Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression.
Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression.
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DOI：
10.18632/oncotarget.5428
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Chiba H
中科院分区：
文献类型：
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作者：
Kaneko T;Kanno C;Ichikawa-Tomikawa N;Kashiwagi K;Yaginuma N;Ohkoshi C;Tanaka M;Sugino T;Imura T;Hasegawa H;Chiba H
肝脏X受体（LXRs）不仅有助于维持胆固醇稳态，而且还控制细胞生长。然而，LXR介导的抗增殖作用背后的分子机制在很大程度上是未知的。我们通过免疫组织化学方法发现LXRα和LXRβ在口腔复层鳞状上皮中的分布是不同的。免疫组化和Western blot分析显示，LXRα在人口腔鳞状细胞癌（HOSCC）组织和细胞系中表达丰富。细胞计数、BrdU标记和细胞周期分析表明，LXR刺激导致HOSCC细胞增殖显著降低。重要的是，我们的研究强调，通过使用RNA干扰，ATP结合盒转运蛋白A1（ABCA 1）加速胆固醇流出是至关重要的生长抑制作用的LXR在HOSCC细胞。此外，我们证明，LXR激活减少了小鼠HOSCC细胞异种移植肿瘤的生长，伴随着ABCA 1表达的上调和肿瘤中胆固醇水平的下降。这些发现强烈表明，靶向LXR调节的胆固醇转运，降低细胞内胆固醇水平，可能是某些类型癌症的有希望的治疗选择。
Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRβ are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers.