The role of human achaete-scute homolog-1 in medullary thyroid cancer cells. Surgery 2003 Dec;134(6):866-71; discussion 871-3
Date
12/12/2003Pubmed ID
14668716DOI
10.1016/s0039-6060(03)00418-5Scopus ID
2-s2.0-0346887056 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
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 microM 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.
Author List
Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen HMESH terms used to index this publication - Major topics in bold
CalcitoninCarcinoma, Medullary
Cell Differentiation
Cell Line, Tumor
DNA-Binding Proteins
Down-Regulation
Humans
Phenotype
Proto-Oncogene Proteins c-raf
Thyroid Neoplasms
Transcription Factors
