Critical role of farnesoid X receptor for hepatocellular carcinoma cell proliferation
Critical role of farnesoid X receptor for hepatocellular carcinoma cell proliferation
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DOI：
10.1093/jb/mvs101
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发表时间：
2012-12-01
影响因子：
2.7
通讯作者：
Hayakawa, Makio
中科院分区：
文献类型：
--
作者：
Fujino, Tomofumi;Takeuchi, Airi;Hayakawa, Makio
Farnesoid X受体（FXR）是维持胆汁酸稳态的关键因子，最近被证明是肝脏再生所需的关键因子。阐明FXR调控肝癌细胞增殖的机制，有助于建立肝癌的治疗方法。在这里，我们发现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。相反，FXR激活可降低p16/INK4a的表达，刺激细胞增殖。Ras活性形式的异位表达引起细胞外信号调节激酶（extracellular signal-regulated kinase， ERK）的强烈激活，导致FXR表达减少，提示FXR表达通过Ras/ERK途径受到负调控。在Huh7和HLE中也观察到p16/INK4a表达的升高和FXR敲低对细胞增殖的抑制。在本研究中，我们提出了一种新的肝癌细胞增殖调控机制：FXR通过抑制p16/INK4a表达刺激细胞增殖，而Ras/ERK通路下调FXR表达，导致肝癌细胞系细胞增殖受到抑制。
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.