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Kras-induced ikk2/nf-kappaB activation by IL-1 alpha and p62 freedforward loops is required for development of pancreatic ductal adenocarcinoma

ABSTRACT: This SuperSeries is composed of the following subset Series: GSE27478: Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice GSE33322: Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Paul Chiao

PROVIDER: E-GEOD-33323 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma.

Ling Jianhua J Kang Ya'an Y Zhao Ruiying R Xia Qianghua Q Lee Dung-Fang DF Chang Zhe Z Li Jin J Peng Bailu B Fleming Jason B JB Wang Huamin H Liu Jinsong J Lemischka Ihor R IR Hung Mien-Chie MC Chiao Paul J PJ

Cancer cell 20120101 1

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 ...[more]

PMID: 22264792

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Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice

Project description:Constitutive Kras and NF-kB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kB activation and completely suppressed PDAC development. Our findings demonstrated that NF-kB is required for development of pancreatic ductal adenocarcinoma that was initiated by Kras activation. Pancreatic tissue from 4 groups of mice were used in this project: (1) the pancreas normal appearance of Pdx1-cre;KrasLSL-G12D;IKK2/beta mice, (2) the normal pancreas of Pdx1-cre;KrasLSL-G12D mice, (3) the pancreatic lesion of pancreatic intraepithelial neoplasia (PanIN) of Pdx1-cre;KrasLSL-G12D mice, and (4) the pancreatic lesion of PDAC of Pdx1-cre;KrasLSL-G12D mice. Each group included three mice. RNA samples from mouse pancreas were hybridized on GeneChip Mouse Gene 1.0 ST arrays (Affymetrix). Group (1) and group (2) were compared, and group (2), group (3) and group (4) were compared.

2012-01-24 | E-GEOD-33322 | biostudies-arrayexpress

Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice

Project description:Constitutive Kras and NF-kappaB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms of constitutive NF-kappaB activation in KrasG12D-induced PDAC are not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and completely suppressed PDAC development in KrasG12D and KrasG12D;Ink4a/Arf mutant mice, demonstrating a genetic link between IKK2/beta and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1alpha, which in turn activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, constitutive NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings establish a pathway linking duel feedforward loops of IL-1alpha/p62 through which IKK2/beta/NF-kappaB is activated by KrasG12D. To study Kras-induced inflammatory responses and to identify differentially expressed genes between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice, cDNA microarray analysis was performed.

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Differential gene expression in EpCAM+ pancreatic cancer cells with Lifr deficiency

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Project description:Gene expression differences between the pancreatic tissues of Pdx1-Cre KrasLSL-G12D and Pdx1-Cre KrasLSL-G12D IKK2/betaF/F mice

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In vivo response of EpCAM+ pancreatic cancer cells to gemcitabine plus anti-LIF neutralizing antibody treatment

Project description:The goal of this study is to investigate the molecular mechanisms of LIF action on pancreatic cancer cells in the classical pancreatic ductal adenocarcinoma mouse model KrasLSL-G12D;Tp53f/f;Rosa26LSL-Luc;Pdx1-Cre mice EpCAM+ pancreatic cancer cells were isolated from pancreatic tumors developped in KrasLSL-G12D;Tp53f/f;Rosa26LSL-Luc;Pdx1-Cre mice treated with either gemcitabine plus control IgG or gemcitabine plus anti-LIF antibody by FACS

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