Extracellular Vesicle-Packaged MIR4435-2HG Facilitates Cigarette Smoke-Induced Bladder Cancer Progression through...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cigarette smoking is a known risk factor for bladder cancer, but the underlying biological mechanisms remain unclear.
• Extracellular vesicles (EVs) and long noncoding RNAs (lncRNAs) are implicated in intercellular communication and cancer progression.

Purpose of the Study:

• To elucidate the biological mechanisms by which cigarette smoking promotes bladder cancer progression.
• To identify and characterize EV-packaged lncRNAs involved in bladder cancer development due to smoking.
• To explore the clinical value and mechanistic role of candidate lncRNAs.

Main Methods:

• RNA sequencing, tissue microarrays, and single-cell RNA sequencing to identify lncRNAs.
• CRISPR/Cas9, Seahorse assays, and N4-acetylcytidine (ac4C) acetylation experiments for mechanistic studies.
• Analysis of urine and plasma samples from bladder cancer patients with a smoking history.

Main Results:

• The EV-packaged lncRNA MIR4435-2HG, secreted by M2 macrophages upon exposure to 4-aminobiphenyl (4-ABP), was identified.
• 4-ABP induced M2 macrophage polarization and STAT6 phosphorylation, leading to FUS expression and MIR4435-2HG packaging into EVs.
• MIR4435-2HG, delivered via EVs, reprogrammed recipient tumor cells by modulating glycolysis (ENO1) through ac4C modification and miR-143-3p sponging, activating PI3K-Akt signaling.
• A feed-forward loop was established where tumor cells recruit monocytes, promoting M2 macrophage polarization.

Conclusions:

• EV-packaged MIR4435-2HG is a key mediator of intercellular communication in smoking-associated bladder cancer.
• MIR4435-2HG plays a critical role in promoting bladder tumor development through glycolytic reprogramming.
• MIR4435-2HG serves as a potential diagnostic marker and therapeutic target for bladder cancer in smokers.