title: TGF-β-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells.
abstract: Cancer cells undergo epithelial-mesenchymal transition (EMT) during invasion and metastasis. Although transforming growth factor-β (TGF-β) and pro-inflammatory cytokines have been implicated in EMT, the underlying molecular mechanisms remain to be elucidated. Here, we studied the effects of proinflammatory cytokines derived from the mouse macrophage cell line RAW 264.7 on TGF-β-induced EMT in A549 lung cancer cells. Co-culture and treatment with conditioned medium of RAW 264.7 cells enhanced a subset of TGF-β-induced EMT phenotypes in A549 cells, including changes in cell morphology and induction of mesenchymal marker expression. These effects were increased by the treatment of RAW 264.7 cells with lipopolysaccharide, which also induced the expression of various proinflammatory cytokines, including TNF-α and IL-1β. The effects of conditioned medium of RAW 264.7 cells were partially inhibited by a TNF-α neutralizing antibody. Dehydroxy methyl epoxyquinomicin, a selective inhibitor of NFκB, partially inhibited the enhancement of fibronectin expression by TGF-β, TNF-α, and IL-1β, but not of N-cadherin expression. Effects of other pharmacological inhibitors also suggested complex regulatory mechanisms of the TGF-β-induced EMT phenotype by TNF-α stimulation. These findings provide direct evidence of the effects of RAW 264.7-derived TNF-α on TGF-β-induced EMT in A549 cells, which is transduced in part by NFκB signalling.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kawata
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ogami
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Caname
authors.initials: C
authors.lastname: Iwata
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008175:Lung Neoplasms; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016212:Transforming Growth Factor beta