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Open AccessArticle

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto 4099-002, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal
Faculty of Medicine, Porto University, Porto 4099-002, Portugal
Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, 3000-075 Coimbra, Portugal
Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal
Public Health Unit, ACeS Baixo Mondego, Coimbra 3000-075, Portugal
Programa de Oncobiologia Celular e Molecular, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brasil
Department of Pathology, Medical Faculty of the University of Porto, Porto 4099-002, Portugal
Department of Pathology, Hospital de S. João, Porto 4200-319, Portugal
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(5), 1448;
Received: 2 May 2018 / Revised: 7 May 2018 / Accepted: 7 May 2018 / Published: 13 May 2018
(This article belongs to the Special Issue mTOR in Human Diseases)
The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression. View Full-Text
Keywords: mTOR; thyroid cancer; sodium iodide symporter (NIS)/SLC5A5 mTOR; thyroid cancer; sodium iodide symporter (NIS)/SLC5A5
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Tavares, C.; Eloy, C.; Melo, M.; Gaspar da Rocha, A.; Pestana, A.; Batista, R.; Bueno Ferreira, L.; Rios, E.; Sobrinho Simões, M.; Soares, P. mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression. Int. J. Mol. Sci. 2018, 19, 1448.

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