Author/Authors :
Ling، نويسنده , , Jianhua and Kang، نويسنده , , Yaʹan and Zhao، نويسنده , , Ruiying and Xia، نويسنده , , Qianghua and Lee، نويسنده , , Dung-Fang and Chang، نويسنده , , Zhe-Wei Li، نويسنده , , Jin and Peng، نويسنده , , Bailu and Fleming، نويسنده , , Jason B. and Wang، نويسنده , , Huamin and Liu، نويسنده , , Jinsong and Lemischka، نويسنده , , Ihor R. and Hung، نويسنده , , Mien-Chie and Chiao، نويسنده , , Paul J.، نويسنده ,
Abstract :
Summary
tutive 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 KrasG12D and KrasG12D;Ink4a/ArfF/F mice, demonstrating a mechanistic link between IKK2/β and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-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 KrasG12D through dual feedforward loops of IL-1α/p62.
