Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma.
Br J Cancer
; 106(12): 1997-2003, 2012 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-22596232
ABSTRACT
BACKGROUND:
Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. While sorafenib, a multikinase inhibitor targeting the Raf/extracellular signal-regulated protein kinase (ERK) pathway, has been shown recently to provide a survival advantage to patients with advanced HCC, a predictive biomarker has not been developed. We studied whether c-Jun N-terminal kinase (JNK), which promotes liver carcinogenesis in mice, affects therapeutic response to sorafenib in HCC patients.METHODS:
We collected pathological specimens from 39 patients with advanced HCC before starting sorafenib treatment, and measured JNK activity in HCCs.RESULTS:
In patients treated with sorafenib, the expression of phospho-c-Jun in HCC, as a read out of JNK activity, was significantly higher (P<0.001) in the non-responder group than in the responder group. c-Jun N-terminal kinase activation in HCC was associated with a decreased time to progression and a poor overall survival (P=0.0028 and P=0.0008, respectively).CONCLUSION:
In addition, JNK activity was significantly correlated with CD133 expression level. Correspondingly, high expression level of CD133 was linked to a poor response to sorafenib. Furthermore, D-JNKi, a specific JNK inhibitor, reduced the growth of xenografted CD133(+) cells in athymic mice. In conclusion, JNK activation was positively correlated with CD133 expression level and inversely correlated with the therapeutic response to sorafenib, suggesting that JNK activity may be considered as a new predictive biomarker for response to sorafenib treatment.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Piridinas
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Benzenossulfonatos
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Glicoproteínas
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Antígenos CD
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Carcinoma Hepatocelular
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Proteínas Quinases JNK Ativadas por Mitógeno
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article