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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.<\/jats:p>","DOI":"10.3390\/ijms19051448","type":"journal-article","created":{"date-parts":[[2018,5,14]],"date-time":"2018-05-14T02:57:20Z","timestamp":1526266640000},"page":"1448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression"],"prefix":"10.3390","volume":"19","author":[{"given":"Catarina","family":"Tavares","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"}]},{"given":"Catarina","family":"Eloy","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"}]},{"given":"Miguel","family":"Melo","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, 3000-075 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6392-9130","authenticated-orcid":false,"given":"Adriana","family":"Gaspar da Rocha","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Public Health Unit, ACeS Baixo Mondego, Coimbra 3000-075, Portugal"}]},{"given":"Ana","family":"Pestana","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"}]},{"given":"Rui","family":"Batista","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9120-7004","authenticated-orcid":false,"given":"Luciana","family":"Bueno Ferreira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Programa de Oncobiologia Celular e Molecular, Instituto Nacional de C\u00e2ncer, Rio de Janeiro 20230-130, Brasil"}]},{"given":"Elisabete","family":"Rios","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"},{"name":"Department of Pathology, Medical Faculty of the University of Porto, Porto 4099-002, Portugal"},{"name":"Department of Pathology, Hospital de S. Jo\u00e3o, Porto 4200-319, Portugal"}]},{"given":"Manuel","family":"Sobrinho Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Universidade do Porto, Porto 4099-002, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4099-002, Portugal"},{"name":"Faculty of Medicine, Porto University, Porto 4099-002, Portugal"},{"name":"Department of Pathology, Medical Faculty of the University of Porto, Porto 4099-002, Portugal"},{"name":"Department of Pathology, Hospital de S. 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