Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells
Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells
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DOI：
10.3892/ijo.2011.1209
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发表时间：
2012-02-01
影响因子：
5.2
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
--
作者：
Tomonaga, Masato;Hashimoto, Nobuyuki;Iwai, Kazuhiro
nf - κ B参与恶性细胞的转移。我们已经证明NF-kappa B激活参与了LM8细胞的肺转移，LM8细胞是邓恩小鼠骨肉瘤细胞的一种高度转移的亚克隆。最近，人们发现一种新发现的多泛素链，即线性多泛素链，它是由线性泛素链组装复合物（LUBAC）特异性产生的，在NF-kappa B活化中起关键作用。在这里，我们评估了lubac介导的NF-kappa B激活在骨肉瘤细胞肺转移发展中的作用。与Dunn细胞相比，LUBAC的三种成分（HOIL-1L、HOIP和SHARPIN）在LM8细胞中均高表达。在LM8细胞中稳定敲低HOIL-1L抑制LUBAC表达，可显著抑制NF-kappa B活性、体外侵袭性和肺转移。LUBAC诱导细胞内粘附分子-1 （ICAM-1）表达参与了静脉注射肿瘤细胞后肺细胞滞留。此外，我们发现LUBAC的敲除不仅减少了肺中LM8细胞转移结节的数量，而且减少了转移结节的大小。这些结果表明，lubac介导的NF-kappa B激活在骨肉瘤肺细胞外渗和生长等转移过程中起着至关重要的作用，抑制lubac介导的线性多泛素化活性可能是治疗这种危及生命的青少年疾病的新方法。
NF-kappa B is involved in the metastasis of malignant cells. We have shown that NF-kappa B activation is involved in the pulmonary metastasis of LM8 cells, a highly metastatic subclone of Dunn murine osteosarcoma cells. Recently, it was determined that a newly identified type of polyubiquitin chain, a linear polyubiquitin chain, which is specifically generated by the linear ubiquitin chain assembly complex (LUBAC), plays a critical role in NF-kappa B activation. Here, we have evaluated the roles of LUBAC-mediated NF-kappa B activation in the development of lung metastasis of osteosarcoma cells. All three components of LUBAC (HOIL-1L, HOIP and SHARPIN) were highly expressed in LM8 cells compared to Dunn cells. Attenuation of LUBAC expression by stable knockdown of HOIL-1L in LM8 cells significantly suppressed NF-kappa B activity, invasiveness in vitro and lung metastasis. Induction of intracellular adhesion molecule-1 (ICAM-1) expression by LUBAC is involved in cell retention in the lungs after an intravenous inoculation of tumor cells. Moreover, we found that knockdown of LUBAC decreased not only the number but also the size of the metastatic nodules of LM8 cells in the lungs. These results indicate that LUBAC-mediated NF-kappa B activation plays crucial roles in several steps involved in metastasis, including extravasation and growth of osteosarcoma cells in the lung, and that suppression of LUBAC-mediated linear polyubiquitination activity may be a new approach to treat this life-threatening disease of young adolescents.