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Extracellular Vesicle-Mediated Regulation of H3C14 Contributes to Gemcitabine Resistance in Bladder Cancer

Cheng-Shuo Huang1,2,3,4,5,6, Dah-Shyong Yu1,6, Shih Sheng Jiang1,4

  • 1Graduate Institute of Life Sciences, College of Biomedical Sciences, National Defense Medical University, Taipei, Taiwan.

Journal of Extracellular Vesicles
|October 29, 2025
PubMed

Insights

Extracellular vesicles (EVs) transfer gemcitabine (GCB) resistance in bladder cancer via H3.2/H3C14. Targeting EV pathways may overcome GCB resistance, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Extracellular vesicles (EVs) mediate intercellular communication in the tumor microenvironment.
  • EVs play a significant role in the development of drug resistance in various cancers.
  • Gemcitabine (GCB) resistance is a major challenge in bladder cancer treatment.

Purpose of the Study:

  • Investigate mechanisms of GCB resistance in bladder cancer.
  • Identify key molecules and pathways involved in EV-mediated drug resistance.
  • Explore potential therapeutic targets for overcoming GCB resistance.

Main Methods:

  • Comparative analysis of GCB-resistant and sensitive bladder cancer cells.
  • Characterization of EV subpopulations using proteomic and transcriptomic analyses.
  • Investigation of histone H3.2 and its transcript H3C14 roles in GCB resistance.
  • Assessment of Rab27A-mediated EV biogenesis and secretion.

Main Results:

  • GCB-resistant cells show altered nucleoside metabolism and specific EV profiles.
  • EVs from resistant cells transfer GCB resistance by modulating recipient cell nucleoside metabolism.
  • Histone H3.2 and H3C14 are identified as key regulators of GCB resistance transmission.
  • Rab27A mediates EV release and H3C14 excretion in resistant cells.
  • A distinct EV subpopulation (Excretion EVs) eliminates resistance-associated proteins without transferring resistance.

Conclusions:

  • EV-mediated transfer of H3.2/H3C14 is a critical mechanism in bladder cancer GCB resistance.
  • Targeting EV pathways, particularly H3C14 excretion, presents a promising therapeutic strategy.
  • Understanding EV subpopulations aids in developing novel approaches to overcome drug resistance.
Keywords:
extracellular vesiclesgemcitabine resistancehistone proteintumour microenvironment

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