TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers.
TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers.
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DOI：
10.1038/onc.2012.171
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发表时间：
2013-03-21
期刊：
影响因子：
8
通讯作者：
Van Waes, C.
中科院分区：
文献类型：
--
作者：
Freudlsperger, C.;Bian, Y.;Wise, S. Contag;Burnett, J.;Coupar, J.;Yang, X.;Chen, Z.;Van Waes, C.
TGF-β 在上皮恶性肿瘤中发挥双重作用，包括头颈鳞状细胞癌 (HNSCC)。经典 TGF-β 信号传导的减弱会增强肿瘤的从头发展，而 TGF-β 过度表达和信号传导却相反地促进恶性进展。我们最近观察到，TGF-β 诱导的生长停滞反应减弱，与核因子-κB (NF-κB) 的异常激活有关，核因子-κB 是一种促进 HNSCC 恶性进展的转录因子。然而，TGF-β 和 NF-κB 通路成分之间的串扰在这些通路激活改变中所起的作用尚未确定。在这里，我们发现 TGF-β 受体 II 和 TGF-β 激活激酶 1 (TAK1) 主要在 HNSCC 肿瘤亚群中表达，并具有 NF-κB 家族成员 RELA (p65) 的核激活。此外，TGF-β1 处理诱导人 HNSCC 系中 TAK1、IKK、IκBα 和 RELA 依次磷酸化。 TAK1 增强 TGF-β 诱导的 NF-κB 激活，因为 TAK1 siRNA 敲除降低了 TGF-β1 诱导的 IKK、IκB 和 RELA 磷酸化、IκBα 降解、核转位和 RELA 的 DNA 结合，以及 NF-κB 诱导的报告基因和靶基因转录。从功能上来说，TAK1 siRNA 抑制细胞增殖、迁移和侵袭。雷公藤红素是一种用于中药的 TAK1 抑制剂和抗炎药，它还能降低 TGF-β1 诱导的 TAK1 和 RELA 磷酸化，抑制基础、TGF-β1 和 TNFα 诱导的 NF-κB 报告基因活性和细胞增殖，同时增加 sub-G0 DNA 碎片和细胞凋亡的膜联蛋白 V 标记。此外，TGF-β和RELA激活促进SMAD7表达。反过来，与组成型或 TNF-α 诱导的 NF-κB 报告基因激活相比，SMAD7 优先抑制 TGF-β 诱导的 SMAD 和 NF-κB 报告基因激活。因此，TGF-β 通过 TAK1 和 NF-κB 的串扰促进了 HNSCC 的恶性表型。此外，NF-κB 可能通过增加 SMAD7 表达而导致经典 TGF-β 信号传导的下游减弱。 Celastrol 强调了靶向 TAK1 的药物作为促癌 TGF-β-NF-κB 信号通路中关键节点的治疗潜力。
TGF-β plays a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, while TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of Nuclear Factor-κB (NF-κB), a transcription factor which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα, and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knock-down decreased TGF-β1-induced phosphorylation of IKK, IκB, and RELA, degradation of IκBα, nuclear translocation, and DNA binding of RELA, and NF–κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, suppressed basal, TGF-β1- and TNFα-induced NF-κB reporter gene activity, and cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway.
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