Heparin-binding EGF-like growth factor enhances the activity of invasion and metastasis in thyroid cancer cells

Thyroid cancer sometimes contains poorly differentiated components, which have the potential of invasion and metastasis. We evaluated the possible roles of heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, in cell growth and invasion of thyroid cancer cells, and demonstrated that HB-EGF is not only a potent mitogen but also a chemotactic factor in the thyroid cancer cells 8305C and SW579. The HB-EGF-mediated chemotaxis was inhibited by neutralizing antibody against the EGF receptor (EGFR/HER1/ErbB1) or tyrphostin AG1478, a specific inhibitor of the EGFR tyrosine kinase. The HB-EGF mRNA and protein expression was also analyzed using RT-PCR and immunofluorescence methods, respectively. In addition, in clinical immunohistochemical study, increased expression of HB-EGF and its receptors, HER1 and EGFR4 (HER4/ErbB4), was observed in thyroid carcinoma cells. Our findings suggest that HB-EGF acts as a potent paracrine and/or autocrine chemotactic factor as well as a mitogen that mediates HER1 and/or HER4 in the invasion and metastasis of thyroid carcinoma cells, including poorly differentiated papillary carcinomas or undifferentiated/anaplastic carcinomas. These data may aid in the development of novel therapeutic strategies for thyroid cancer.