Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2.
Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2.
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Intelectin 1 通过上调 N-myc 下游调节基因 2 来抑制神经母细胞瘤细胞的生长、侵袭和转移。
DOI：
10.1186/s12943-015-0320-6
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发表时间：
2015-02-21
期刊：
影响因子：
37.3
通讯作者：
Tong Q
中科院分区：
文献类型：
--
作者：
Li D;Mei H;Pu J;Xiang X;Zhao X;Qu H;Huang K;Zheng L;Tong Q
研究背景近年来的研究表明，intelectin 1（ITLN 1）在肿瘤发生中可能发挥重要作用。然而，它的功能和潜在的机制，在神经母细胞瘤（NB），最常见的颅外实体瘤在childhood，仍然在很大程度上underived.Methodshuman神经母细胞瘤细胞系处理与重组ITLN 1蛋白或稳定转染ITLN 1表达和短发夹RNA载体。Western blot和实时荧光定量RT-PCR检测基因表达和信号通路。荧光素酶报告基因和染色质免疫沉淀法检测基因启动子活性和转录因子结合。采用MTT比色法、集落形成法、划痕法、基质胶侵袭法和裸鼠模型检测肿瘤细胞的生长和侵袭能力。结果公开的基因芯片数据库挖掘显示，NB中N-myc下游调节基因2（NDRG 2）与ITLN 1显著相关。功能获得和丧失研究表明，分泌型ITLN 1促进NDRG 2表达，导致NB细胞系SH-SY 5 Y、SK-N-BE（2）和SK-N-SH中血管内皮生长因子（VEGF）和基质金属蛋白酶9（MMP-9）下调。Krüppel样因子4（KLF 4）是NDRG 2表达的关键转录因子，ITLN 1通过抑制磷酸肌醇3-激酶（PI 3 K）/AKT信号通路上调KLF 4表达。ITLN 1的异位表达在体外和体内均能抑制NB细胞的生长、侵袭和转移。相反，ITLN 1的敲低促进NB细胞的生长、侵袭和转移。此外，在ITLN 1过表达或沉默的NB细胞中的拯救实验表明，NDRG 2表达的恢复防止肿瘤细胞发生ITLN 1介导的这些生物学特征的变化。在临床NB组织中，ITLN 1表达下调，且与NDRG 2表达呈正相关。ITLN 1或NDRG 2高表达的患者有更大的生存probability.ConclusionsThese研究结果表明，ITLN 1功能作为一种肿瘤抑制剂，影响NB的生长，侵袭和转移，通过上调NDRG 2。
BackgroundRecent studies have revealed the potential roles of intelectin 1 (ITLN1) in tumorigenesis. However, its functions and underlying mechanisms in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain largely unknown.MethodsHuman neuroblastoma cell lines were treated with recombinant ITLN1 protein or stably transfected withITLN1expression and short hairpin RNA vectors. Gene expression and signaling pathway were detected by western blot and real-time quantitative RT-PCR. Gene promoter activity and transcription factor binding were detected by luciferase reporter and chromatin immunoprecipitation assays. Growth and aggressiveness of tumor cells were measured by MTT colorimetry, colony formation, scratch assay, matrigel invasion assay, and nude mice model.ResultsMining of public microarray databases revealed that N-myc downstream regulated gene 2 (NDRG2) was significantly correlated with ITLN1 in NB. Gain- and loss-of-function studies indicated that secretory ITLN1 facilitated the NDRG2 expression, resulting in down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9), in NB cell lines SH-SY5Y, SK-N-BE(2), and SK-N-SH. Krüppel-like factor 4 (KLF4), a transcription factor crucial for NDRG2 expression, was up-regulated by ITLN1 in NB cells via inactivation of phosphoinositide 3-kinase (PI3K)/AKT signaling. Ectopic expression ofITLN1suppressed the growth, invasion and metastasis of NB cellsin vitroandin vivo. Conversely, knockdown ofITLN1promoted the growth, invasion, and metastasis of NB cells. In addition, rescue experiments in ITLN1 over-expressed or silenced NB cells showed that restoration of NDRG2 expression prevented the tumor cells from ITLN1-mediated changes in these biological features. In clinical NB tissues, ITLN1 was down-regulated and positively correlated with NDRG2 expression. Patients with high ITLN1 or NDRG2 expression had greater survival probability.ConclusionsThese findings indicate that ITLN1 functions as a tumor suppressor that affects the growth, invasion and metastasis of NB through up-regulation of NDRG2.
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