Tu YJ, Liu YQ, Cai HY, Pan YY, Liu C. Regulatory T cell-derived exosomes regulate β-catenin expression to promote the stem cell-like properties of hepatocellular carcinoma. World J Stem Cells 2026; 18(7): 119892 [DOI: 10.4252/wjsc.119892]
Corresponding Author of This Article
Chang Liu, PhD, Affiliate Associate Professor, Central Laboratory, Central Hospital of Dalian University of Technology, No. 826 Southwest Road, Dalian 116033, Liaoning Province, China. liuch2024@dlut.edu.cn
Research Domain of This Article
Oncology
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research-article
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Tu YJ, Liu YQ, Cai HY, Pan YY, Liu C. Regulatory T cell-derived exosomes regulate β-catenin expression to promote the stem cell-like properties of hepatocellular carcinoma. World J Stem Cells 2026; 18(7): 119892 [DOI: 10.4252/wjsc.119892]
World J Stem Cells. Jul 26, 2026; 18(7): 119892 Published online Jul 26, 2026. doi: 10.4252/wjsc.119892
Regulatory T cell-derived exosomes regulate β-catenin expression to promote the stem cell-like properties of hepatocellular carcinoma
Yi-Jun Tu, Yun-Qi Liu, Hong-Yang Cai, Yan-Yan Pan, Chang Liu
Yi-Jun Tu, Department of Pharmacy, Central Hospital of Dalian University of Technology, Dalian 116033, Liaoning Province, China
Yun-Qi Liu, Hong-Yang Cai, Yan-Yan Pan, Chang Liu, Central Laboratory, Central Hospital of Dalian University of Technology, Dalian 116033, Liaoning Province, China
Author contributions: Tu YJ conducted the experiments and was responsible for data collection and analysis; Liu YQ, Cai HY, and Pan YY assisted with the experimental work; Liu C conceived the study, designed the research, analyzed the data, and wrote and revised the manuscript. All authors have reviewed and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82303572; Department of Science & Technology of Liaoning Province, No. 2024-MS-285; and Hospital Initiated Project of “Liaoning Province Key Specialty”, No. 2023SZ015.
Institutional review board statement: The study was approved by the Ethics Committee of Shenzhen People’s Hospital (Approval No. LL-KY-2020171).
Institutional animal care and use committee statement: All animal experiments were approved by the Laboratory Animal Ethics Committee of Central Hospital of Dalian University of Technology, No. 2023-014-11.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets generated and/or analyzed during the current study are available in the Figshare repository, https://10.6084/m9.figshare.31129933.
Corresponding author: Chang Liu, PhD, Affiliate Associate Professor, Central Laboratory, Central Hospital of Dalian University of Technology, No. 826 Southwest Road, Dalian 116033, Liaoning Province, China. liuch2024@dlut.edu.cn
Received: February 10, 2026 Revised: February 27, 2026 Accepted: April 3, 2026 Published online: July 26, 2026 Processing time: 165 Days and 4.1 Hours
Abstract
BACKGROUND
Regulatory T (Treg) cells have been demonstrated to be associated with poor prognosis in patients with hepatocellular carcinoma (HCC). In our previous research, we showed that Treg cells increase the number of cancer stem cells (CSCs) in HCC by inhibiting forkhead box P3 (FOXP3) and upregulating β-catenin expression.
AIM
To investigate whether the long non-coding RNA (lncRNA) Flicr, present in Treg-derived exosomes, promotes the stem-like properties of HCC.
METHODS
GW4869 was applied during the co-culture of HCC cells with Treg cells or Treg cell-conditioned medium. LncRNA Flicr was manipulated to investigate whether FLICR suppresses FOXP3 and activates β-catenin, thereby promoting an increase in CSCs in HCC. The stem cell-like properties of HCC were evaluated using reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining, fluorescence in situ hybridization, flow cytometry, tumor-sphere formation assays, and in vivo tumorigenicity experiments. Western blot analysis was performed to measure the protein levels of FOXP3, glycogen synthase kinase-3 beta, and β-catenin.
RESULTS
After co-culturing with Treg cells or their conditioned medium, HCC cells exhibited increased expression of CSC-related genes, including octamer-binding transcription factor 4, NANOG, CD133, sex-determining region Y-box 2, myelocytomatosis oncogene, and Kruppel-like factor 4, along with a higher proportion of CSCs, enhanced tumor-sphere formation ability in vitro, and increased tumorigenic potential in vivo. Furthermore, Treg-derived exosomes promoted the stem cell-like traits of HCC cells in a dose-dependent manner. Exposure of HCC cells to Treg-derived exosomes resulted in elevated levels of lncRNA Flicr. Overexpression or knockdown of lncRNA Flicr caused corresponding decreases or increases in FOXP3 levels, which were associated with inverse changes in β-catenin levels, thereby respectively promoting or diminishing the CSC-like characteristics of HCC cells.
CONCLUSION
These findings demonstrated that lncRNA Flicr was present in Treg-derived exosomes, leading to the inhibition of FOXP3, activation of β-catenin, and the subsequent promotion of stem-like characteristics in HCC cells.
Core Tip: In our previous study, we demonstrated that regulatory T (Treg) cells increase the population of tumor-initiating cells in hepatocellular carcinoma by suppressing forkhead box P3 and enhancing β-catenin expression. However, it remained unclear whether Treg cells exert these effects through exosomes and which specific components within Treg-derived exosomes are responsible. In this study, we revealed that exosomal long non-coding RNA Flicr, derived from Treg cells, suppresses forkhead box P3 and glycogen synthase kinase-3 beta expression and activates the Wnt/β-catenin signaling pathway, thereby promoting stem cell-like properties in hepatocellular carcinoma cells.
