NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.
NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.
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DOI：
10.18632/oncotarget.11583
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发表时间：
2016-09-06
期刊：
影响因子：
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通讯作者：
MacPherson D
中科院分区：
文献类型：
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作者：
Wu N;Jia D;Ibrahim AH;Bachurski CJ;Gronostajski RM;MacPherson D
小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌肿瘤类型，通常在诊断时发生转移。我们对控制SCLC进展和转移的因素了解甚少。NFIB转录因子在SCLC小鼠模型中经常扩增，但缺乏NFIB促进体内SCLC的明确证据。我们报告说，在小鼠模型中，Nfib扩增在肝转移灶中的频率远高于原发性SCLC，表明其在肿瘤进展/转移中的作用。在致敏小鼠模型中Nfib的过表达导致SCLC的加速，表明Nfib作为真正的癌基因发挥作用。抑制多西环素诱导的Rb/p53/TET-Nfib模型衍生的细胞系中的Nfib表达导致细胞凋亡增加和增殖抑制。转录分析显示，Nfib调节轴突导向、粘着斑和细胞外基质-受体相互作用相关基因的表达。这些数据表明，Nfib是SCLC中的有效致癌基因，并且肝转移灶中Nfib扩增相对于原发性SCLC的富集表明Nfib是SCLC转移的候选驱动因素。
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor type that is typically metastatic upon diagnosis. We have a poor understanding of the factors that control SCLC progression and metastasis. TheNFIB transcription factor is frequently amplified in mouse models of SCLC, but clear evidence that NFIB promotes SCLC in vivo is lacking. We report that in mouse models, Nfib amplifications are far more frequent in liver metastases over primary SCLC, suggesting roles in tumor progression/metastasis. Overexpression of Nfib in a sensitized mouse model led to acceleration of SCLC, indicating that Nfib functions as a bona fide oncogene. Suppression of Nfib expression in cell lines derived from the doxycycline-inducible Rb/p53/TET-Nfib model led to increased apoptosis and suppression of proliferation. Transcriptional analysis revealed that Nfib regulates the expression of genes related to axon guidance, focal adhesion and extracellular matrix-receptor interactions. These data indicate that Nfib is a potent oncogene in SCLC, and the enrichment of Nfib amplifications in liver metastases over primary SCLC points to Nfib as a candidate driver of SCLC metastasis.