Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma.
Hepatology
; 56(4): 1380-90, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22706665
ABSTRACT
UNLABELLED Glypican-3 (GPC3) is a heparan sulfate proteoglycan that has an important role in cell growth and differentiation, and its function in tumorigenesis is tissue-dependent. In hepatocellular carcinoma (HCC), the overexpression of GPC3 has been demonstrated to be a reliable diagnostic indicator. However, the mechanisms that regulate the expression and function of GPC3 remain unclear. The oncoprotein c-Myc is a transcription factor that plays a significant role in more than 50% of human tumors. We report here that GPC3 is a transcriptional target of c-Myc and that the expression of c-Myc is also regulated by GPC3, thus forming a positive feedback signaling loop. We found that the overexpression of c-Myc could induce GPC3 promoter-dependent luciferase activity in luciferase reporter experiments. Furthermore, mutational analysis identified c-Myc-binding sites within the GPC3 promoter. The exogenous overexpression of c-Myc increased the endogenous messenger RNA (mRNA) and protein levels of GPC3. Chromatin immunoprecipitation experiments revealed the binding of c-Myc to the endogenous GPC3 promoter, indicating that c-Myc can directly transcriptionally activate GPC3. Interestingly, GPC3 can also elevate c-Myc expression. Overexpression of GPC3 increased c-Myc protein levels, whereas the knockdown of GPC3 reduced c-Myc expression levels. Lastly, the elevated levels of c-Myc correlate with the overexpression of GPC3 in human HCC samples. CONCLUSION:
These data provide new mechanistic insight into the roles of GPC3 and of c-Myc in the development of HCC.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas c-myc
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Carcinoma Hepatocelular
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Glipicanas
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Neoplasias Hepáticas
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
China