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Int. J. Mol. Sci. 2018, 19(5), 1448; https://doi.org/10.3390/ijms19051448

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

1
Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto 4099-002, Portugal
2
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal
3
Faculty of Medicine, Porto University, Porto 4099-002, Portugal
4
Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, 3000-075 Coimbra, Portugal
5
Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal
6
Public Health Unit, ACeS Baixo Mondego, Coimbra 3000-075, Portugal
7
Programa de Oncobiologia Celular e Molecular, Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brasil
8
Department of Pathology, Medical Faculty of the University of Porto, Porto 4099-002, Portugal
9
Department of Pathology, Hospital de S. João, Porto 4200-319, Portugal
*
Author to whom correspondence should be addressed.
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)
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Abstract

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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