title: Selective inhibition of NF-κB suppresses bone invasion by oral squamous cell carcinoma in vivo.
abstract: Nuclear factor-κB (NF-κB) is constitutively activated in many cancers, including oral squamous cell carcinoma (OSCC), and is involved in the invasive characteristics of OSCC, such as growth, antiapoptotic activity and protease production. However, the cellular mechanism underlying NF-κB's promotion of bone invasion by OSCC is unclear. Therefore, we investigated the role of NF-κB in bone invasion by OSCC in vivo. Immunohistochemical staining of OSCC invading bone in 10 patients indicated that the expression and nuclear translocation of p65, a main subunit of NF-κB, was increased in OSCC compared with normal squamous epithelial cells. An active form of p65 phosphorylated at serine 536 was present mainly in the nucleus in not only differentiated tumor cells but also tumor-associated stromal cells and bone-resorbing osteoclasts. We next injected mouse OSCC SCCVII cells into the masseter region of C(3) H/HeN mice. Mice were treated for 3 weeks with a selective NF-κB inhibitor, NBD peptide, which disrupts the association of NF-κB essential modulator (NEMO) with IκB kinases. NBD peptide treatment inhibited TNFα-induced and constitutive NF-κB activation in SCCVII cells in vitro and in vivo, respectively. Treatment with NBD peptide decreased zygoma and mandible destruction by SCCVII cells, reduced number of osteoclasts by inhibiting RANKL expression in osteoblastic cells and SCCVII cells, increased apoptosis and suppressed the proliferation of SCCVII cells. Taken together, our data clearly indicate that inhibition of NF-κB is useful for inhibiting bone invasion by OSCC.
authors.affiliation: Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furuta
authors.forename: Kenji
authors.initials: K
authors.lastname: Osawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Shin
authors.forename: Ayataka
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Kou
authors.initials: K
authors.lastname: Matsuo
authors.forename: Masud
authors.initials: M
authors.lastname: Khan
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohya
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tominaga
authors.forename: Tetsu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakanishi
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D001862:Bone Resorption; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D021381:Protein Transport; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; C467063:NBD peptide, mouse; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010455:Peptides; D053245:RANK Ligand; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases