title: Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma.
abstract: Nuclear factor-κB (NF-κB) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF-κB inhibition on OSCC metastasis. OSCC sublines were established from a GFP-expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vitro migration and invasion were assessed in these cells, and the NF-κB activities and expression of NF-κB-regulated metastasis-related molecules were also examined. In in vivo experiments, the metastasis and survival of tumor-engrafted mice were monitored. Furthermore, the effects of a selective NF-κB inhibitor, NEMO-binding domain (NBD) peptide, on metastasis in GSAS/N5-engrafted mice were assessed, and engrafted tongue tumors were immunohistochemically examined. Highly metastatic GSAS/N3 and N5 cells showed an enhanced NF-κB activity, thus contributing to increased migration, invasion, and a poor prognosis compared with the parent cells. Furthermore, the expression levels of NF-κB-regulated metastasis-related molecules, such as fibronectin, β1 integrin, MMP-1, -2, -9, and -14, and VEGF-C, were upregulated in the highly metastatic cells. The NBD peptide suppressed metastasis and tongue tumor growth in GSAS/N5-inoculated mice, and was accompanied by the downregulation of the NF-κB-regulated metastasis-related molecules in engrafted tongue tumors. Our results suggest that the selective inhibition of NF-κB activation by NBD peptide may provide an effective approach for the treatment of highly metastatic OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshitake
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.forename: Kenta
authors.initials: K
authors.lastname: Kawahara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takamune
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yoshida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hidenao
authors.initials: H
authors.lastname: Ogi
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Ota
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Hiraki
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikebe
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides