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Zinc finger protein 703 (ZNF703) is a new member of the zinc finger protein family of transcription factors that plays an important role during embryogenesis in metazoans. The overexpression of ZNF703 contributes to tumorigenesis and progression of a number of malignancies by activating the Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is activated in medullary thyroid cancer (MTC), but its mechanism of action is not yet fully understood. The aim of the present study was to examine the role of ZNF703 and its association with Akt/mTOR activation in MTC. The present study used the phosphorylation of Akt1 protein at serine 473 (pAkt473) as an indicator of signaling activation. Immunohistochemistry (IHC) staining and western blot analyses were performed in order to examine the expression of ZNF703 in 34 cases of MTC and 12 cases of corresponding normal thyroid tissues. ZNF703 expression in MTC was significantly higher compared with the corresponding normal thyroid tissues (P<0.05). Furthermore, expression of ZNF703 was associated with tumor size, lymph node metastasis and advanced stage of disease. IHC also demonstrated that the level of ZNF703 was positively correlated with p-Akt473 in the 34 cases of MTC. The human MTC cell line TT was selected for further investigation as TT cells exhibit Akt/mTOR activation. The biological effects of silencing ZNF703 in TT cells on proliferation and apoptosis, both in vitro and in vivo were investigated in the present study. ZNF703 silencing inhibited the proliferation of TT cells in vitro and inhibited xenograft tumor growth in vivo. These effects were accompanied by the substantial decrease of pAkt473 and the induction of p53 protein. These results demonstrate that ZNF703 may play a relevant role in MTC due to its association with the Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]