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mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2018 May 13; Vol. 19 (5). Date of Electronic Publication: 2018 May 13. - Publication Year :
- 2018
-
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.
- Subjects :
- Carcinoma, Papillary pathology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Mechanistic Target of Rapamycin Complex 1 metabolism
Mechanistic Target of Rapamycin Complex 2 metabolism
Phosphorylation
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins B-raf metabolism
Proto-Oncogene Proteins c-akt metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Thyroid Cancer, Papillary
Thyroid Neoplasms pathology
Carcinoma, Papillary genetics
Carcinoma, Papillary metabolism
Signal Transduction
Symporters genetics
TOR Serine-Threonine Kinases metabolism
Thyroid Neoplasms genetics
Thyroid Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 19
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 29757257
- Full Text :
- https://doi.org/10.3390/ijms19051448