School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
J Biochem. 2012 Dec;152(6):577-86. doi: 10.1093/jb/mvs101. Epub 2012 Sep 10.
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.
法尼醇 X 受体（FXR）是维持胆汁酸动态平衡的关键因素，最近研究表明它是肝再生所必需的关键因素。阐明 FXR 如何控制肝癌细胞增殖的机制对于建立肝癌治疗方法是有用的。在这里，我们表明 FXR 在人肝癌细胞系 HepG2、Huh7 和 HLE 的增殖中起着至关重要的作用。用 FXR siRNA 处理 HepG2 可提高 p16/INK4a 的表达水平，从而抑制细胞增殖。相比之下，FXR 的激活降低了 p16/INK4a 的表达并刺激了细胞增殖。导致细胞外信号调节激酶（ERK）强烈激活的 Ras 的异位表达导致 FXR 表达降低，表明 FXR 表达通过 Ras/ERK 途径受到负调控。FXR 敲低导致 p16/INK4a 表达升高和细胞增殖抑制也观察到在 Huh7 和 HLE 中。在这项研究中，我们提出了一种新的机制，即肝癌细胞增殖受到调节：FXR 通过抑制 p16/INK4a 的表达刺激细胞增殖，而 Ras/ERK 途径下调 FXR 的表达，导致肝癌细胞系中的细胞增殖受到抑制。
