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

Oncogene volume 26, pages 2006–2016 (2007)Cite this article

Abstract

We have shown that one of the principle mechanisms of chemotherapy resistance involves the activation of nuclear factor kappa-B (NF-κB). In an effort to identify NF-κB-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-κB 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-κB activation. Constitutive HB-EGF expression rescued AP-1/NF-κB 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.

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Acknowledgements

This study was supported by NIH grant support CA77278-01A1 and CA98871-01 (J Cusack).

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Authors and Affiliations

  1. Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    F Wang, R Liu, C M Sloss & J C Cusack

  2. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    S W Lee

  3. Bauer Center for Genomics Research, Harvard University, Cambridge, MA, USA

    J Couget

Authors
  1. F Wang
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  2. R Liu
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  3. S W Lee
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  4. C M Sloss
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  5. J Couget
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  6. J C Cusack
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Correspondence to J C Cusack.

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Wang, F., Liu, R., Lee, S. et al. Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene 26, 2006–2016 (2007). https://doi.org/10.1038/sj.onc.1209999

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