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CD4+ CD25+ regulatory T cells promote hepatocellular carcinoma invasion via TGF-β1-induced epithelial–mesenchymal transition

Authors Shi C, Chen Y, Chen Y, Yang Y, Bing W, Qi J

Received 27 April 2018

Accepted for publication 18 September 2018

Published 28 December 2018 Volume 2019:12 Pages 279—289

DOI https://doi.org/10.2147/OTT.S172417

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 4

Editor who approved publication: Dr William Cho


Chunying Shi,1 Ying Chen,1 Yaodong Chen,1 Yuchuan Yang,1 Wang Bing,1 Jiping Qi2

1Department of Radiology, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, China; 2Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin 150001, China

Background: CD4+ CD25+ regulatory T cells (Tregs), a crucial component of the infiltration of immune cells in tumor microenvironment, are associated with progression and metastasis of hepatocellular carcinoma (HCC).
Methods: The mechanism of Tregs in the invasion and metastasis of HCC was investigated in vivo and in vitro using immunohistochemical analysis, western blot, and quantitative reverse transcription-PCR (qRT-PCR).
Results: Analysis of 78 clinical HCC samples indicated that high expression of Tregs was strongly associated with poor cancer-free survival and overall survival of patients. The reduced expression of E-cadherin and enhanced expression of Vimentin and transforming growth factor-beta 1 (TGF-β1) were found in HCC tissue compared with normal liver tissue. The HCC Hepa1-6 cells were treated with the supernatant of Tregs-conditioned medium (Tregs-CM) to investigate the epithelial-mesenchymal transition (EMT) and TGF-β1. Western blot and qRT-PCR also showed that down-regulated E-cadherin and up-regulated Vimentin and TGF-β1 were found in Tregs-CM-treated Hepa1-6 cells. An experiment of tumorigenicity in C57 mice showed larger and heavier tumors in Tregs-CM-treated group than in the control group. Tregs produced higher TGF-β1 compared with Tregs treated with FOXP3 shRNA. TGF-β1 with neutralizing antibodies was used to deplete TGF-β1 in Tregs-CM, which enhanced expression of E-cadherin, reduced expression of Vimentin and TGF-β1, and decreased migratory and invasive capacity of Hepa1-6 cells.
Conclusion: Tregs could promote the invasion and migration of Hepa1-6 cells, which are possibly maintained by TGF-β1-induced EMT. This study showed that the development of therapeutic strategies against TGF-β1 pathway is valuable in HCC therapy.

Keywords: hepatocellular carcinoma, CD4+ CD25+ regulatory T cells, epithelial to mesenchymal transition, TGF-β1

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