Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high rate of mortality. Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA in human HCC, plays important roles in promoting the growth and metastasis of HCC cells. So downregulating HULC will be benefit to HCC treatment. The nuclear receptor LXR (liver X receptor), consist of α and β isoforms, exerts significant anti-HCC effects, but the corresponding mechanisms are not well known, especially, it's unclear whether LXR is involved in the regulation of HULC. In this study, we found that LXR inhibited HCC cell growth by downregulating HULC, and LXRα (but not LXRβ) caused HULC downregulation. Luciferase reporter assays showed that LXR suppressed transcriptional activity of HULC gene promoter, and chromatin immunoprecipitation assays revealed that LXRα (but not LXRβ) bound to HULC promoter region. Furthermore, LXR increased miR-134-5p while decreased FOXM1 by reducing HULC. Additionally, HULC upregulated FOXM1 via sequestrating miR-134-5p, and miR-134-5p downregulated FOXM1 by targeting 3′-UTR of its mRNA. The in vivo experiments showed that LXR repressed the growth of HCC xenografts, and decreased HULC and FOXM1 while increased miR-134-5p in the xenografts. In summary, these findings for the first time demonstrate that LXR inhibits HCC cell growth by modulating HULC/miR-134-5p/FOXM1 axis, suggesting that the pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a novel target for HCC treatment.

肝细胞癌（HCC）是最常见的恶性肿瘤之一，死亡率很高。在肝癌 (HULC) 中高度上调，人 HCC 中特异表达的长链非编码 RNA，在促进 HCC 细胞的生长和转移中起重要作用。因此下调 HULC 将有利于 HCC 的治疗。核受体LXR（肝X受体）由α和β亚型组成，具有显着的抗HCC作用，但相应的机制尚不清楚，尤其是LXR是否参与HULC的调控尚不清楚。在这项研究中，我们发现 LXR 通过下调 HULC 抑制 HCC 细胞生长，而 LXRα（但不是 LXRβ）导致 HULC 下调。荧光素酶报告基因检测表明 LXR 抑制了HULC 的转录活性基因启动子和染色质免疫沉淀分析显示 LXRα（但不是 LXRβ）与HULC启动子区域结合。此外，LXR 通过减少 HULC 增加 miR-134-5p，同时减少 FOXM1。此外，HULC 通过隔离 miR-134-5p 上调 FOXM1，而 miR-134-5p 通过靶向其 mRNA 的 3'-UTR 下调 FOXM1。体内实验表明，LXR 抑制 HCC 异种移植物的生长，降低 HULC 和 FOXM1，同时增加异种移植物中的 miR-134-5p。总之，这些发现首次证明LXR通过调节HULC/miR-134-5p/FOXM1轴抑制HCC细胞生长，表明LXR/HULC/miR-134-5p/FOXM1通路可能作为一个新的靶点用于 HCC 治疗。