Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1−0.5 μM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.

最近的研究表明，肝 X 受体 (LXR) 激动剂在包括肝细胞癌 (HCC) 在内的多种肿瘤细胞系中发挥显着的抗肿瘤作用。但 LXR 抗肿瘤活性的分子机制尚不完全清楚。在这项研究中，我们研究了 LXR 激动剂 T0901317 (T317) 对 HCC 发展的影响及其与 RalA 结合蛋白 1 (RALBP1) 相关的 EPS 结构域包含 2 (REPS2)/表皮生长因子受体 (EGFR) 信号轴的关系。我们发现 T317 (0.1–0.5 μM) 剂量依赖性地增加正常肝细胞（BNLCL.2 和 LO2）和 HCC 细胞（HepG2 和 Huh-7）中的 REPS2 表达。使用启动子活性测定和染色质免疫沉淀 (CHIP) 测定，我们证明 T317 通过促进 LXR 蛋白与 REPS2 启动子区域中的 LXR 反应元件 (LXRE) 的结合，增强了转录水平的 REPS2 表达。我们发现T317对HCC细胞增殖和迁移的抑制作用与REPS2密切相关。此外，我们发现 T317 (400 nM) 可增加 HepG2 细胞中 REPS2 的表达，从而抑制表皮生长因子 (EGF) 介导的 EGFR 内吞作用以及 AKT/NF-κB、p38MAPK 和 ERK1/2 的下游激活信号通路。临床数据分析显示，REPS2 表达水平与 HCC 的发展呈负相关，REPS2 表达降低与预后不良相关，表明 REPS2 可能参与 HCC 的发展。总之，本研究为 LXR 激动剂抑制 HCC 的潜在机制提供了新的见解。