DataVXACS NanoPaper
journal article·2025-12-23

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

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

ACS Nano· Volume 19· Issue 50
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Source abstract

Abstract

High Resolution Image Download MS PowerPoint Slide 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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Research context

OpenAlex topics: Extracellular vesicles in disease · Ferroptosis and cancer prognosis · Cancer-related molecular mechanisms research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Departments of Environmental Genomics and Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Institute of Clinical Research, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine

Nanjing Medical University

Department of Occupational Medicine and Environmental Health, School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province

Department of Urology, Jiangsu Key Laboratory of Urological Disease Prevention and Treatment, The Second Affiliated Hospital of Nanjing Medical University

School of Public Health

Guangxi Medical University

Department of Urology

The Third Affiliated Hospital of Nanjing Medical University (Changzhou Second People’s Hospital)

Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health

Southeast University

The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Second Chinese Medicine Hospital

The First Affiliated Hospital of Nanjing Medical University

Departments of Environmental Genomics and Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health

Department of Biostatistics, Center for Global Health, School of Public Health, and Department of Urology, Jiangsu Key Laboratory of Urological Disease Prevention and Treatment, The Second Affiliated Hospital of Nanjing Medical University

Funding

National Natural Science Foundation of China · Science and Technology Innovation Team (Tianshan Innovation Team) Project of Xinjiang Uighur Autonomous Region · the Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University · the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)

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