Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1.
Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1.
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Farnesoid X受体是非小细胞肺癌中的一种新型原癌基因，通过直接反式激活CCND1促进肿瘤生长
DOI：
10.1038/s41598-017-00698-4
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发表时间：
2017-04-04
影响因子：
4.6
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
You W;Chen B;Liu X;Xue S;Qin H;Jiang H
法尼醇X受体(FXR)是一种维持胆汁酸稳态的核受体，在肝组织中被认为是一种肿瘤抑制因子。然而，其在非小细胞肺癌(NSCLC)中的表达和功能仍不清楚。我们报告，FXR在非小细胞肺癌患者中显著增加，并预测非小细胞肺癌患者的临床结局较差。FXR基因敲除抑制了非小细胞肺癌细胞的体外增殖，抑制了裸鼠移植瘤的生长，延缓了细胞周期的G1/S转变，而异位过表达FXR则促进了NSCLC细胞的增殖。机制分析表明，FXR可以直接与CCND1启动子中的反向重复序列0结合并激活其转录。Cyclin D1过表达可使非小细胞肺癌细胞免于延迟的G1/S转变和FXR基因敲除所致的细胞增殖受阻。重要的是，FXR和细胞周期蛋白D1在NSCLC中的表达呈正相关，且FXR和细胞周期蛋白D1同时高表达的患者预后最差。总之，我们的结果表明，FXR在非小细胞肺癌的发展中具有致癌潜力，提供了可以用于预后和治疗目的的机制洞察力。
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.