title: Activation of nuclear factor-kappa B by linear ubiquitin chain assembly             complex contributes to lung metastasis of osteosarcoma cells.
abstract: NF-κB is involved in the metastasis of malignant cells. We have shown that             NF-κB activation is involved in the pulmonary metastasis of LM8 cells, a highly             metastatic subclone of Dunn murine osteosarcoma cells. Recently, it was determined             that a newly identified type of polyubiquitin chain, a linear polyubiquitin chain,             which is specifically generated by the linear ubiquitin chain assembly complex             (LUBAC), plays a critical role in NF-κB activation. Here, we have evaluated the             roles of LUBAC-mediated NF-κB activation in the development of lung metastasis             of osteosarcoma cells. All three components of LUBAC (HOIL-1L, HOIP and SHARPIN)             were highly expressed in LM8 cells compared to Dunn cells. Attenuation of LUBAC             expression by stable knockdown of HOIL-1L in LM8 cells significantly suppressed             NF-κB activity, invasiveness in vitro and lung metastasis. Induction of intracellular             adhesion molecule-1 (ICAM-1) expression by LUBAC is involved in cell retention             in the lungs after an intravenous inoculation of tumor cells. Moreover, we found             that knockdown of LUBAC decreased not only the number but also the size of the             metastatic nodules of LM8 cells in the lungs. These results indicate that LUBAC-mediated             NF-κB activation plays crucial roles in several steps involved in metastasis,             including extravasation and growth of osteosarcoma cells in the lung, and that             suppression of LUBAC-mediated linear polyubiquitination activity may be a new             approach to treat this life-threatening disease of young adolescents.
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. masatotomonaga@ort.med.osaka-u.ac.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Tomonaga
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
authors.forename: Megumi
authors.initials: M
authors.lastname: Onishi
authors.forename: Akira
authors.initials: A
authors.lastname: Myoui
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000378:metabolism / Q000556:secondary*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; C554944:Sipl1 protein, mouse; C492590:Rnf31 protein, mouse; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse; C000607389:Rbck1 protein, mouse