Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14.
Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14.
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肝细胞核因子4α通过靶向基质金属蛋白酶14促进神经母细胞瘤细胞的侵袭、转移和血管生成。
DOI：
10.1016/j.canlet.2015.01.008
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Tong Qiangsong
中科院分区：
文献类型：
--
作者：
Xiang Xuan;Zhao Xiang;Qu Hongxia;Li Dan;Yang Dehua;Pu Jiarui;Mei Hong;Zhao Jihe;Huang Kai;Zheng Liduan;Tong Qiangsong
基质金属蛋白酶14（MMP-14）是唯一的膜锚定的MMP，在肿瘤的发生和侵袭性中起关键作用。然而，MMP-14在神经母细胞瘤（NB）中高表达的调控机制仍不清楚。在此，我们采用综合方法分析公开数据集，并确定肝细胞核因子4 α（hepatocyte nuclear factor 4 alpha，HNF 4 α）是促进NB中MMP-14表达的关键转录因子。在临床NB组织中，HNF 4 α表达上调，与MMP-14表达呈正相关，是影响患者预后的独立预后因素。荧光素酶报告基因和染色质免疫沉淀分析表明HNF 4 α直接靶向MMP-14启动子内的结合位点以促进其转录。HNF 4 α基因的敲低可抑制NB细胞的侵袭、转移和血管生成。相反，HNF 4 α的异位表达促进NB细胞的侵袭、转移和血管生成。重要的是，MMP-14表达的恢复阻止了肿瘤细胞HNF 4 α介导的这些生物学特征的变化。总之，HNF 4 α具有致癌活性，通过激活MMP-14的转录影响NB的侵袭性和血管生成。
Matrix metalloproteinase 14 (MMP-14) is the only membrane-anchored MMP that plays critical roles in tumorigenesis and aggressiveness. However, the regulatory mechanisms underlying the high MMP-14 expression in neuroblastoma (NB), a highly malignant tumor in childhood, still remain unclear. Herein, we applied an integrative approach to analyze the public datasets, and identified hepatocyte nuclear factor 4 alpha (HNF4α) as a crucial transcription factor facilitating the MMP-14 expression in NB. In clinical NB tissues, HNF4α was up-regulated and positively correlated with MMP-14 expression, and was an independent prognostic factor for unfavorable outcome of patients. Luciferase reporter and chromatin immunoprecipitation assays indicated that HNF4α directly targeted the binding site within theMMP-14promoter to facilitate its transcription. Knockdown of HNF4α suppressed the invasion, metastasis and angiogenesis of NB cellsin vitroandin vivo. Conversely, ectopic expression of HNF4α promoted the invasion, metastasis and angiogenesis of NB cells. Importantly, restoration of MMP-14 expression prevented the tumor cells from HNF4α-mediated changes in these biological features. Taken together, HNF4α exhibits oncogenic activity that affects the aggressiveness and angiogenesis of NB through activating the transcription ofMMP-14.
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影响因子：
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作者：
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DOI：
10.1002/hep.24280
发表时间：
2011-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
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