Activation of mTOR signaling in medullary and aggressive papillary thyroid carcinomas

Kouvaraki, Maria A.; Liakou, Chrysoula; Paraschi, Adriani; Dimas, Konstantinos; Patsouris, Efstratios; Tseleni‐Balafouta, Sofia; Rassidakis, George Z.; Moraitis, Dimitrios

doi:10.1016/j.surg.2011.09.022

Cited by 36 publications

(34 citation statements)

References 22 publications

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“…We think that the most interesting results of our study concern the mTOR pathway activation in MTC (13,15,17). In a previous study, mTOR pathway expression was found to be frequently detected in MTC, namely in MTC metastatic lesions (13).…”

Section: Discussionmentioning

confidence: 58%

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mTOR activation in medullary thyroid carcinoma with RAS mutation

Lyra

Vinagre

Batısta

et al. 2014

European Journal of Endocrinology

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Objective: Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in RET-and RAS-mutated MTC. Materials and methods: In this study, we analysed the presence of RET, H-RAS, and K-RAS mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation -using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) -by immunohistochemistry. Results: Our results revealed that RET mutations were present in 52.9% of the cases (46/87) and RAS mutations in 12.6% (11/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of RET and RAS mutations was mutually exclusive. RAS mutations were significantly associated with higher intensity of p-S6 expression (PZ0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (PZ0.042) and in MTCs with lymph node metastases (PZ0.046). Cytoplasmic PTEN expression was detected in 58.8% of the cases; cases WT for RAS showed a significantly lower expression of PTEN (PZ0.045). Conclusions: We confirmed the presence of RAS mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC.

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Section: Discussionmentioning

confidence: 58%

“…It has been demonstrated that the mTOR pathway is activated in sporadic and hereditary MTC (13,15,16,17) and that RET mutations seem to play a role in the activation of such pathway in MTC (4,6,15). It remains unknown whether RAS mutations can also lead to mTOR pathway activation in MTCs.…”

Section: Introductionmentioning

confidence: 99%

mTOR activation in medullary thyroid carcinoma with RAS mutation

Lyra

Vinagre

Batısta

et al. 2014

European Journal of Endocrinology

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“…Dysregulation of these processes is associated with human pathologies including infertility, birth defects and cancers (Graff et al, 2008;Song and Lu, 2011). Clinical studies have shown that the eukaryotic translation initiation factor eIF4E is overexpressed in multiple cancers including ovarian, esophageal, breast, thyroid and prostate (Furic et al, 2010;Ko et al, 2009;Kouvaraki et al, 2011;Salehi and Mashayekhi, 2006). Its overexpression upregulates the translation of mRNAs for cell cycle, growth and reactive oxygen species (ROS) regulatory proteins (De Benedetti and Graff, 2004;De Benedetti and Rhoads, 1990;Rosenwald, 2004;Rosenwald et al, 1993), leading to the cancer phenotype.…”

Section: Introductionmentioning

confidence: 99%

Spatial and temporal translational control of germ cell mRNAs mediated by the eIF4E isoform IFE-1

Friday

Henderson

Morrison

et al. 2015

Journal of Cell Science

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Regulated mRNA translation is vital for germ cells to produce new proteins in the spatial and temporal patterns that drive gamete development. Translational control involves the de-repression of stored mRNAs and their recruitment by eukaryotic initiation factors (eIFs) to ribosomes. C. elegans expresses five eIF4Es (IFE-1-IFE-5); several have been shown to selectively recruit unique pools of mRNA. Individual IFE knockouts yield unique phenotypes due to inefficient translation of certain mRNAs. Here, we identified mRNAs preferentially translated through the germline-specific eIF4E isoform IFE-1. Differential polysome microarray analysis identified 77 mRNAs recruited by IFE-1. Among the IFE-1-dependent mRNAs are several required for late germ cell differentiation and maturation. Polysome association of gld-1, vab-1, vpr-1, rab-7 and rnp-3 mRNAs relies on IFE-1. Live animal imaging showed IFE-1-dependent selectivity in spatial and temporal translation of germline mRNAs. Altered MAPK activation in oocytes suggests dual roles for IFE-1, both promoting and suppressing oocyte maturation at different stages. This single eIF4E isoform exerts positive, selective translational control during germ cell differentiation.

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“…14 In a previous report, we demonstrated that mTORC1 and its signaling are activated in aggressive histologic types of thyroid cancer and suggested the use of rapamycin analogs as a therapeutic modality in these patients. 15 We also showed that eIF4E, the ultimate downstream target of the mTORC1 signaling that is critically involved in protein synthesis control, is overexpressed almost exclusively in aggressive thyroid carcinomas and correlates with tumor stage.…”

mentioning

confidence: 64%

“…These cases have been reported previously by our group. 15 The primary cells were put in culture and maintained in RPMI 1640 medium supplemented with 10% fetal calf serum and 1% streptomycin-penicillin. All cells were incubated at 378C in a humidified atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%