Ethanol-TGFα-MEK Signaling Promotes Growth of Human Hepatocellular Carcinoma

Matthew Hennig, Michele T. Yip-Schneider, Patrick Klein, Sabrina Wentz, Jesus M. Matos, Courtney Doyle, Jennifer Choi, Huangbing Wu, Amanda O'Mara, Alex Menze, Stephen Noble, Iain H. McKillop, C. Max Schmidt

Research output: Contribution to journalArticle

12 Scopus citations


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-α), 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-α, TGF-α neutralization antibody or the MEK inhibitor U0126. TGF-α 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-α levels in HepG2 cells (118%-198%) and SKHep cells (112%-177%). Exogenous administration of recombinant TGF-α mimicked the ethanol-induced growth in HepG2 and SKHep cells; TGF-α 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-α levels in HCC cells and enhances growth through cell cycles changes, which appear to be mediated through TGF-α-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.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalJournal of Surgical Research
Issue number2
StatePublished - Jun 15 2009


  • ERK
  • ethanol
  • HCC
  • hepatocellular carcinoma
  • MEK
  • TGF-α

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)

Fingerprint Dive into the research topics of 'Ethanol-TGFα-MEK Signaling Promotes Growth of Human Hepatocellular Carcinoma'. Together they form a unique fingerprint.

Cite this