Role of TGFβ3-Smads-Sp1 axis in DcR3-mediated immune escape of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of tumour-associated mortality worldwide, but no significant improvement in treating HCC has been reported with currently available systemic therapies. Immunotherapy represents a new frontier in tumour therapy. Therefore, the immunobiology of hepatoc...

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Published in:Oncogenesis (New York, NY) NY), 2019-08, Vol.8 (8), p.43-13, Article 43
Main Authors: Zhu, Hui-fang, Liu, Yan-ping, Liu, Ding-li, Ma, Yi-dan, Hu, Zhi-yan, Wang, Xiao-yan, Gu, Chuan-sha, Zhong, Yan, Long, Ting, Kan, He-ping, Li, Zu-guo
Format: Article
Language:English
Subjects:
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Apoptosis
CD4 antigen
Cell Biology
Cell differentiation
Hepatocellular carcinoma
Human Genetics
Immune evasion
Immunotherapy
Internal Medicine
Liver cancer
Lymphocytes T
Medicine
Medicine & Public Health
Metastases
Metastasis
Oncology
Signal transduction
Smad protein
Tumor necrosis factor
Tumor necrosis factor receptors
Tumorigenesis
Tumors
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Summary:Hepatocellular carcinoma (HCC) is a leading cause of tumour-associated mortality worldwide, but no significant improvement in treating HCC has been reported with currently available systemic therapies. Immunotherapy represents a new frontier in tumour therapy. Therefore, the immunobiology of hepatocarcinoma has been under intensive investigation. Decoy receptor 3 (DcR3), a member of the tumour necrosis factor receptor (TNFR) superfamily, is an immune suppressor associated with tumourigenesis and cancer metastasis. However, little is known about the role of DcR3 in the immunobiology of hepatocarcinoma. In this study, we found that overexpression of DcR3 in HCC is mediated by the TGFβ3-Smad-Sp1 signalling pathway, which directly targets DcR3 promoter regions. Moreover, overexpression of DcR3 in HCC tissues is associated with tumour invasion and metastasis and significantly promotes the differentiation and secretion of Th2 and Treg cells while inhibiting the differentiation and secretion of Th1 cells. Conversely, knockdown of DcR3 expression in HCC significantly restored the immunity of CD4 + T cells. Inhibition of DcR3 expression may provide a novel immunotherapeutic approach to restoring immunity in HCC patients.
ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-019-0152-0