Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma

Hiromitsu Hatakeyama, Haixia Cheng, Pamela Wirth, Ashley Counsell, Samuel R. Marcrom, Carey Burton Wood, Paula R. Pohlmann, Jill Gilbert, Barbara Murphy, Wendell G. Yarbrough, Deric L. Wheeler, Paul M. Harari, Yan Guo, Yu Shyr, Robbert J. Slebos, Christine H. Chung

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106 Citations (Scopus)

Abstract

Background: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC). Methodology/Principal Findings: Genome-wide changes in gene and miR expression were determined in cetuximabsensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparinbinding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease. Conclusions/Significance: Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.

Original languageEnglish
Article numbere12702
Pages (from-to)1-13
Number of pages13
JournalPloS one
Volume5
Issue number9
DOIs
Publication statusPublished - 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hatakeyama, H., Cheng, H., Wirth, P., Counsell, A., Marcrom, S. R., Wood, C. B., Pohlmann, P. R., Gilbert, J., Murphy, B., Yarbrough, W. G., Wheeler, D. L., Harari, P. M., Guo, Y., Shyr, Y., Slebos, R. J., & Chung, C. H. (2010). Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PloS one, 5(9), 1-13. [e12702]. https://doi.org/10.1371/journal.pone.0012702