Research Papers:

Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer

Li Ren, Yang Yu, Li Wang, Zhifeng Zhu, Rong Lu and Zhi Yao _

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Oncotarget. 2016; 7:75763-75773. https://doi.org/10.18632/oncotarget.12409

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Li Ren1,2,*, Yang Yu2,*, Li Wang2, Zhifeng Zhu2, Rong Lu2, Zhi Yao2

1Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, P.R. China

2Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, School of Medical Sciences, Tianjin Medical University, Tianjin, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Zhi Yao, email: [email protected]

Keywords: CCL28, Treg, HCC, angiogenesis, HIF1α

Received: July 04, 2016    Accepted: September 21, 2016    Published: October 03, 2016


Tumor cells craft microenvironment to overcome growth disadvantages and adjust to escape the immunosurveillance during tumorigenesis and metastasis. The evolving adaption to the changing microenvironment is exemplified by the development of strategies to deal with hypoxia resulted from fast proliferation of the tumor cells. In this study, we found that hypoxia hepatocellular carcinoma (HCC) cells recruited Regulatory T cells (Tregs) and expressed more Chemokine (C-C motif) ligand 28 (CCL28). Deletion of CCL28 inhibited Treg recruitment. Furthermore, overexpression of CCL28 promoted tumor growth and Treg infiltration in vivo. Enhanced angiogenesis and VEGF expression was also observed. Moreover, inhibition of HIF1α reversed hypoxia-induced CCL28 upregulation. Taken together, our results demonstrate that HCC recruits Tregs to promote angiogenesis under hypoxic condition by upregulating CCL28 expression. These findings establish a link between Tregs and hypoxia in HCC growth and may provide a new potential therapeutic target for treating HCC.

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