scholarly journals Mir-30a and lin28b conform a double-negative feedback loop regulated by pi3k modulating thyroid cancer progression

2016 ◽  
Vol 62 (5) ◽  
pp. 50-51
Author(s):  
León Wert-Lamas ◽  
Garcilaso Riesco-Eizaguitte ◽  
Richard I. Gregory ◽  
Pilar Santisteban
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Expression Vectors ◽  
Thyroid Cell ◽  
Double Negative ◽  
Tumor Supressor ◽  
Protein Levels ◽  
Activating Mutations ◽  
Pi3k Activation

Background. Our recent results showed that tumor supressor miR-30a is firmly downregulated in Thyroid carcinomas. On the other hand, recent studies showed RNA- and DNA- binding proteins LIN28B and HMGA2 induce EMT, thus playing an important role in dedifferentiation and cancer malignification. Finally, latterly several authors agreed on the importance of a robust activation of PI3K for thyroid cancer emergency and progression.Aim: to study the link between the emergency of LIN28B and HMGA2, miR-30a silencing and PI3K hyperactivation, and to determine their effect on thyroid cancer progression.Methors. MiRNA targets computational predictions were performed with MiRanda algorythm. LIN28B and miR-30a expression vectors were transfected in ATC derived and normal thyroid cell lines; mRNA and protein levels were determined by qPCR, Luciferase and Western Blot. Invasion, proliferation and cell cycle assays were performed in Transwell, cell counter, and FACScan respectively.Results. MiRanda algorythm identified multiple miR30a recognition elements in all LIN28B, HMGA2 and PI3K effectors. LIN28B expression correlated with PI3K activating mutations in ATC derived cell lines. Overexpression of miR30a resulted in LIN28B, HMGA2, and several PI3K effectors silencing, and in an increase in p27(Kip) protein levels. Inversely, LIN28B overexpressing cells showed a decrease in miR30a levels and an increased expression of HMGA2 and PI3K effectors. The general outcome was a significant decrease in invasion and proliferation in miR-30a overexpressing cells and, conversely, an increase in these parameters by LIN28B.Conclusions. These data suggest the existence of a PI3K regulated feedback with a double-negative loop between miR-30a and LIN28B. Here, PI3K activation acts to switch the steady states. Initially, high miR-30a levels repress LIN28B expression. After PI3K is activated, LIN28B is produced and miR-30a is repressed. This state reinforces PI3K hyperactivation. Thus, the feedback implements a tumoral gene expression shift, contributing to thyroid cancer progression.

scholarly journals OPNa Overexpression Is Associated with Matrix Calcification in Thyroid Cancer Cell Lines

2018 ◽  
Vol 19 (10) ◽  
pp. 2990 ◽  
Author(s):  
Luciana Ferreira ◽  
Raquel Lima ◽  
Ana Bastos ◽  
Andreia Silva ◽  
Catarina Tavares ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Common Type ◽  
Dystrophic Calcification ◽  
Thyroid Cancer Cell ◽  
Papillary Thyroid ◽  
Psammoma Bodies ◽  
Calcification Process ◽  
Thyroid Cancer Cell Lines

Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells.

scholarly journals Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

2020 ◽  
Vol 13 (9) ◽  
pp. 208
Author(s):  
Min-Hee Kim ◽  
Tae Hyeong Lee ◽  
Jin Soo Lee ◽  
Dong-Jun Lim ◽  
Peter Chang-Whan Lee
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Soft Agar ◽  
Dependent Manner ◽  
Thyroid Cancer Cell Lines ◽  
Dose Dependent

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

scholarly journals TIMP-2 regulates proliferation, invasion and STAT3-mediated cancer stem cell-dependent chemoresistance in ovarian cancer cells

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruth M. Escalona ◽  
Maree Bilandzic ◽  
Patrick Western ◽  
Elif Kadife ◽  
George Kannourakis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Mrna Level ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Ovarian Cancer Cells ◽  
Knock Down ◽  
Protein Levels ◽  
Response To Chemotherapy

