Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Haixia Cheng, Elana J. Fertig, Hiroyuki Ozawa, Hiromitsu Hatakeyama, Jason D. Howard, Jimena Perez, Michael Considine, Manjusha Thakar, Ruchira Ranaweera, Gabriel Krigsfeld, Christine H. Chung

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26 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic.

Original languageEnglish
Pages (from-to)1252-1258
Number of pages7
JournalCancer Biology and Therapy
Volume16
Issue number8
DOIs
Publication statusPublished - 2015

Keywords

  • Cetuximab
  • Epithelial-to-mesenchymal transition
  • Head and neck squamous cell carcinoma
  • SMAD4

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Cheng, H., Fertig, E. J., Ozawa, H., Hatakeyama, H., Howard, J. D., Perez, J., Considine, M., Thakar, M., Ranaweera, R., Krigsfeld, G., & Chung, C. H. (2015). Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma. Cancer Biology and Therapy, 16(8), 1252-1258. https://doi.org/10.1080/15384047.2015.1056418