Expression of the constitutively activated RelA/NF-kappaB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion.
Although malignant gliomas are highly invasive tumors, a characteristic that contributes to the commonly observed therapeutic failures and local disease recurrences, the molecular events that regulate invasion in these tumors remain poorly understood. Because the transcription factor RelA/NF-kappaB has been shown to regulate invasion during several cellular processes, we have examined immunohistochemically expression of the constitutively activated RelA/NF-kappaB in tissues obtained from 49 astrocytic tumors [8 diffuse astrocytomas, 9 anaplastic astrocytomas (AAs) and 32 glioblastomas (GBMs)]. In addition, we examined the in vitro effects of antisense oligonucleotides and curcumin on the expression and activation of RelA/NF-kappaB, urokinase-type plasminogen activator (u-PA) expression, migration, and invasion in the T98G glioma cell line. Expression of the constitutively activated RelA/NF-kappaB was observed in 2 (25%) of 8 cases of diffuse astrocytomas, 5 (55.6%) of 9 cases of AAs, and 30 (93.8%) of 32 cases of GBMs. This expression was significantly correlated with the malignant potential in astrocytic tumors (P < 0.001). Moreover, antisense oligonucleotides and curcumin inhibited phorbol-12-myristate-13-acetate (PMA)-induced RelA/NF-kappaB expression or activation (or both), down-regulated u-PA expression, and reduced the migration and invasive potentials of T98G glioma cells. Thus, the expression of constitutively activated RelA/NF-kappaB is associated with malignancy potential in astrocytic tumors and may play a critical role in the regulation of u-PA expression and invasiveness in gliomas. RelA/NF-kappaB may therefore be an intriguing candidate for studies aimed at understanding and prevention of the invasiveness of gliomas.
Tsunoda
Keishi
K
Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto-machi, Nagasaki 852-8501, Japan. ktsuno@net.nagasaki-u.ac.jp
Kitange
Gaspar
G
Anda
Takeo
T
Shabani
Hamisi Kimaro
HK
Kaminogo
Makio
M
Shibata
Shobu
S
Nagata
Izumi
I
D001254:Astrocytoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned; D003474:Curcumin / Q000494:pharmacology; D004790:Enzyme Induction / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016328:NF-kappa B / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012189:Retrospective Studies; D016037:Single-Blind Method; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics
D017077:Culture Media, Conditioned; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; C498143:RELA protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051996:Transcription Factor RelA; D014568:Urokinase-Type Plasminogen Activator; D003474:Curcumin; D013755:Tetradecanoylphorbol Acetate