Τίτλος:
SIN1, a critical component of the mTOR-Rictor complex, is overexpressed and associated with AKT activation in medullary and aggressive papillary thyroid carcinomas
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background. Mammalian target of rapamycin (mTOR) forms 2 active complexes in the cell: the rapamycinsensitive 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 andAKTphosphorylation at Ser473 residue (Ser473-p-AKT).Eight of 18 papillary carcinomaswere 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 AKTactivation might represent a target for experimental therapy. © 2014 Elsevier Inc.
Συγγραφείς:
Moraitis, D.
Karanikou, M.
Liakou, C.
Dimas, K.
Tzimas, G.
Tseleni-Balafouta, S.
Patsouris, E.
Rassidakis, G.Z.
Kouvaraki, M.A.
Περιοδικό:
Otolaryngology - Head and Neck Surgery (United States)
Εκδότης:
Mosby Year Book Inc
Λέξεις-κλειδιά:
isoprotein; mammalian target of rapamycin complex 2; protein kinase B; protein p55; protein p76; stress activated protein kinase interacting protein 1; synapsin I; unclassified drug; MAPKAP1 protein, human; MTOR protein, human; oncoprotein; signal transducing adaptor protein; target of rapamycin kinase, adolescent; adult; aged; Article; carcinogenesis; clinical article; controlled study; enzyme activation; enzyme phosphorylation; female; gene overexpression; histology; human; human cell; human tissue; immunoblotting; immunohistochemistry; male; medullary thyroid carcinoma cell; papillary thyroid carcinoma cell; poorly differentiated thyroid cancer; primary cell culture; priority journal; protein analysis; thyroid cancer cell line; thyroid follicular carcinoma; thyroid medullary carcinoma; thyroid papillary carcinoma; thyroid tumorigenesis; Western blotting; carcinoma; comparative study; epidemiology; gene expression regulation; genetics; middle aged; needle biopsy; pathology; sensitivity and specificity; thyroid tumor; transcription initiation, Adaptor Proteins, Signal Transducing; Adult; Aged; Biopsy, Needle; Blotting, Western; Carcinoma; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Middle Aged; Oncogene Protein v-akt; Sampling Studies; Sensitivity and Specificity; Thyroid Neoplasms; TOR Serine-Threonine Kinases; Transcriptional Activation
DOI:
10.1016/j.surg.2014.08.095
