TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization

Yinan Shen; Yongpeng Wei; Zhouchong Wang; Yingying Jing; Haiguan He; Jianyong Yuan; Rong Li; Qiudong Zhao; Lixin Wei; Tian Yang; Junhua Lu

doi:10.1159/000373976

TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization

Cell Physiol Biochem. 2015;35(4):1623-32. doi: 10.1159/000373976. Epub 2015 Mar 18.

Authors

Yinan Shen¹, Yongpeng Wei, Zhouchong Wang, Yingying Jing, Haiguan He, Jianyong Yuan, Rong Li, Qiudong Zhao, Lixin Wei, Tian Yang, Junhua Lu

Affiliation

¹ The 5th Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China.

PMID: 25824460
DOI: 10.1159/000373976

Abstract

Background/aims: TGF-β plays a key role in the progression of various tumors. The main objective of our study was to investigate whether TGF-β is able to regulate N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) progression in a mouse model by inducing Treg cell polarization.

Methods: HCC progression, TGF-β and Foxp3 expression levels, serum TGF-β, IL10 and GP73 levels as well as percentage of Treg cells were analyzed in healthy, HCC and HCC+SM-16 mouse groups. The effect of TGF-β on Treg cell polarization in vitro was measured by flow cytometric analysis. The expression of TGF-β and IL10 was identified by IHC in HCC patients and the correlation between TGF-β and IL10 was also assessed.

Results: TGF-β expression is up-regulated in a DEN-induced HCC mouse model. TGF-β can promote the differentiation of Foxp3(+)CD4(+) T cells (Treg cells) in vitro. However, blocking the TGF-β pathway with a specific TGF-β receptor inhibitor, SM-16, reduced HCC progression and the percentage of Treg cells in liver tissue. The correlation between TGF-β and Treg cells was also confirmed in HCC patients and the expression of both TGF-β and IL-10 was shown to be associated with HCC progression.

Conclusion: TGF-β is necessary for HCC progression, acting by inducing Treg cell polarization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azabicyclo Compounds / pharmacology
Carcinoma, Hepatocellular / chemically induced
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Differentiation / drug effects
Cell Polarity / drug effects
Cell Proliferation / drug effects
Diethylnitrosamine / toxicity
Disease Models, Animal
Disease Progression
Enzyme-Linked Immunosorbent Assay
Forkhead Transcription Factors / metabolism
Interleukin-10 / blood
Interleukin-10 / genetics
Interleukin-10 / metabolism
Liver Neoplasms / chemically induced
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
Male
Membrane Proteins / blood
Mice
Phosphoproteins / blood
Receptors, Transforming Growth Factor beta / antagonists & inhibitors
Receptors, Transforming Growth Factor beta / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
Transforming Growth Factor beta / antagonists & inhibitors
Transforming Growth Factor beta / blood
Transforming Growth Factor beta / metabolism*
Up-Regulation / drug effects

Substances

Azabicyclo Compounds
Forkhead Transcription Factors
Foxp3 protein, mouse
GP73 protein, mouse
Membrane Proteins
Phosphoproteins
Receptors, Transforming Growth Factor beta
SM16 compound
Transforming Growth Factor beta
Interleukin-10
Diethylnitrosamine