Institute of Life Sciences, Jiangsu University, Zhenjiang, China.
The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China.
J Cell Mol Med. 2019 Feb;23(2):789-797. doi: 10.1111/jcmm.13974. Epub 2018 Oct 19.
Liver X receptors (LXRs) are involved in various diseases associated with lipid disorders, and in regulating cancer cell proliferation. However, the underlying molecular mechanisms, especially those in gastric cancer (GC) remain to be clarified. In this study, immunohistochemistry analysis revealed that LXRβ was mainly expressed in GC tissue, with less expression in adjacent normal tissues. The LXRβ agonist T0901317 efficiently suppressed the proliferation and colony formation of various GC cell lines. We further showed that LXRβ translocated from the cytoplasm to the nucleus when activated by T0901317. LXRβ nuclear localization suppressed the activation of Wnt signalling and decreased the expression of target genes such as MYC, BMP4, and MMP7 through binding to their promoters. Moreover, we demonstrated that the LXR agonist efficiently suppressed GC tumour growth in a nude mouse xenograft model. Taken together, these results revealed that LXRβ agonist inhibited GC cells proliferation by suppressing Wnt signalling via LXRβ relocalization. The results strongly suggest that LXRβ could be a promising target in GC therapy.
肝 X 受体 (LXRs) 参与与脂质紊乱相关的各种疾病，并调节癌细胞增殖。然而，其潜在的分子机制，特别是在胃癌 (GC) 中的机制仍有待阐明。在这项研究中，免疫组织化学分析显示 LXRβ 主要在 GC 组织中表达，在相邻的正常组织中表达较少。LXRβ 激动剂 T0901317 有效地抑制了各种 GC 细胞系的增殖和集落形成。我们进一步表明，当被 T0901317 激活时，LXRβ 从细胞质转位到细胞核。LXRβ 的核定位通过与启动子结合抑制 Wnt 信号的激活，并降低靶基因如 MYC、BMP4 和 MMP7 的表达。此外，我们证明 LXR 激动剂在裸鼠异种移植模型中有效地抑制了 GC 肿瘤的生长。总之，这些结果表明 LXRβ 激动剂通过 LXRβ 重定位抑制 Wnt 信号抑制 GC 细胞增殖。这些结果强烈表明 LXRβ 可能成为 GC 治疗的一个有前途的靶点。
