title: Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis.
abstract: Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a(+/+) (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a(-/-) mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a(-/-) mice and 8% of Gprc5a(+/+) mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a(-/-) mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a(+/+) mice to stimulation of NF-kappaB activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a(-/-) and Gprc5a(+/+) mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor alpha-induced, and lipopolysaccharide-induced NF-kappaB activation, which were reversed partially in Gprc5a(-/-) adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a(+/+) cells, the Gprc5a(-/-) cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-kappaB in Gprc5a(+/+) and Gprc5a(-/-) cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-kappaB activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Deng
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Ye
authors.forename: Tao-Yan
authors.initials: TY
authors.lastname: Men
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Van Pelt
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Chen
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Lin
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Tao
authors.forename: Dafna
authors.initials: D
authors.lastname: Lotan
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled