KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

被引：519

作者：

Ling, Jianhua ^{[1
]}

Kang, Ya'an ^{[2
]}

Zhao, Ruiying ^{[1
]}

Xia, Qianghua ^{[1
,4
]}

Lee, Dung-Fang ^{[5
,6
]}

Chang, Zhe ^{[1
,4
]}

Li, Jin ^{[7
]}

Peng, Bailu ^{[8
]}

Fleming, Jason B. ^{[2
]}

Wang, Huamin ^{[3
,4
]}

Liu, Jinsong ^{[3
,4
]}

Lemischka, Ihor R. ^{[5
,6
]}

Hung, Mien-Chie ^{[1
,4
,9
,10
]}

Chiao, Paul J. ^{[1
,4
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[4] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA

[5] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA

[6] Mt Sinai Sch Med, Black Family Stem Cell Inst, New York, NY 10029 USA

[7] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[8] Guangdong Entomol Inst, Guangzhou 510260, Guangdong, Peoples R China

[9] China Med Univ, Ctr Mol Med, Taichung 447, Taiwan

[10] China Med Univ, Grad Inst Canc Biol, Taichung 447, Taiwan

来源：

CANCER CELL | 2012年 / 21卷 / 01期

关键词：

NF-KAPPA-B; IKK-BETA; DEFECTIVE INTERLEUKIN-1; INHIBITION; KINASE; INFLAMMATION; PROGRESSION; CANCER; ALPHA; OSTEOPETROSIS;

D O I：

10.1016/j.ccr.2011.12.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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

引用

页码：105 / 120

页数：16

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