The role of human achaete-scute homolog-1 in medullary thyroid cancer cells

Rebecca S. Sippel, Jennifer E. Carpenter, Muthusamy Kunnimalaiyaan, Herbert Chen, Fiemu Nwariaku, Tobias Carling, John E. Olson, Martha A. Zeiger

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Abstract

Background. Human achaete-scute homolog-1 (hASH1) is a transcription factor that is expressed highly in neuroendocrine tumors such as medullary thyroid cancer (MTC). Thyroid C-cells do not develop in hASH1 knockout mice, which suggests that hASH1 is essential for normal C-cell development. Methods. To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells). TT or TT-raf cells were treated with control or 1 μM estradiol. After 48 hours, the cells were analyzed for levels of hASH1 and chromogranin A by Western blotting and for calcitonin production by enzyme-linked immunosorbent assay. Results. Activation of raf-1 in the TT-raf cells resulted in high levels of phosphorylated MEK and ERK1/2, a morphologic transdifferentiation, and a decrease in chromogranin A and calcitonin levels that are associated with a reduction in hASH1 production. Furthermore, using MEK inhibitors, we demonstrated that these raf-1-mediated changes are dependent on MEK but not ERK1/2 activation. Conclusion. hASH1 down-regulation by raf-1 in MTC cells is associated with a significant decrease in hormone production. Thus, hASH1 appears to be important in the endocrine phenotype of MTC tumors and may serve as a molecular target for the treatment of patients with MTC.

Original languageEnglish (US)
Pages (from-to)866-873
Number of pages8
JournalSurgery
Volume134
Issue number6
DOIs
Publication statusPublished - Dec 2003

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ASJC Scopus subject areas

  • Surgery

Cite this

Sippel, R. S., Carpenter, J. E., Kunnimalaiyaan, M., Chen, H., Nwariaku, F., Carling, T., ... Zeiger, M. A. (2003). The role of human achaete-scute homolog-1 in medullary thyroid cancer cells. Surgery, 134(6), 866-873. https://doi.org/10.1016/S0039-6060(03)00418-5