Kras^G12D-Induced IKK2/¦Â/NF-¦ÊB Activation by IL-1¦Á and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

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• 作者：Jianhua Ling¹ ; Ya'an Kang² ; Ruiying Zhao¹ ; Qianghua Xia¹ ; ⁴ ; Dung-Fang Lee⁵ ; Zhe Chang¹ ; ⁴ ; Jin Li⁶ ; Bailu Peng⁷ ; Jason  ; B. Fleming² ; Huamin Wang³ ; ⁴ ; Jinsong Liu³ ; ⁴ ; Ihor  ; R. Lemischka⁵ ; Mien-Chie Hung¹ ; ⁴ ; ⁸ ; Paul  ; J. Chiao¹ ; ⁴ ; ^{pjchiao@mdanderson.org}
• 刊名：Cancer Cell
• 出版年：2012
• 出版时间：17 January 2012
• 年：2012
• 卷：21
• 期：1
• 页码：105-120
• 全文大小：5002 K

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Summary

Constitutive Kras and NF-¦ÊB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-¦ÊB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/¦Â inactivation inhibited NF-¦ÊB activation and PDAC development in Kras^G12D and Kras^G12D;Ink4a/Arf^F/F mice, demonstrating a mechanistic link between IKK2/¦Â and Kras^G12D in PDAC inception. Our findings reveal that Kras^G12D-activated AP-1 induces IL-1¦Á, which, in turn, activates NF-¦ÊB and its target genes IL-1¦Á and p62, to initiate IL-1¦Á/p62 feedforward loops for inducing and sustaining NF-¦ÊB activity. Furthermore, IL-1¦Á overexpression correlates with Kras mutation, NF-¦ÊB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/¦Â/NF-¦ÊB is activated by Kras^G12D through dual feedforward loops of IL-1¦Á/p62.