https://orcid.org/0009-0003-1422-227X
Abstract
Hepatocellular carcinoma (HCC) represents a significant global health challenge, with chemoresistance severely limiting treatment efficacy. This study investigates the role of miRNA-425-5p in exosomes in modulating the tumor microenvironment (TME) and contributing to chemoresistance and immune evasion in HCC. Differentially expressed miRNAs were identified using TaqMan low-density array technology in serum samples from XELOX-resistant and -sensitive HCC patients. miRNA-425-5p expression was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Exosomes from HCC cell lines were characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Functional assays, including luciferase reporter assays and flow cytometry, elucidated the mechanisms of miRNA-425-5p. In vivo studies with mouse xenograft models evaluated the impact of miRNA-425-5p on tumor growth and chemosensitivity. miRNA-425-5p was significantly upregulated in the serum of XELOX-resistant HCC patients and correlated with poorer survival outcomes. Exosomes from chemoresistant HCC cells exhibited increased levels of miRNA-425-5p, which, when internalized by CD4+ T cells, promoted regulatory T cell (Treg) expansion by targeting PTEN. In vivo, miRNA-425-5p overexpression enhanced tumor growth and chemoresistance, while its inhibition reduced tumor size and increased chemosensitivity. These findings indicate that miRNA-425-5p in exosomes plays a crucial role in HCC chemoresistance and immune evasion by modulating the TME and promoting Treg expansion through PTEN targeting. miRNA-425-5p serves as a potential biomarker for predicting chemoresistance and a therapeutic target for overcoming drug resistance in HCC.
Accepted manuscripts
