BACKGROUND: Cluster of differentiation 8 positive (CD8 + ) T cells play a crucial role in the response against tumors, including hepatocellular carcinoma (HCC), where their dysfunction is commonly observed. While the association between elevated peroxisome proliferator-activated receptor alpha (PPARα) expression in HCC cells and exosomes and unfavorable prognosis in HCC patients is well-established, the underlying biological mechanisms by which PPARα induces CD8 + T cell exhaustion mediated by HCC exosomes remain poorly understood. METHODS: Bioinformatics analyses and dual-luciferase reporter assays were used to investigate the regulation of microRNA-27b-3p ( miR-27b-3p ) and thymocyte selection-associated high mobility group box ( Tox ) by Pparα . In vitro and in vivo experiments were conducted to validate the effects of HCC-derived exosomes, miR-27b-3p overexpression, and Pparα on T cell function. Exosome characterization was confirmed using transmission electron microscopy, Western blotting, and particle size analysis. Exosome tracing was performed using small animal in vivo imaging and confocal microscopy. The expression levels of miR-27b-3p , Pparα , and T cell exhaustion-related molecules ( Tox , Havcr2 , and Pdcd1 ) were detected using quantitative reverse transcription polymerase chain reaction analysis, Western blotting analysis, immunofluorescence staining, and flow cytometry analysis. RESULTS: Pparα expression was significantly increased in HCC and negatively correlated with prognosis. It showed a positive correlation with Tox and a negative correlation with miR-27b-3p . The overexpressed Pparα from HCC cells was delivered to CD8 + T cells via exosomes, which absorbed miR-27b-3p both in vitro and in vivo , acting as "miRNA sponges". Further experiments demonstrated that Pparα can inhibit the negative regulation of Tox mediated by miR-27b-3p through binding to its 3'untranslated regions. CONCLUSIONS HCC-derived exosomes deliver Pparα to T cells and promote CD8 + T cell exhaustion and malignant progression of HCC via the miR-27b-3p /TOX regulatory axis. The mechanisms underlying T-cell exhaustion in HCC can be utilized for the advancement of anticancer therapies.
MicroRNAs/metabolism* ; PPAR alpha/genetics* ; Carcinoma, Hepatocellular/genetics* ; Humans ; Liver Neoplasms/genetics* ; CD8-Positive T-Lymphocytes/immunology* ; Exosomes/metabolism* ; Animals ; Cell Line, Tumor ; Mice ; High Mobility Group Proteins/genetics* ; Male ; T-Cell Exhaustion

Objective To evaluate long-term outcome of simultaneous kissing sirolimus-eluting stent (SKS) technique versus single sirolimus-eluting stent (SSS) technique for percutaneous treatment of true coronary bifurcation lesions in large-size vessels.Methods This randomized study assigned 190 patients with a coronary bifurcation lesion to simultaneous kissing stenting (SKS) in both main and side branches and 190 patients to main vessel stenting only (SSS).The endpoints included restenosis,death,non-fatal myocardial infarction,target-lesion revascularization (TLR),stent thrombosis,success rate of percutaneous coronary intervention (PCI) and the operation duration.Results During 1-year follow-up,the SKS group and the SSS group had similar incidences of overall re stenosis [30 ( 15.8 ％ ) vs.24 ( 15.2 ％ ),x2=0.000,P＜0.05],mainbranch restenosis [20 ( 10.5％ ) vs.16 ( 10.1％ ),x2=0.003,P ＞ 0.05];side-branch restenosis [13 ( 6.8％ )vs.23 ( 14.6％ );x2=4.73,P＜0.05];death [2 ( 1.1％ ) vs.1 ( 0.6％ ),x2=0.026,P ＞ 0.05],non-fatal myocardial infarction [4 (2.1％ ) vs.2 ( 1.3％ ),x2=0.034,P ＞ 0.05],TLR [23 ( 12.1％ ) vs.20 ( 12.7％ ),x2=0.000,P ＞ 0.05] and stent thrombosis [4 (2.1％ ) vs.2 ( 1.3 ％ ),x2=0.034,P ＞ 0.05] and a shorter operation duration[(20 ± 8) min vs.(45 ± 9) min,t=1.98,P＜0.05] than the SSS group.Conclusion For true coronary bifurcation lesions in large-size vessels,SKS and SSS have similar long-term outcomes.The SKS group has a higher success rate of PCI and shorter operation duration.