Regulatory T cells inhibit FoxP3 to increase the population of tumor initiating cells in hepatocellular carcinoma

Author:

Liu Chang,Tu Yi-jun,Cai Hong-Yang,Pan Yan-yan,Wu Yuan-yuan,Zhang Li

Abstract

Abstract Purpose Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC ‘stemness’ is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. Methods Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC ‘stemness’. Additionally, after forced expression or inhibition of FoxP3, β-catenin expression and HCC ‘stemness’ were investigated. Results Tregs enhanced the ‘stemness’ of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, β-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC ‘stemness’ was inhibited after treatment with Wnt/β-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3β, decreased β-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3β, enhanced β-catenin and TIC ratio of HCC. Conclusion This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting β-catenin expression.

Funder

National Natural Science Foundation of China

Dalian Science and Technology Bureau

Publisher

Springer Science and Business Media LLC

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. A quartet of cancer stem cell niches in hepatocellular carcinoma;Cytokine & Growth Factor Reviews;2024-10

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