Extracellular Vesicle-Packaged MIR4435-2HG Facilitates Cigarette Smoke-Induced Bladder Cancer Progression through Enolase 1-Dependent Glycolytic Reprogramming

作者：Rui Zheng, Yanping Xiao, Jialei Yang, Zhenguang Mao, Zhiwei Tan, Chengcheng Wei, Fang Gao, Jiajin Wu, Yang Shen, Zhengkai Huang, Meilin Wang, Mulong Du, Zhengdong Zhang · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.4c15108 · 被引用次数：3 · 研究领域：Extracellular vesicles in disease、Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research

Epidemiological studies have reported that cigarette smoking promotes bladder cancer progression, but the corresponding biological mechanisms must be elucidated. Cigarette smoking-related extracellular vesicle (EV)-packaged long noncoding RNAs (lncRNAs) derived from bladder tumors were identified via RNA sequencing, tissue microarrays, and single-cell RNA sequencing. The clinical value of candidate EV-packaged lncRNAs was evaluated in the urine and plasma of bladder cancer patients with smoking history. The underlying mechanism of EV-packaged lncRNAs was explored using CRISPR/Cas9, Seahorse, and N4-acetylcytidine (ac4C) acetylation experiments in vivo and in vitro . The EV-packaged lncRNA MIR4435-2HG, which was originally secreted by M2 macrophages in response to exposure to the cigarette smoking-related carcinogen 4-aminobiphenyl (4-ABP), exhibited an abundant expression pattern. Mechanistically, 4-ABP promoted M2 macrophage polarization and increased fused in sarcoma (FUS) expression by inducing signal transducer and activator of transcription 6 (STAT6) phosphorylation, contributing to the direct packaging of MIR4435-2HG into M2 macrophage-derived EVs and subsequent delivery to recipient tumor cells. The nuclear EV-packaged MIR4435-2HG subsequently bound N -acetyltransferase 10 (NAT10) and increased the stability of the glycolysis regulator Enolase 1 (ENO1) through the ac4C modification; cytoplasmic EV-packaged MIR4435-2HG sponged miR-143-3p, increased ENO1 expression, and ...