Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China.
Department of Reproductive Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China.
Cell Death Dis. 2020 Aug 17;11(8):640. doi: 10.1038/s41419-020-02819-w.
Farnesoid X receptor (FXR, encoded by NR1H4), a critical regulator of bile acid homeostasis, is widely implicated in human tumorigenesis. However, the functional role of FXR in colorectal cancer (CRC) and the precise molecular mechanism remain unclear. In this study, we demonstrated that FXR expression was downregulated in colon cancer tissues and decreased expression of FXR predicted a poor prognosis. Knockdown of FXR promoted colon cancer cell growth and invasion in vitro, and facilitated xenograft tumor formation and distant metastasis in vivo, whereas ectopic expression of FXR had the reserved change. Mechanistic studies indicated that FXR exerted its tumor suppressor functions by antagonizing Wnt/β-catenin signaling. Furthermore, we identified an FXR/β-catenin interaction in colon cancer cells. The FXR/β-catenin interaction impaired β-catenin/TCF4 complex formation. In addition, our study suggested a reciprocal relationship between FXR and β-catenin, since loss of β-catenin increased the transcriptional activation of SHP by FXR. Altogether, these data indicated that FXR functions a tumor-suppressor role in CRC by antagonizing Wnt/β-catenin signaling.
法尼醇 X 受体（FXR，由 NR1H4 编码）是胆汁酸动态平衡的关键调节因子，广泛参与人类肿瘤发生。然而，FXR 在结直肠癌（CRC）中的功能作用及其确切的分子机制尚不清楚。在这项研究中，我们证明 FXR 在结肠癌组织中表达下调，且 FXR 表达降低预示着预后不良。体外实验中，FXR 的敲低促进了结肠癌细胞的生长和侵袭，促进了异种移植肿瘤的形成和远处转移，而 FXR 的异位表达则具有保留性的变化。机制研究表明，FXR 通过拮抗 Wnt/β-catenin 信号发挥其肿瘤抑制功能。此外，我们在结肠癌细胞中鉴定到了 FXR/β-catenin 相互作用。FXR/β-catenin 相互作用破坏了 β-catenin/TCF4 复合物的形成。此外，我们的研究还提示了 FXR 和 β-catenin 之间存在相互关系，因为β-catenin 的缺失增加了 FXR 对 SHP 的转录激活。总之，这些数据表明，FXR 通过拮抗 Wnt/β-catenin 信号在 CRC 中发挥肿瘤抑制作用。
