Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition.
Carcinogenesis
; 36(4): 459-68, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25750173
ABSTRACT
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Interleucina-6
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Proteínas Proto-Oncogênicas c-fos
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Fator de Transcrição STAT3
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Transição Epitelial-Mesenquimal
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article