RESUMO
The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor which is abundant in the liver, intestine, and kidney. FXR is a pivotal factor in cholesterol/bile acid homeostasis but is involved in the growth of hepatocellular carcinoma cells. In the present study, we investigated whether FXR is also involved in the growth of renal adenocarcinoma cells. The cell growth of renal adenocarcinoma cell line ACHN was inhibited by FXR knockdown and stimulated by FXR ligand, while that of a normal renal cell-derived cell line, HK-2, was not affected. The carcinoma-specific stimulation of cell growth by FXR was found to arise from down-regulation of p53 and p21/Cip1 mRNA expression. Our study showed that FXR stimulates proliferation of renal adenocarcinoma cells and that FXR knockdown is useful for growth suppression of renal adenocarcinoma without cytotoxicity to normal renal cells.
Assuntos
Adenocarcinoma/patologia , Processos de Crescimento Celular/genética , Transformação Celular Neoplásica/genética , Neoplasias Renais/patologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Adulto , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação para Baixo , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Farnesoid X receptor (FXR), a pivotal factor maintaining bile acid homeostasis, has been recently shown to be a critical factor required for liver regeneration. The elucidation of the mechanism how FXR controls the proliferation of hepatocellular carcinoma cells is useful to establish the therapy for liver cancer. Here, we show that FXR plays a crucial role in the proliferation of human hepatocellular carcinoma cell line, HepG2, Huh7 and HLE. The treatment of HepG2 with FXR siRNA elevates the level of p16/INK4a expression resulting in the inhibition of cell proliferation. By contrast, FXR activation reduces p16/INK4a expression and stimulates the cell proliferation. The ectopic expression of the active form of Ras that causes strong activation of extracellular signal-regulated kinase (ERK) leads to the decrease in FXR expression, suggesting that FXR expression is negatively regulated via Ras/ERK pathway. The elevation of p16/INK4a expression and the inhibition of cell proliferation by FXR knockdown are also observed in Huh7 and HLE. In this study, we have suggested a novel mechanism by which hepatocellular carcinoma cell proliferation is regulated: FXR stimulates cell proliferation by suppressing the p16/INK4a expression, whereas Ras/ERK pathway down-regulates the FXR expression, leading to the suppressed cell proliferation in hepatocellular carcinoma cell lines.