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 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Centre, Houston, 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ling
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.forename: Ruiying
authors.initials: R
authors.lastname: Zhao
authors.forename: Qianghua
authors.initials: Q
authors.lastname: Xia
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chang
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Bailu
authors.initials: B
authors.lastname: Peng
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Ihor R
authors.initials: IR
authors.lastname: Lemischka
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053582:Interleukin-1alpha; C117307:KRAS protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D018808:Transcription Factor AP-1; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins