Selective inhibition of nuclear factor‐κB by nuclear factor‐κB essential modulator‐binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma-猫眼课题宝

DOI：

10.1111/j.1349-7006.2011.02174.x

发表时间：

2012-03

期刊：

Cancer Science

影响因子：

5.7

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

Takuya Tanaka;H. Nakayama;Y. Yoshitake;A. Irie;M. Nagata;K. Kawahara;Y. Takamune;R. Yoshida;Y. Nakagawa;Hidenao Ogi;S. Shinriki;K. Ota;A. Hiraki;T. Ikebe;Y. Nishimura;M. Shinohara

核因子-κB (NF-κB) 激活有助于转移的发展，从而导致包括 OSCC 在内的许多癌症的预后不良。然而，关于 NF-κB 抑制对 OSCC 转移影响的体内实验数据很少。 OSCC亚系是从表达GFP的亲代细胞系GSAS建立的，并根据连续原位移植模型颈淋巴结转移后的体内传代数命名为GSAS/N3和N5。对这些细胞的体外迁移和侵袭进行了评估，并检查了 NF-κB 活性和 NF-κB 调节的转移相关分子的表达。在体内实验中，监测了肿瘤移植小鼠的转移和存活。此外，还评估了选择性 NF-κB 抑制剂 NEMO 结合域 (NBD) 肽对 GSAS/N5 移植小鼠转移的影响，并对移植的舌肿瘤进行了免疫组织化学检查。高度转移的 GSAS/N3 和 N5 细胞表现出增强的 NF-κB 活性，因此与亲本细胞相比，导致迁移、侵袭增加和预后不良。此外，高度转移细胞中NF-κB调节的转移相关分子的表达水平上调，例如纤连蛋白、β1整合素、MMP-1、‐2、‐9和‐14以及VEGF-C。 NBD 肽抑制了 GSAS/N5 接种小鼠的转移和舌肿瘤生长，并伴随着移植舌肿瘤中 NF-κB 调节的转移相关分子的下调。我们的结果表明，NBD 肽选择性抑制 NF-κB 活化可能为治疗高度转移性 OSCC 提供有效的方法。（《癌症科学》2012 年；103：455–463）

Nuclear factor‐κB (NF‐κB) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF‐κB inhibition on OSCC metastasis. OSCC sublines were established from a GFP‐expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vitro migration and invasion were assessed in these cells, and the NF‐κB activities and expression of NF‐κB‐regulated metastasis‐related molecules were also examined. In in vivo experiments, the metastasis and survival of tumor‐engrafted mice were monitored. Furthermore, the effects of a selective NF‐κB inhibitor, NEMO‐binding domain (NBD) peptide, on metastasis in GSAS/N5‐engrafted mice were assessed, and engrafted tongue tumors were immunohistochemically examined. Highly metastatic GSAS/N3 and N5 cells showed an enhanced NF‐κB activity, thus contributing to increased migration, invasion, and a poor prognosis compared with the parent cells. Furthermore, the expression levels of NF‐κB‐regulated metastasis‐related molecules, such as fibronectin, β1 integrin, MMP‐1, ‐2, ‐9, and ‐14, and VEGF‐C, were upregulated in the highly metastatic cells. The NBD peptide suppressed metastasis and tongue tumor growth in GSAS/N5‐inoculated mice, and was accompanied by the downregulation of the NF‐κB‐regulated metastasis‐related molecules in engrafted tongue tumors. Our results suggest that the selective inhibition of NF‐κB activation by NBD peptide may provide an effective approach for the treatment of highly metastatic OSCC. (Cancer Sci 2012; 103: 455–463)

Selective inhibition of nuclear factor‐κB by nuclear factor‐κB essential modulator‐binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma

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