title: Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas.
abstract: Pancreatic carcinoma, a leading cause of cancer death, is thought to develop out of pancreatic intraepithelial neoplasia (PanIN). PanIN lesions have not yet attained the fully malignant phenotype, but show increased proliferation and dysplasia, and frequently bear an oncogenic KRAS mutation. Pancreatic cancer development is associated with increased activity of the transcription factor NF-κB. NEMO (IKKγ) is a subunit of the IKK complex essential for the activation of canonical NF-κB signaling and has been ascribed both oncogenic and tumor-suppressive roles in gastrointestinal tumors. Here, we wanted to address the function of NEMO in pancreatic tumorigenesis. We therefore conditionally ablated NEMO in a mouse model for pancreatic carcinoma based on the expression of oncogenic KRAS in pancreatic precursor cells. Mice were analyzed for PanIN lesions and for the activation of associated signaling pathways. NEMO ablation in the pancreas, while in itself not causing any overt pathology, led to a drastic (>93%) decrease in the prevalence of both low-grade and high-grade PanIN in 10-month-old mice expressing oncogenic KRAS. Also, the inflammatory and fibrotic response associated with KRAS action in the pancreas was virtually abolished, including expression of inflammatory cytokines and activation of the interleukin-6/STAT3 axis. Moreover, the activation of MAPK signaling, Notch and KLF4 signaling normally observed in KRAS-induced PanIN was strongly reduced or absent when NEMO was ablated. Our study suggests that NEMO, an IKK subunit necessary for canonical NF-κB activation, is dispensable for normal pancreatic development and function, but essential for the propagation of KRAS-induced PanIN lesions.
authors: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors: H J
authors: HJ
authors: Maier
authors: M
authors: M
authors: Wagner
authors: T G
authors: TG
authors: Schips
authors: H H
authors: HH
authors: Salem
authors: B
authors: B
authors: Baumann
authors: T
authors: T
authors: Wirth
mesh_terms: D000818:Animals; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor
chemical_list: D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C514981:NEMO protein, mouse; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051550:I-kappa B Kinase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)