Shi Huifang, Wang Peng, Wang Jiaan, Chen Lei, Qin Yan, Lv Jie
Clinical Laboratory, The Rizhao People's Hospital Affiliated to Jining Medical University, Rizhao, Shandong, China.
Clinical Laboratory, Rizhao Center for Disease Control and Prevention, Rizhao, Shandong, China.
Front Immunol. 2024 Nov 29;15:1506561. doi: 10.3389/fimmu.2024.1506561. eCollection 2024.
Lung metastasis has garnered significant attention due to its prevalent occurrence. Pre-metastatic niche (PMN) establishment is a critical prerequisite for the onset of lung metastasis. Emerging evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in the metastatic cascade to the lungs. However, the relationship between lncRNA expression profiles and the formation of PMN remains uncharacterized. This study aims to explore the expression profiles and potential roles of lncRNAs in the context of pre-metastatic lung microenvironment.
RNA sequencing was utilized to elucidate the lncRNA landscape in pre-metastatic lung of murine models. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to infer the prospective functions of the differentially expressed lncRNAs. Among these, lncRNA Gm5144-202 in alveolar macrophages (AMs) was further scrutinized for its role in driving M2 macrophage polarization, facilitating the formation of PMN, and orchestrating the apoptosis, proliferation, and migration of tumor cells .
A total of 232 lncRNAs exhibited differential expression in pre-metastatic murine lungs compared to normal controls, predominantly enriching pathways such as PI3K-Akt signaling, calcium signaling, neuroactive ligand-receptor interaction, and NF-κB signaling. Notably, lncRNA Gm5144-202 exhibited the most pronounced difference, with elevated level in alveolar macrophages (AMs) during the pre-metastatic phase. Silencing of lncRNA Gm5144-202 impeded the polarization of M2-like macrophages, suppressed the expression of factors critical for the formation of the PMN, and inhibited tumor cell invasion.
Our research delineated the lncRNA expression profiles in pre-metastatic pulmonary tissues and identified, for the first time, the pivotal role of lncRNA Gm5144-202 in modulating M2 macrophage polarization and tumor cell invasiveness. Consequently, targeting lncRNA Gm5144-202 holds substantial promise for translational applications aimed at mitigating pulmonary metastasis.
肺转移因其普遍发生而备受关注。转移前生态位（PMN）的建立是肺转移发生的关键前提。新出现的证据表明，长链非编码RNA（lncRNAs）在肺转移级联反应中起关键作用。然而，lncRNA表达谱与PMN形成之间的关系仍未明确。本研究旨在探讨lncRNAs在转移前肺微环境中的表达谱及潜在作用。
利用RNA测序来阐明小鼠模型转移前肺中的lncRNA情况。进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，以推断差异表达lncRNAs的潜在功能。其中，对肺泡巨噬细胞（AMs）中的lncRNA Gm5144 - 202在驱动M2巨噬细胞极化、促进PMN形成以及协调肿瘤细胞凋亡、增殖和迁移方面的作用进行了进一步研究。
与正常对照相比，共有232个lncRNAs在转移前小鼠肺中表现出差异表达，主要富集在PI3K - Akt信号传导、钙信号传导、神经活性配体 - 受体相互作用和NF - κB信号传导等通路。值得注意的是，lncRNA Gm5144 - 202表现出最显著的差异，在转移前期肺泡巨噬细胞（AMs）中水平升高。沉默lncRNA Gm5144 - 202可阻碍M2样巨噬细胞的极化，抑制PMN形成关键因子的表达，并抑制肿瘤细胞侵袭。
我们的研究描绘了转移前肺组织中的lncRNA表达谱，并首次确定了lncRNA Gm5144 - 202在调节M2巨噬细胞极化和肿瘤细胞侵袭性方面的关键作用。因此，靶向lncRNA Gm5144 - 202在旨在减轻肺转移的转化应用中具有巨大潜力。
