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

• Published in: Surgery Vol. 134; no. 6; pp. 866 - 871
• Main Authors: Sippel, Rebecca S, Carpenter, Jennifer E, Kunnimalaiyaan, Muthusamy, Chen, Herbert
• Format: Journal Article
• Language: English
• Published: United States Mosby, Inc 01.12.2003
• Subjects: Basic Helix-Loop-Helix Transcription Factors; Calcitonin - metabolism; Carcinoma, Medullary - metabolism; Carcinoma, Medullary - pathology; Cell Differentiation; Cell Line, Tumor; DNA-Binding Proteins - physiology; Down-Regulation; Humans; Phenotype; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription Factors - physiology
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(03)00418-5

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. 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. 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. 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.