title: Inhibition of human osteosarcoma cell migration and invasion by a gene silencer, pyrrole-imidazole polyamide, targeted at the human MMP9 NF-κB binding site.
abstract: Osteosarcoma is one of the most prevalent bone tumors, occurring mostly in adolescence. However, no noticeable progress has been achieved in developing new therapeutic agents for this disease. Matrix metalloproteinase 9 (MMP9), a type IV collagenase, is a known anticancer target and is overexpressed in osteosarcomas. MMPs can degrade components of the extracellular matrix and are known to be involved in tumor invasion and metastasis. In the present study, we designed and synthesized a pyrrole-imidazole polyamide (HN.49), a gene-silencing agent that specifically targets the nuclear factor-kappa B (NF-κB) binding site of the human MMP9 promoter. We then examined the effect of HN.49 on the enzyme activity of MMP9 and the migration activity of osteosarcoma cells in vitro. It was clearly shown that HN.49 polyamide reduced the expression level of MMP9 mRNA and the enzymatic activity of MMP-9 in SaOS-2 cells. Moreover, HN.49 polyamide inhibited migration and invasion by SaOS-2 cells in in vitro wound-closure and matrigel-invasion assays. These results indicate that HN.49 may be a potential therapeutic agent for inhibiting the invasion and metastasis of osteosarcoma.
authors.affiliation: Department of Orthopedic Surgery, Nihon University School of Medicine.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Shunzo
authors.initials: S
authors.lastname: Osaka
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Eiji
authors.initials: E
authors.lastname: Osaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueno
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tokuhashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D001665:Binding Sites; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009757:Nylons / Q000494:pharmacology*; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014945:Wound Healing
chemical_list: C000597891:HN.49 polyamide; D016328:NF-kappa B; D009757:Nylons; D012333:RNA, Messenger; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9