Background. Human achaete-scute homolog-1 (hASH1), a fetal neural transcription factor, is highly expressed in neuroendocrine tumors such as medullary thyroid cancer (MTC). Although hASH1 probably plays a part in the growth and development of these tumors, its precise role and mechanism are unknown. Methods. To further elucidate the function and regulation of hASH1 in neuroendocrine tumor differentiation, we used a model of MTC tumor differentiation mediated by the ras/raf-1 signaling pathway. The MTC TT cells alone or transduced with a β-estradiol activatable raf-1 construct (TT:ΔRaf-1:ER) were treated with β-estradiol or carrier. Northern analysis and nuclear run-off assays were performed to determine the hASH1 messenger RNA (mRNA) levels and transcription rate, respectively. Results. The TT:ΔRaf-1:ER cells treated with β-estradiol underwent marked biochemical and morphologic changes, including cell rounding, increase in calcitonin transcription, loss of RET proto-oncogene expression, and cessation of cell growth. During this differentiation process expression of hASH1 mRNA was silenced. Nuclear run-off experiments revealed that this decrease in steady-state hASH1 mRNA by raf-1 activation resulted predominantly from transcriptional inhibition. Conclusions. Silencing of hASH1 in parallel with loss of RET is associated with development of a mature C-cell differentiation pattern. Mechanisms leading to transcriptionail silencing of hASH1 may be crucial in regulating the proliferative capacity or differentiation status of MTC. Downstream targets of hASH1 could play a role in C-cell proliferation and progression to MTC.
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