Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Respiratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Sci Rep. 2017 Apr 4;7(1):591. doi: 10.1038/s41598-017-00698-4.
Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation. Mechanistic analysis demonstrated that FXR could directly bind to an inverted repeat-0 sequence in the CCND1 promoter and activate its transcription. Cyclin D1 overexpression rescued NSCLC cells from the delayed G1/S transition and the impaired cell proliferation induced by FXR knockdown. Importantly, a positive correlation between the expression of FXR and cyclin D1 was confirmed in NSCLC samples, and patients with high expression of both FXR and cyclin D1 had the worst prognosis. In summary, our results suggest that FXR has oncogenic potential in NSCLC development, providing mechanistic insights that could be exploited for both prognostic and therapeutic purposes.
法尼醇 X 受体 (FXR) 是一种维持胆汁酸稳态的核受体，已被认为是肠肝组织中的肿瘤抑制因子。然而，它在非小细胞肺癌 (NSCLC) 中的表达和功能作用尚不清楚。我们报告 FXR 在 NSCLC 中显著增加，并且它预测 NSCLC 患者的临床预后不良。在 NSCLC 细胞中敲低 FXR 可抑制体外细胞增殖，阻断裸鼠异种移植生长，并延迟细胞周期的 G1/S 期转变，而 FXR 的异位过表达可促进 NSCLC 细胞增殖。机制分析表明，FXR 可以直接结合 CCND1 启动子中的反向重复 0 序列并激活其转录。细胞周期蛋白 D1 的过表达可挽救 FXR 敲低引起的 G1/S 期转变延迟和细胞增殖受损的 NSCLC 细胞。重要的是，在 NSCLC 样本中证实了 FXR 和细胞周期蛋白 D1 的表达之间存在正相关，并且同时表达 FXR 和细胞周期蛋白 D1 的患者预后最差。总之，我们的研究结果表明，FXR 在 NSCLC 发展中具有致癌潜力，为预后和治疗目的提供了潜在的机制见解。
