Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand

Zhang,Shujuan; Xia,Chao; Xu,Cong; Liu,Jing; Zhu,Han; Yang,Ya; Xu,Fei; Zhao,Juanfeng; Chang,Ying; Zhao,Qiu

doi:10.3892/ijo.2017.3855

Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand

Authors:
- Shujuan Zhang
- Chao Xia
- Cong Xu
- Jing Liu
- Han Zhu
- Ya Yang
- Fei Xu
- Juanfeng Zhao
- Ying Chang
- Qiu Zhao
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Affiliations: Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: January 18, 2017 https://doi.org/10.3892/ijo.2017.3855
Pages: 805-814

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Abstract

Hepatocellular carcinoma (HCC) is a prevalent malignancy with aggressive biological behavior and poor prognosis. Early growth response 3 (EGR3) is a zinc finger transcription factor, and has been studied primarily in the context of neurodevelopment, autoimmunity, inflammation and angiogenesis. Accumulating evidence indicates that EGR3 is a novel suppressor gene of tumor initiation and progression in certain cancer events, but little work has been carried out in exploring the relationship between EGR3 and HCC growth. The purpose of this study was to investigate the possible effects of EGR3 on cell proliferation and apoptosis in HCC, and determine the underlying mechanisms. Here, we observed that EGR3 expression was frequently downregulated in HCC tissues and cell lines. Ectopic expression of EGR3 contributed to cell proliferation inhibition and apoptosis induction in HCC cells in vitro. Furthermore, the expression of Fas ligand (FasL) was significantly enhanced following upregulation of EGR3 in HCC cells, accompanied by an obvious increase of pro-apoptotic Bak and cell cycle inhibitor p21 expression. Based on nude mouse models, we demonstrated that ectopic expression of EGR3 markedly restricted tumor growth, and the expression of FasL was significantly increased in the xenograft tumor tissues which exhibited high EGR3 expression. We further established a co-transfection in HCC cells with EGR3 overexpression plasmid and FasL siRNA. We found that silencing of FasL gene impeded the anti-proliferative and pro-apoptotic effects, as well as the increase of Bak and p21 expression, suggesting an essential role of FasL in EGR3-mediated growth suppression in HCC cells. Collectively, in conclusion, EGR3 contributes to cell growth inhibition via upregulation of FasL in HCC.

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