细胞外囊泡包装的MIR4435-2HG通过依赖于鸟苷酸酶1的糖酵解重编程促进香烟烟雾诱导的膀胱癌进展

细胞外囊泡包装的MIR4435-2HG通过依赖于鸟苷酸酶1的糖酵解重编程促进香烟烟雾诱导的膀胱癌进展

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

期刊:ACS nano

▲图片由Nano Banana根据摘要描述生成

摘要

流行病学研究报道吸烟促进膀胱癌的进展，但其对应的生物学机制尚需阐明。通过RNA测序、组织微阵列和单细胞RNA测序，鉴定出源自膀胱肿瘤、由吸烟相关致癌物4-氨基联苯（4-ABP）刺激M2巨噬细胞分泌的细胞外囊泡（EV）包装的长链非编码RNA（lncRNA）。在吸烟史膀胱癌患者的尿液和血浆中评估候选EV包装lncRNA的临床价值。采用CRISPR/Cas9、Seahorse分析及N4-乙酰胞苷（ac4C）修饰实验，探讨EV包装lncRNA的潜在机制。结果显示，EV包被的lncRNA MIR4435-2HG在膀胱癌中表现出丰富的表达，其最初由M2巨噬细胞分泌，响应4-ABP的刺激。机制上，4-ABP通过诱导信号转导与转录激活因子6（STAT6）磷酸化，促进M2巨噬细胞极化，并上调融合肿瘤蛋白（FUS）表达，进而促进MIR4435-2HG的直接包装进入M2巨噬细胞来源的EV中，并递送至受体肿瘤细胞。核内EV包装的MIR4435-2HG与N-乙酰转移酶10（NAT10）结合，通过ac4C修饰增强糖酵解调控蛋白烯酶1（ENO1）的稳定性；而细胞质中的EV包被MIR4435-2HG则通过海绵作用阻断miR-143-3p，提升ENO1表达，激活PI3K-Akt信号通路，促进糖酵解重编程，从而推动肿瘤发展。此外，受体肿瘤细胞摄取EV内的MIR4435-2HG，并同时分泌趋化因子以募集单核细胞，形成M2巨噬细胞与肿瘤细胞之间的潜在正反馈环路。本研究确认EV包装的MIR4435-2HG作为膀胱癌的重要标志物，介导吸烟暴露期间的细胞间通讯，为膀胱癌的预防与治疗提供了新的潜在策略。

Abstract

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 ultimately activated PI3K-Akt signaling for glycolytic reprogramming to promote tumor development. In addition, recipient tumor cells internalized EV-packaged MIR4435-2HG and simultaneously secreted chemokines to recruit monocytes, establishing a potential feed-forward loop between M2 macrophages and tumor cells. This study identified EV-packaged MIR4435-2HG as a crucial bladder cancer marker that mediates intercellular communication during cigarette smoke exposure, suggesting a promising approach for bladder cancer prevention and treatment.

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