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Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF-beta signal

Authors

  • Quanrongzi Wang MD,

    1. Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    2. Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, China
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  • Tongfu Yu MD,

    1. Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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  • Yifeng Yuan MD,

    1. Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, China
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  • Haiwen Zhuang MD,

    1. Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, China
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  • Zhaojing Wang MD,

    1. Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, China
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  • Xisheng Liu PhD, MD,

    Corresponding author
    1. Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    • Xisheng Liu, Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Fax: +86-25-84625772.===

      Min Feng, Department of General Surgery, Drum Tower Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. Fax: +86-25-84670769.===

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  • Min Feng PhD, MD

    Corresponding author
    1. Department of General Surgery, Drum Tower Affiliated Hospital of Nanjing University Medical School, Nanjing, China
    • Xisheng Liu, Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Fax: +86-25-84625772.===

      Min Feng, Department of General Surgery, Drum Tower Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. Fax: +86-25-84670769.===

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Abstract

Background and Objectives

Sorafenib has been shown to improve survival rate of hepatocellular carcinoma (HCC) patients significantly. Decline of tumor infiltrated regulatory T cells (TITs) may account for the activity of sorafenib partially. In this study, the underlying mechanism of sorafenib reducing TITs was investigated.

Methods

Tumor infiltrated mononuclear cells (TIMs), which were isolated form 19 HCC patients with or without sorafenib therapy, were analyzed by flow cytometry. TGF-β signal pathways were analyzed by immunoblotting. In vitro test, naïve T cells were induced to regulatory T cells (Tregs) with or without sorafenib. After 3 days of culture, percentage of Tregs from CD4+ cells and TGF-β signal pathways were analyzed. Meanwhile, TIMs from HCC patients without sorafenib treatment were cultured in the presence of sorafenib, and then the percentage of Foxp3 expressing cells from TIMs was analyzed.

Results

TITs were increased in HCC patients compared with controls. However, after sorafenib therapy, TITs were decreased significantly and TGF-β signal pathways were down-regulated. Additionally, in the presence of sorafenib, induction of Tregs was inhibited and TGF-β signal pathways in resulting cells were down-regulated. However, sorafenib treatment did not affect the percentage of Foxp3 expressing cells from TIMs in vitro.

Conclusions

Sorafenib reducing TITs in HCC patients are associated with down-regulation of TGF-β signal. This finding may help us for better understanding the activity of sorafenib in HCC patients. J. Surg. Oncol. 2013;107:422–427. © 2012 Wiley Periodicals, Inc.

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