Ethanol-TGFalpha-MEK signaling promotes growth of human hepatocellular carcinoma.
J Surg Res
; 154(2): 187-95, 2009 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-19321179
ABSTRACT
BACKGROUND:
Chronic ethanol intake is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The effects of ethanol on extracellular signal-regulated kinase (ERK) activation, transforming growth factor alpha (TGF-alpha), and HCC growth were examined in this study.METHODS:
HepG2, SKHep, Hep3B human HCC cells, or normal human hepatocytes were treated with ethanol (0-100 mM), exogenous TGF-alpha, TGF-alpha neutralization antibody or the MEK inhibitor U0126. TGF-alpha levels were quantified by ELISA. Growth was determined by trypan blue-excluded cell counts. Cell cycle phase distribution was determined by flow cytometry. Protein expression was determined by Western blot.RESULTS:
Ethanol treatment (10-40 mM) increased ERK activation in HepG2 and SKHep HCC cells but not in Hep3B or human hepatocyte cells. Growth increased in HepG2 (174 +/- 29%, P < 0.05) and SKHep (149 +/- 12%, P < 0.05) cells in response to ethanol treatment. Correspondingly, ethanol increased S phase distribution in these cells. U0126 suppressed ethanol-induced growth increases. Ethanol treatment for 24 h also raised TGF-alpha levels in HepG2 cells (118%-198%) and SKHep cells (112%-177%). Exogenous administration of recombinant TGF-alpha mimicked the ethanol-induced growth in HepG2 and SKHep cells; TGF-alpha neutralization antibody effectively abrogated this effect. The TGF-a neutralization antibody also prevented ERK activation by ethanol in HepG2 cells.CONCLUSIONS:
These data demonstrate that clinically relevant doses of ethanol stimulate ERK-dependent proliferation of HCC cells. Ethanol up-regulates TGF-alpha levels in HCC cells and enhances growth through cell cycles changes, which appear to be mediated through TGF-alpha-MEK-ERK signaling. Ethanol-MEK signaling in normal hepatocytes is absent, suggesting that ethanol promotion of HCC growth may in part depend upon the acquisition of cancer-specific signaling by hepatocytes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Depressores do Sistema Nervoso Central
/
Carcinoma Hepatocelular
/
Sistema de Sinalização das MAP Quinases
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Etanol
/
Neoplasias Hepáticas
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Surg Res
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos