Expression and regulation of c-ERBB ligands in human head and neck squamous carcinoma cells

Int J Cancer. 2000 Dec 1;88(5):759-65. doi: 10.1002/1097-0215(20001201)88:5<759::aid-ijc12>;2-0.


We recently reported that multiple c-erbB ligands differentially modulate in vitro proliferation, invasion and expression of matrix metalloproteinases in human head and neck squamous carcinoma cells (HNSCC). In order to evaluate further the importance of c-erbB ligands in tumor progression, the expression and regulation of this growth factor family in HNSCC cells was studied. We demonstrate that mRNAs for the 6 major c-erbB ligands, namely, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), betacellulin (BTC), heparin-binding epidermal growth factor-like growth factor (HB-EGF), amphiregulin (AR) and heregulin (HRG), are expressed in a large panel of HNSCC cell lines. In addition to TGF-alpha, other ligands (notably BTC and HRG-beta1) are involved in the autocrine growth regulation of these cells. Each c-erbB ligand when applied exogenously, induced mRNA expression of both itself and the remaining family members and a differential response in the kinetics of induction was found. HB-EGF and HRG mRNAs were induced rapidly (within 1 hr) and to a greater extent (3.2-6.2- and 4.8-7. 3-fold increase) than TGF-alpha, BTC and AR mRNAs (1.6-2.7, 1.8-3.6- and 1.6-4.2-fold, respectively). This pattern was observed for all inducing ligands tested. Analysis of mRNA stability, and concurrent treatment with BTC (as an inducing ligand) and cycloheximide (to inhibit protein synthesis) suggested both transcriptional and post-transcriptional regulatory mechanisms. These results support and extend previous observations of c-erbB receptor signaling as a critical element in the pathogenesis and progression of HNSCC, and emphasize the role of autocrine ligand production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin
  • Antibodies / pharmacology
  • Betacellulin
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Division / drug effects
  • EGF Family of Proteins
  • Epidermal Growth Factor / biosynthesis
  • Epidermal Growth Factor / genetics
  • Gene Expression Regulation, Neoplastic
  • Glycoproteins / biosynthesis
  • Glycoproteins / genetics
  • Growth Substances / biosynthesis
  • Growth Substances / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Ligands
  • Neuregulin-1 / biosynthesis
  • Neuregulin-1 / genetics
  • Neuregulin-1 / immunology
  • RNA, Messenger / biosynthesis
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Transforming Growth Factor alpha / biosynthesis
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / immunology
  • Tumor Cells, Cultured


  • AREG protein, human
  • Amphiregulin
  • Antibodies
  • BTC protein, human
  • Betacellulin
  • EGF Family of Proteins
  • Glycoproteins
  • Growth Substances
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Neuregulin-1
  • RNA, Messenger
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2