title: BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation.
abstract: The BRAFV600E mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAFV600E are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAFV600E, we developed two different cell culture models: 1) doxycycline-inducible BRAFV600E-expressing clonal line derived from human thyroid cancer WRO cells originally harboring wild-type BRAF; 2) WRO, KTC-3, and NPA cells infected with an adenovirus vector carrying BRAFV600E. BRAFV600E expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAFV600E-overexpressing cells also showed an increase of nuclear factor kappaB (NF-kappaB) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappaB pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-kappaB inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAFV600E activates not only MAPK but also NF-kappaB signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappaB may provide a new therapeutic modality for thyroid cancers with BRAFV600E.
authors.affiliation: Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki University Hospital, 852-8523, Japan.
authors.forename: Iryna
authors.initials: I
authors.lastname: Palona
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Namba
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Dmytro
authors.initials: D
authors.lastname: Starenki
authors.forename: Alexei
authors.initials: A
authors.lastname: Podtcheko
authors.forename: Ilya
authors.initials: I
authors.lastname: Sedliarou
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtsuru
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saenko
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020125:Mutation, Missense; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011489:Protein Denaturation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf