Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells

J Hepatol. 2011 Aug;55(2):351-8. doi: 10.1016/j.jhep.2010.10.041. Epub 2010 Dec 13.


Background & aims: Transforming growth factor-beta (TGF-β) induces apoptosis in hepatocytes, a process that is inhibited by the epidermal growth factor receptor (EGFR) pathway. The aim of this work was to ablate EGFR in hepatocellular carcinoma (HCC) cells to understand its role in impairing TGF-β-induced cell death.

Methods: Response to TGF-β in terms of apoptosis was analyzed in different HCC cell lines and the effect of canceling EGFR expression was evaluated.

Results: TGF-β induces apoptosis in some HCC cells (such as Hep3B, PLC/PRF/5, Huh7, or SNU449), but it also mediates survival signals, coincident with the up-regulation of EGFR ligands. Inhibition of the EGFR, either by targeted knock-down with specific siRNA or by pharmacological inhibition, significantly enhances apoptotic response. TGF-β treatment in EGFR targeted knock-down cells correlates with higher levels of the NADPH oxidase NOX4 and changes in the expression profile of BCL-2 and IAP families. However, other HCC cells, such as HepG2, which show over activation of the Ras/ERKs pathway, SK-Hep1, with an endothelial phenotype, or SNU398, where the TGF-β-Smad signaling is altered, show apoptosis resistance that is not restored through EGFR blockade.

Conclusions: The inhibition of EGFR in HCC may enhance TGF-β-induced pro-apoptotic signaling. However, this effect may only concern those tumors with an epithelial phenotype which do not bear alterations in TGF-β signaling nor exhibit an over-activation of the survival pathways downstream of the EGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology
  • Carcinoma, Hepatocellular / therapy*
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Genes, bcl-2
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology
  • Liver Neoplasms / therapy*
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transcriptome
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*


  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • ErbB Receptors