Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling
Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling
复制标题
昼夜节律调节剂 HLF 的下调通过 PPAR/NF-κ b 信号传导促进非小细胞肺癌的多器官远处转移
DOI：
10.1016/j.canlet.2020.04.007
复制
发表时间：
2020-07-10
期刊：
影响因子：
9.7
通讯作者：
Huang, Yanming
中科院分区：
文献类型：
--
作者：
Chen, Jiarong;Liu, Aibin;Huang, Yanming
非小细胞肺癌（NSCLC）由于其早期复发和广泛的转移潜力，是癌症相关死亡的主要原因。越来越多的研究表明，昼夜节律相关调节因子的失调与NSCLC的复发和转移有关。因此，识别转移相关的昼夜节律基因是临床上必要的。在这里，我们报告的昼夜节律基因肝白血病因子（HLF），这是显着减少，在早期复发的NSCLC组织，是显着相关的早期进展和远处转移的NSCLC患者。在体内，上调HLF抑制，而沉默HLF促进肺定植以及NSCLC细胞向骨、肝和脑的转移。重要的是，HLF的下调表达通过破坏PPAR α和PPAR γ的易位激活NF-κ B/p65信号传导，促进厌氧代谢，以支持NSCLC细胞在低营养条件下的锚定非依赖性生长。进一步的研究发现，基因缺失和甲基化均导致HLF在NSCLC组织中的表达下调。总之，我们的研究结果揭示了HLF抑制NSCLC远处转移的可能机制，表明HLF可能作为NSCLC临床干预的新靶点。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythmsassociated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-kappa B/p65 signaling through disrupting translocation of PPAR alpha and PPAR gamma. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.