Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Centre, Houston, 77030, USA.
Cancer Cell. 2012 Jan 17;21(1):105-20. doi: 10.1016/j.ccr.2011.12.006.
Constitutive Kras and NF-κB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-κB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in Kras(G12D) and Kras(G12D);Ink4a/Arf(F/F) mice, demonstrating a mechanistic link between IKK2/β and Kras(G12D) in PDAC inception. Our findings reveal that Kras(G12D)-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/β/NF-κB is activated by Kras(G12D) through dual feedforward loops of IL-1α/p62.
在胰腺导管腺癌（PDAC）中鉴定出组成性 Kras 和 NF-κB 激活是特征性改变。然而，NF-κB 在 PDAC 中是如何被激活的尚不清楚。在这里，我们报告胰腺靶向 IKK2/β 失活抑制了 Kras(G12D)和 Kras(G12D);Ink4a/Arf(F/F)小鼠中的 NF-κB 激活和 PDAC 的发展，证明了 IKK2/β 和 Kras(G12D)在 PDAC 起始中的机制联系。我们的研究结果表明，Kras(G12D)激活的 AP-1 诱导 IL-1α，反过来又激活 NF-κB 和其靶基因 IL-1α 和 p62，以启动 IL-1α/p62 正反馈环，从而诱导和维持 NF-κB 活性。此外，IL-1α 的过表达与 PDAC 患者的 Kras 突变、NF-κB 活性和不良预后相关。因此，我们的研究结果表明，通过 IL-1α/p62 的双正反馈环，IKK2/β/NF-κB 被 Kras(G12D)激活的机制。
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