PMID- 25456951 OWN - NLM STAT- MEDLINE DCOM- 20150218 LR - 20211203 IS - 1532-7361 (Electronic) IS - 0039-6060 (Linking) VI - 156 IP - 6 DP - 2014 Dec TI - SIN1, a critical component of the mTOR-Rictor complex, is overexpressed and associated with AKT activation in medullary and aggressive papillary thyroid carcinomas. PG - 1542-8; discussion 1548-9 LID - S0039-6060(14)00580-7 [pii] LID - 10.1016/j.surg.2014.08.095 [doi] AB - BACKGROUND: Mammalian target of rapamycin (mTOR) forms 2 active complexes in the cell: the rapamycin-sensitive mTOR-Raptor (mTORC1) and the rapamycin-insensitive mTOR-Rictor (mTORC2). The latter activates AKT kinase, which promotes tumor cell survival and proliferation by multiple downstream targets. Mammalian stress-activated protein kinase interacting protein 1 (SIN1), an essential subunit of the mTORC2 complex, maintains the integrity of the complex and substrate specificity and regulates Akt activation. The role of mTOR-Rictor complex activation in thyroid carcinogenesis remains unknown. Therefore, we investigated expression patterns of Sin1 in the cells lines of thyroid carcinoma and tumors and their association with AKT activation, histologic type, and tumor aggressiveness. METHODS: Tissue specimens from 42 patients with thyroid cancer, including follicular (5), papillary (18), medullary (16), and poorly differentiated (3) carcinomas were analyzed via immunohistochemistry for SIN1 expression and AKT phosphorylation at Ser473 residue (Ser473-p-AKT). Eight of 18 papillary carcinomas were aggressive histologic variants. In addition, expression of Sin1 and activation of AKT kinase were analyzed in fresh-frozen tissue samples (normal/tumor), primary cell cultures (papillary thyroid carcinoma [PTC]), and an established thyroid cancer cell line (medullary thyroid carcinoma) by Western blotting. RESULTS: With immunohistochemistry, we found that Sin1 was overexpressed in medullary thyroid carcinomas and aggressive variants of papillary thyroid carcinoma compared with conventional papillary and follicular carcinomas (P < .001). Sin1 expression correlated with AKT activation in the entire study group (P = .002). Using Western blot analysis, we found that Sin1 and p-AKT were detected at a greater level in cultured primary cells from aggressive PTC compared with conventional PTC as well as in cell lines of medullary and anaplastic thyroid carcinoma. High expression levels of SIN1 were detected in papillary thyroid carcinomas compared with benign nodules in immunoblots in which we used fresh-frozen patient samples. Two of the Sin1 protein isoforms, p76 and p55, were detected predominantly in PTC samples. CONCLUSION: Sin1, a critical factor of the mTORC2 complex is overexpressed in clinically aggressive thyroid cancer types and is associated strongly with activation of AKT kinase. Sin1-dependent AKT activation might represent a target for experimental therapy. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Moraitis, Dimitrios AU - Moraitis D AD - Department of Surgery, Hygeia Hospital, Athens, Greece. FAU - Karanikou, Maria AU - Karanikou M AD - First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. FAU - Liakou, Chryssa AU - Liakou C AD - First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. FAU - Dimas, Konstantinos AU - Dimas K AD - Department of Pharmacology, University of Thessaly, Larissa, Greece. FAU - Tzimas, George AU - Tzimas G AD - Department of Surgery, Hygeia Hospital, Athens, Greece. FAU - Tseleni-Balafouta, Sofia AU - Tseleni-Balafouta S AD - First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. FAU - Patsouris, Efstratios AU - Patsouris E AD - First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. FAU - Rassidakis, George Z AU - Rassidakis GZ AD - First Department of Pathology, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; Department of Pathology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. FAU - Kouvaraki, Maria A AU - Kouvaraki MA AD - Department of Surgery, Hygeia Hospital, Athens, Greece; Department of Endocrine Surgery, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. Electronic address: markouvaraki@hotmail.com. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141111 PL - United States TA - Surgery JT - Surgery JID - 0417347 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (MAPKAP1 protein, human) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Thyroid cancer, medullary SB - IM MH - Adaptor Proteins, Signal Transducing/genetics MH - Adult MH - Aged MH - Biopsy, Needle MH - Blotting, Western MH - Carcinoma/*genetics/pathology MH - Carcinoma, Neuroendocrine MH - Carcinoma, Papillary MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Oncogene Protein v-akt/genetics MH - Sampling Studies MH - Sensitivity and Specificity MH - TOR Serine-Threonine Kinases/genetics MH - Thyroid Cancer, Papillary MH - Thyroid Neoplasms/*genetics/pathology MH - *Transcriptional Activation EDAT- 2014/12/03 06:00 MHDA- 2015/02/19 06:00 CRDT- 2014/12/03 06:00 PHST- 2014/03/01 00:00 [received] PHST- 2014/08/28 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/02/19 06:00 [medline] AID - S0039-6060(14)00580-7 [pii] AID - 10.1016/j.surg.2014.08.095 [doi] PST - ppublish SO - Surgery. 2014 Dec;156(6):1542-8; discussion 1548-9. doi: 10.1016/j.surg.2014.08.095. Epub 2014 Nov 11.