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

Jianhua Ling; Ya'an Kang; Ruiying Zhao; Qianghua Xia; Dung Fang Lee; Zhe Chang; Jin Li; Bailu Peng; Jason B. Fleming; Huamin Wang; Jinsong Liu; Ihor R. Lemischka; Mien Chie Hung; Paul J. Chiao

doi:10.1016/j.ccr.2011.12.006

Kras^G12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

Jianhua Ling, Ya'an Kang, Ruiying Zhao, Qianghua Xia, Dung Fang Lee, Zhe Chang, Jin Li, Bailu Peng, Jason B. Fleming, Huamin Wang, Jinsong Liu, Ihor R. Lemischka, Mien Chie Hung, Paul J. Chiao

Research output: Contribution to journal › Article › peer-review

411 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	105-120
Number of pages	16
Journal	Cancer cell
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2011.12.006
State	Published - Jan 17 2012

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2011.12.006

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Ling, J., Kang, Y., Zhao, R., Xia, Q., Lee, D. F., Chang, Z., Li, J., Peng, B., Fleming, J. B., Wang, H., Liu, J., Lemischka, I. R., Hung, M. C., & Chiao, P. J. (2012). Kras^G12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer cell, 21(1), 105-120. https://doi.org/10.1016/j.ccr.2011.12.006

Ling, J, Kang, Y, Zhao, R, Xia, Q, Lee, DF, Chang, Z, Li, J, Peng, B, Fleming, JB, Wang, H , Liu, J, Lemischka, IR, Hung, MC & Chiao, PJ 2012, 'Kras^G12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma', Cancer cell, vol. 21, no. 1, pp. 105-120. https://doi.org/10.1016/j.ccr.2011.12.006

@article{671b1d0eeced46b5b231c33219148068,

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

abstract = "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 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.",

author = "Jianhua Ling and Ya'an Kang and Ruiying Zhao and Qianghua Xia and Lee, {Dung Fang} and Zhe Chang and Jin Li and Bailu Peng and Fleming, {Jason B.} and Huamin Wang and Jinsong Liu and Lemischka, {Ihor R.} and Hung, {Mien Chie} and Chiao, {Paul J.}",

note = "Funding Information: We thank Dr. Michael Karin for the IKK2/β F/F mice, Dr. Douglas Melton for the Pdx1-Cre transgenic mice, Dr. Tyler Jacks for the Kras LSL-G12D mice, Dr. Ronald DePinho for the Ink4a/Arf F/F mice, and Dr. Kenneth Hess in the Department of Biostatistics, M.D. Anderson Cancer Center, for statistical analysis, Dr. Chang-gong Liu in Sequencing & Non-coding RNA Program and Dr. Wei Zhang at Genomic Core, M.D. Anderson Cancer Center, for microarray analysis. We also thank Yu (June) Cao for technical assistance and Kathryn Hale for editorial assistance. The work was supported in part by grants from the National Cancer Institute (CA109405 and CA142674 to P.J.C.), a Cancer Center Core Supporting grant (CA16672), and Sister Institution Fund of China Medical University and Hospital and MD Anderson Cancer Center to M. C. H. ",

year = "2012",

month = jan,

day = "17",

doi = "10.1016/j.ccr.2011.12.006",

language = "English (US)",

volume = "21",

pages = "105--120",

journal = "Cancer cell",

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T1 - KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

AU - Ling, Jianhua

AU - Kang, Ya'an

AU - Zhao, Ruiying

AU - Xia, Qianghua

AU - Lee, Dung Fang

AU - Chang, Zhe

AU - Li, Jin

AU - Peng, Bailu

AU - Fleming, Jason B.

AU - Wang, Huamin

AU - Liu, Jinsong

AU - Lemischka, Ihor R.

AU - Hung, Mien Chie

AU - Chiao, Paul J.

N1 - Funding Information: We thank Dr. Michael Karin for the IKK2/β F/F mice, Dr. Douglas Melton for the Pdx1-Cre transgenic mice, Dr. Tyler Jacks for the Kras LSL-G12D mice, Dr. Ronald DePinho for the Ink4a/Arf F/F mice, and Dr. Kenneth Hess in the Department of Biostatistics, M.D. Anderson Cancer Center, for statistical analysis, Dr. Chang-gong Liu in Sequencing & Non-coding RNA Program and Dr. Wei Zhang at Genomic Core, M.D. Anderson Cancer Center, for microarray analysis. We also thank Yu (June) Cao for technical assistance and Kathryn Hale for editorial assistance. The work was supported in part by grants from the National Cancer Institute (CA109405 and CA142674 to P.J.C.), a Cancer Center Core Supporting grant (CA16672), and Sister Institution Fund of China Medical University and Hospital and MD Anderson Cancer Center to M. C. H.

PY - 2012/1/17

Y1 - 2012/1/17

N2 - 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 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.

AB - 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 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.

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AN - SCOPUS:84855946746

SN - 1535-6108

VL - 21

SP - 105

EP - 120

JO - Cancer cell

JF - Cancer cell

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ER -

Kras^G12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

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