Exosomal lncRNA Mir100hg from lung cancer stem cells activates H3K14 lactylation to enhance metastatic activity in non-stem lung cancer cells

作者：Lei Shi, Bowen Li, Jiyu Tan, Ling Zhu, Sicheng Zhang, Yuhan Zhang, Meng Xiang, Jie Li, Jie Li, Yan Chen, Xue Han, Jiacheng Xie, Yao Tang, H. Rosie Xing, Jingyu Li, Jingyu Li, Jianyu Wang · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03198-0 · 被引用次数：29 · 研究领域：Cancer-related molecular mechanisms research、RNA modifications and cancer、Circular RNAs in diseases

The mean survival of metastatic lung adenocarcinoma is less than 1 year, highlighting the urgent need to understand the mechanisms underlying its high mortality rate. The role of Extracellular vesicles (EVs) in facilitating the interactions between cancer cells and the metastatic microenvironment has garnered increasing attention. Previous studies on the role of EVs in metastasis have been primarily focused on cancer cell-derived EVs in modulating the functions of stromal cells. However, whether cancer stem cells (CSCs) can alter the metastatic properties of non-CSC cells, and whether EV crosstalk can mediate such interaction, have not been demonstrated prior to this report. In the present study, we integrated multi-omics sequencing and public database analysis with experimental validation to demonstrate, for the first time, the exosomal Mir100hg, derived from CSCs, could enhance the metastatic potential of non-CSCs both in vitro and in vivo. Mechanistically, HNRNPF and HNRNPA2B1 directly binds to Mir100hg, facilitating its trafficking via exosomes to non-CSCs. In non-CSCs, Mir100hg upregulates ALDOA expression, subsequently leading to elevated lactate production. Consequently, the increased lactate levels enhance H3K14 lactylation by 2.5-fold and promote the transcription of 169 metastasis-related genes. This cascade of events ultimately results in enhanced ALDOA-driven glycolysis and histone lactylation-mediated metastatic potential of non-CSC lung cancer cells. We have del...