Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-κB-dependent activation of snail and epithelial mesenchymal transition.
Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-κB-dependent activation of snail and epithelial mesenchymal transition.
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DOI：
10.1186/s12943-016-0564-9
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发表时间：
2016-12-03
期刊：
影响因子：
37.3
通讯作者：
Lai M
中科院分区：
文献类型：
--
作者：
Feng M;Feng J;Chen W;Wang W;Wu X;Zhang J;Xu F;Lai M
Lipocalin2(Lcn2)是一种分泌型蛋白，在多种类型的癌症中异常表达，参与了肿瘤的转移过程。然而，Lcn2在结直肠癌转移中的作用和机制尚不清楚。采用免疫组织化学方法检测400例结直肠癌组织中Lcn2的表达，并进行Kaplan-Meier生存分析。采用实时定量聚合酶链式反应、免疫印迹、克隆形成实验、免疫荧光实验、伤口愈合实验、迁移和侵袭实验分别观察Lcn2在上皮细胞间充质转化、迁移和侵袭过程中的作用。采用小鼠体内移植和转移模型检测成瘤能力和转移能力，免疫组织化学、实时荧光定量聚合酶链式反应、免疫印迹检测相关蛋白的表达。用荧光素酶报告基因检测LCN2在NF-ĸB启动子上的作用。LCN2在66.5%的癌组织中高表达，并与胞膜E-钙粘蛋白阳性和核β-连环蛋白阴性呈显著正相关。Lcn2的高表达和NF-κB的阴性表达与钉螺的核积聚呈负相关，预示着良好的预后。LCN2在体内外阻断了细胞的增殖、迁移和侵袭，并抑制了NF-κB的核内转位。NF-κB可逆转Lcn2对血管内皮细胞转化的影响，促进蜗牛表达。在不影响NF-κB活性的情况下，解救后的蜗牛表达也有类似的效果。LCN2可能作为NF-κB/Snail信号通路的上游，在结直肠癌的侵袭转移中发挥重要的负性调节作用。因此，联合应用LCN2和NF-κB/Snail通路可能为结直肠癌患者提供一种新的治疗途径。本文的在线版本(doi：10.1186/s12943-0160564-9)包含补充材料，授权用户可以使用。
Lipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. However, neither mechanisms nor the role that LCN2 plays in the metastasis of colorectal cancer are clear. LCN2 expression in colorectal cancer was detected by immunohistochemistry in 400 tissue specimens and Kaplan-Meier survival analysis was performed. In vitro, real-time PCR, western blot, colony formation assay, immunofluorescence assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LCN2 in epithelial mesenchymal transition (EMT), migration and invasion, respectively. In vivo mouse xenograft and metastasis models were utilized to determine tumorigenicity and metastasis ability, and immunohistochemistry, real-time PCR, western blot were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of LCN2 on NF-ĸB promoter. LCN2 was highly expressed in 66.5% of the specimens, and significantly correlated with positive E-cadherin in the membrane and negative nuclear β-catenin. Higher expression of LCN2 together with negative NF-κB expression was negatively related to nuclear accumulation of snail and predicted favorable prognosis. LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into nucleus. NF-κB could reverse the effect of LCN2 on EMT and promote snail expression. Rescued snail expression had similar effect without influencing NF-κB activity. LCN2 may be an important negative regulator in EMT, invasion and metastasis of CRC via acting as upstream of NF-κB/snail signaling pathway. Thereby combinative manipulation of LCN2 and NF-κB/snail pathway may represent a novel and promising therapeutic approach for the patients with CRC. The online version of this article (doi:10.1186/s12943-016-0564-9) contains supplementary material, which is available to authorized users.
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