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首页> 外文期刊>Oncogene >Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-|[kappa]|B activation and proliferation in human head and neck squamous cell carcinoma
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Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-|[kappa]|B activation and proliferation in human head and neck squamous cell carcinoma

机译：TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK途径介导人头颈部鳞状细胞癌中本构性NF- |κ| B活化和增殖的证据

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Constitutively activated nuclear factor-B (NF-B) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-B in a series of HNSCC cell lines. We confirmed that NF-B was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-B-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-B (IB), the natural inhibitor of NF-B. Constitutive NF-B activation in HNSCC was found to be due to constitutive activation of IB kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IB and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-B activation. The expression of constitutively active NF-B in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-B reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor--activated kinase 1 (TAK1), DN--Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-B activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-B and its ligand in HNSCC cells but not interleukin (IL)-1. All HNSCC cell lines expressed IL-6, a NF-B-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-B, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-B is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.
机译：组成性激活的核因子-B（NF-B）与多种侵袭性肿瘤类型相关，包括头颈部鳞状细胞癌（HNSCC）;但是，其激活机理尚不完全清楚。因此，我们研究了在一系列HNSCC细胞系中介导NF-B组成型激活的分子途径。我们证实了NF-B在所有HNSCC细胞系（FaDu，LICR-LON-HN5和SCC4）中都具有组成型活性，这可以通过DNA结合，p65的免疫细胞化学定位，NF-B依赖的报告基因表达及其抑制来检测。 NF-B（IB）（一种天然的NF-B抑制剂）的显性负（DN）抑制亚基。发现HNSCC中的组成性NF-B激活是由于IB激酶（IKK）的组成性激活。并且这与IB和p65蛋白的磷酸化形式的组成型表达有关。所有HNSCC均显示p50，p52，p100和受体相互作用蛋白的表达。所有与NF-B激活有关。 HNSCC中组成型活性NF-B的表达是通过肿瘤坏死因子（TNF）信号传导途径介导的，因为DN-TNF受体相关的死亡域（TRADD）和DN-TNF受体相关的NF-B报告基因活性受到抑制。因子（TRAF）2，DN受体相互作用蛋白（RIP），DN转化生长因子激活的激酶1（TAK1），DN-Ras，DN-AKT和DN-IKK，但不是DN-TRAF5或DN -TRAF6。组成性NF-B激活还与HNSCC细胞中TNF的自分泌表达，TNF受体和NF-B及其配体的受体激活剂有关，而与白介素（IL）-1无关。所有HNSCC细胞系均表达IL-6（一种由NF-B调控的基因产物）。此外，用抗TNF抗体处理HNSCC细胞下调了组成型活性NF-B，这与抑制IL-6表达和细胞增殖有关。我们的结果清楚地表明，NF-B的组成型激活是通过TRADD-TRAF2-RIP-TAK1-IKK途径介导的，从而使TNF成为治疗头颈癌的新靶标。

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