Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma.
J Neurosurg
; 128(5): 1428-1437, 2018 05.
Article
em En
| MEDLINE
| ID: mdl-28753115
ABSTRACT
OBJECTIVE Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma. METHODS Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression. RESULTS All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line. CONCLUSIONS Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.
Palavras-chave
DMSO = dimethyl sulfoxide; EMT = epithelial-mesenchymal transition; FC = fold change; KEGG = Kyoto Encyclopedia of Genes and Genomes; PFS = progression-free survival; PI3K/Akt pathway; brachyury; cDNA = complementary DNA; chordoma; copy number; hESC = human embryonic stem cell; mTOR = mammalian target of rapamycin; oncology; qRT-PCR = quantitative real-time reverse transcription polymerase chain reaction; skull base
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cordoma
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Neoplasias da Base do Crânio
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Fosfatidilinositol 3-Quinases
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Proteínas com Domínio T
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Proteínas Proto-Oncogênicas c-akt
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Proteínas Fetais
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Neurosurg
Ano de publicação:
2018
Tipo de documento:
Article