TIMP-1 mediates TGF-ß-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling.
Sci Rep
; 5: 16492, 2015 Nov 09.
Article
em En
| MEDLINE
| ID: mdl-26549110
ABSTRACT
Transforming growth factor-ß (TGF-ß) signaling plays a key role in progression and metastasis of HCC. This study was undertaken to gain the proof of concept of a small-molecule inhibitor of TGF-ß type I receptor kinase, EW-7197 as a potent anti-cancer therapy for HCC. We identified tissue inhibitors of metalloproteinases-1 (TIMP-1) as one of the secreted proteins of hepatic stellate cells (HSCs) and a key mediator of TGF-ß-mediated crosstalk between HSCs and HCC cells. TGF-ß signaling led to increased expression of TIMP-1, which activates focal adhesion kinase (FAK) signaling via its interaction with CD63. Inhibition of TGF-ß signaling using EW-7197 significantly attenuated the progression and intrahepatic metastasis of HCC in an SK-HEP1-Luc orthotopic-xenograft mouse model. In addition, EW-7197 inhibited TGF-ß-stimulated TIMP-1 secretion by HSCs as well as the TIMP-1-induced proliferation, motility, and survival of HCC cells. Further, EW-7197 interrupted TGF-ß-mediated epithelial-to-mesenchymal transition and Akt signaling, leading to significant reductions in the motility and anchorage-independent growth of HCC cells. In conclusion, we found that TIMP-1 mediates TGF-ß-regulated crosstalk between HSCs and HCC cells via FAK signaling. In addition, EW-7197 demonstrates potent in vivo anti-cancer therapeutic activity and may be a potential new anti-cancer drug of choice to treat patients with liver cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Comunicação Celular
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Fator de Crescimento Transformador beta
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Carcinoma Hepatocelular
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Inibidor Tecidual de Metaloproteinase-1
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Proteína-Tirosina Quinases de Adesão Focal
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Células Estreladas do Fígado
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Coréia do Sul