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

Abstract

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.

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

“…Early growth response 3 (EGR3), as a novel zinc finger transcription factor, is a newly discovered tumor suppressor gene, which can inhibit the growth of hepatocellular carcinoma, gastric cancer, and other cancer cells by up-regulation of Fas ligand [77]. Zhang et al [78] found that the low levels of EGR3 were significantly discovered in hepatocellular carcinoma tissues and various hepatoma cell lines (PLC/PRF/5, HCC-LM3, Huh7, and HepG2), but could be explored in human normal hepatic cell lines (L02). The experimental results of nude mouse models showed that the expression of FasL in xenograft tumor tissues with high expression of EGR3 was also significantly increased.…”

Silencing of microRNA-210 inhibits the progression of liver cancer and hepatitis B virus-associated liver cancer via targeting EGR3

“…Note worthily, the abnormal expression of EGR3 is also observed in liver cancer. Zhang et al [16] showed that the expression of EGR3 is frequently down-regulated in HCC tissues and cell lines, and the ectopic expression of EGR3 inhibits the proliferation and induce the apoptosis of HCC cells in vitro. In this study, EGR3 was identified as a target of miRNA-210.…”

“…A total of 4046 transcripts containing 5853 sites were predicted. A target gene EGR3 (ENST00000317216.2) was selected due to its anti-tumor role on liver cancer [16].…”

Silencing of microRNA-210 inhibits the progression of liver cancer and Hepatitis B virus-associated liver cancer via targeting EGR3

“…Note worthily, the abnormal expression of EGR3 is also observed in liver cancer. Zhang et al 16 showed that the expression of EGR3 is frequently down-regulated in HCC tissues and cell lines,…”

“…A total of 4046 transcripts containing 5853 sites were predicted. A target gene EGR3 6 (ENST00000317216.2) was selected due to its anti-tumor role on liver cancer 16 .…”