vesicles Induce Lung Cancer Progression in the Idiopathic Pulmonary Fibrosis Microenvironment
影响因子:5.30000
分区:医学2区 / 生化与分子生物学2区 细胞生物学2区 呼吸系统2区
发表日期:2023 Jul
作者:
Yu Fujita, Shota Fujimoto, Atsushi Miyamoto, Reika Kaneko, Tsukasa Kadota, Naoaki Watanabe, Ryusuke Kizawa, Hironori Kawamoto, Junko Watanabe, Hirofumi Utsumi, Hiroshi Wakui, Shunsuke Minagawa, Jun Araya, Takashi Ohtsuka, Takahiro Ochiya, Kazuyoshi Kuwano
摘要
特发性肺纤维化（IPF）是一种与肺癌风险增加有关的进行性衰老相关的肺部疾病。尽管以前的研究表明，IPF会使肺癌患者的存活率恶化，但IPF是否独立影响癌症恶性肿瘤和预后仍然尚无定论。细胞外囊泡（EV）最近成为分子生物标志物的活跃载体，以及肺稳态和发病机理中细胞间通信的介体。 EV货物介导的成纤维细胞肿瘤的通信可能通过调节各种信号通路来参与肺癌的发展和发展。在这项研究中，我们检查了肺成纤维细胞（LF）衍生的EV对IPF微环境中非小细胞肺癌（NSCLC）恶性肿瘤的影响。在这里，我们表明来自IPF患者的LF具有肌纤维细胞分化和细胞衰老的表型。此外，我们发现IPF LF衍生的EV明显改变了MicroRNA组成，并在NSCLC细胞上发挥了定义的功能。从机械上讲，表型主要归因于MiR-19a在IPF LF衍生的EV中的富集。作为下游信号通路，IPF LF衍生的EV中的miR-19a调节NSCLC中ZMYND11介导的C-MYC激活，有可能导致NSCLC患者使用IPF的不良预后。我们的发现提供了理解IPF微环境中肺癌进展的新型机械见解。因此，阻止IPF LF衍生的EV miR-19a的分泌及其信号通路是管理IPF和肺癌进展的潜在治疗策略。
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargo-mediated fibroblast-tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.