纤维母细胞来源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
DOI 原文链接
用sci-hub下载
如无法下载，请从 Sci-Hub 选择可用站点尝试。
影响因子:5.3
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
DOI:
10.1165/rcmb.2022-0253OC
摘要
特发性肺纤维化（IPF）是一种与年龄相关的进行性肺疾病，伴随肺癌风险增加。虽有研究表明IPF会恶化肺癌患者的生存，但IPF是否独立影响癌症恶性程度和预后仍未定论。细胞外囊泡（EV）作为分子生物标志物和细胞间通讯的重要载体，在肺部稳态和发病机制中发挥作用。EV的货物介导的成纤维细胞-肿瘤细胞通信，可能通过调控多种信号通路参与肺癌的发生和发展。本研究评估了肺成纤维细胞（LF）来源的EV在IPF微环境中对非小细胞肺癌（NSCLC）恶性程度的影响。结果显示，IPF患者的LF表现出肌成纤维细胞分化和细胞衰老的表型。此外，IPF LF来源的EV具有显著改变的微RNA组成，并对NSCLC细胞表现出促增殖作用。从机制上看，主要由于IPF LF来源的EV中miR-19a的富集。作为下游信号通路，IPF LF EV中的mir-19a调控ZMYND11介导的c-Myc激活，可能导致伴有IPF的NSCLC患者预后不佳。这些发现为理解IPF微环境中肺癌的进展提供了新机制。相应地，阻断IPF LF来源的EV中miR-19a的分泌及其信号通路，是治疗IPF和肺癌进展的潜在策略。
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.