Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance

Oncogene. 2007 Mar 29;26(14):2006-16. doi: 10.1038/sj.onc.1209999. Epub 2006 Sep 25.


We have shown that one of the principle mechanisms of chemotherapy resistance involves the activation of nuclear factor kappa-B (NF-kappaB). In an effort to identify NF-kappaB-regulated chemotherapy response genes, we performed a microarray assay and observed that heparin-binding EGF-like growth factor (HB-EGF) was significantly upregulated by SN38 (a strong inducer of NF-kappaB activity) in colon cancer cells. Further studies revealed that HB-EGF was rapidly induced following a variety of chemotherapy treatments. Using RNA interference, we demonstrated that the chemotherapy-induced HB-EGF was largely dependent on activator protein-1 (AP-1) and NF-kappaB activation. Constitutive HB-EGF expression rescued AP-1/NF-kappaB small interfering RNA (siRNA) cells from chemotherapy-induced apoptosis. Meanwhile, we found that the enzymatic shedding of HB-EGF was also regulated by chemotherapy treatment, resulting in the elevated release of soluble HB-EGF from the cellular membrane. Induction of HB-EGF expression and ectodomain shedding synergistically led to robust epidermal growth factor receptor (EGFR) phosphorylation, whereas inhibition of HB-EGF expression by use of the HB-EGF inhibitor (CRM197) or siRNA resulted in the suppression of chemotherapy-induced EGFR phosphorylation. These results suggest that the chemotherapy-induced EGFR activation is regulated by HB-EGF. Finally, we demonstrated that overexpression of HB-EGF led to apoptotic resistance to chemotherapy, whereas suppression of HB-EGF expression by siRNA resulted in a dramatic increase in cell death. In summary, our study suggests that chemotherapy-induced HB-EGF activation represents a critical mechanism of inducible chemotherapy resistance. Therefore, therapeutic intervention aimed at inhibiting HB-EGF activity may be useful in cancer prevention and treatments.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / genetics
  • Bacterial Proteins / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Epidermal Growth Factor / agonists
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / physiology*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • Genes, fos
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • RNA, Small Interfering / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor RelA / genetics


  • Bacterial Proteins
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • CRM197 (non-toxic variant of diphtheria toxin)
  • Epidermal Growth Factor