Abstract Background The metzincin family of metalloproteinases and the tissue inhibitors of metalloproteinases (TIMPs) are essential proteins required for biological processes during cancer progression. This study aimed to determine the role of TIMP-2 in ovarian cancer progression and chemoresistance by reducing TIMP-2 expression in vitro in Fallopian tube secretory epithelial (FT282) and ovarian cancer (JHOS2 and OVCAR4) cell lines. Methods FT282, JHOS2 and OVCAR4 cells were transiently transfected with either single or pooled TIMP-2 siRNAs. The expression of different genes after TIMP-2 knock down (T2-KD) or in response to chemotherapy was determined at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence. Sensitivity of the cell lines in response to chemotherapy after TIMP-2 knock down was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Ethynyl-2′-deoxyuridine (EdU) assays. Cell invasion in response to TIMP-2 knockdown was determined by xCELLigence. Results Sixty to 90 % knock down of TIMP-2 expression was confirmed in FT282, OVCAR4 and JHOS2 cell lines at the mRNA and protein levels. TIMP-2 knock down did not change the mRNA expression of TIMP-1 or TIMP-3. However, a significant downregulation of MMP-2 in T2-KD cells occurred at both the protein and activation levels, compared to Control (Cont; scrambled siRNA) and Parental cells (P, transfection reagent only). In contrast, membrane bound MT1-MMP protein levels were significantly upregulated in T2-KD compared to Cont and P cells. T2-KD cells exhibited enhanced proliferation and increased sensitivity to cisplatin and paclitaxel treatments. Enhanced invasion was observed in the T2-KD-JOSH2 and OVCAR4 cells but not in T2-KD-FT282 cells. Treatment with cisplatin or paclitaxel significantly elevated the expression of TIMP-2 in Cont cells but not in T2-KD cells, consistent with significantly elevated expression of chemoresistance and CSC markers and activation of STAT3. Furthermore, a potent inhibitor of STAT3 activation, Momelotinib, suppressed chemotherapy-induced activation of P-STAT3 in OVCAR4 cells with concomitant reductions in the expression of chemoresistance genes and CSC markers. Conclusions The above results suggest that TIMP-2 may have a novel role in ovarian cancer proliferation, invasion and chemoresistance.

scholarly journals VEGFA and NFE2L2 Gene Expression and Regulation by MicroRNAs in Thyroid Papillary Cancer and Colloid Goiter

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 954 ◽  
Author(s):  
Leonardo P. Stuchi ◽  
Márcia Maria U. Castanhole-Nunes ◽  
Nathália Maniezzo-Stuchi ◽  
Patrícia M. Biselli-Chicote ◽  
Tiago Henrique ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differential Expression ◽  
Cancer Progression ◽  
Tissue Samples ◽  
Protein Levels ◽  
Normal Tissues ◽  
Thyroid Papillary ◽  
Related Transcription Factor ◽  
Thyroid Papillary Cancer ◽  
Endothelial Growth Factor

Deregulation of VEGFA (Vascular Endothelial Growth Factor A) and NFE2L2 (Nuclear Factor (Erythroid-derived 2)-Like 2), involved in angiogenesis and oxidative stress, can lead to thyroid cancer progression. MiR-17-5p and miR-612 are possible regulators of these genes and may promote thyroid disorders. In order to evaluate the involvement of VEGFA, NFE2L2, hsa-miR-17-5p, and hsa-miR-612 in thyroid pathology, we examined tissue samples from colloid goiter, papillary thyroid cancer (PTC), and a normal thyroid. We found higher levels of VEGFA and NFE2L2 transcripts and the VEGFA protein in goiter and PTC samples than in normal tissue. In the goiter, miR-612 and miR-17-5p levels were lower than those in PTC. Tumors, despite showing lower VEGFA mRNA expression, presented higher VEGFA protein levels compared to goiter tissue. In addition, NRF2 (Nuclear Related Transcription Factor 2) protein levels in tumors were higher than those in goiter and normal tissues. Inhibition of miR-17-5p resulted in reduced NFE2L2 expression. Overall, both transcript and protein levels of NFE2L2 and VEGFA were elevated in PTC and colloid goiter. Hsa-miR-612 showed differential expression in PTC and colloid goiter, while hsa-miR-17-5p showed differential expression only in colloid goiter, suggesting that hsa-miR-17-5p may be a positive regulator of NFE2L2 expression in PTC.

scholarly journals TRAF4 Enhances Osteosarcoma Cell Proliferation and Invasion by Akt Signaling Pathway

2014 ◽  
Vol 22 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Weitao Yao ◽  
Xin Wang ◽  
Qiqing Cai ◽  
Songtao Gao ◽  
Jiaqiang Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Lung Metastasis ◽  
Cancer Progression ◽  
Bone Cells ◽  
Osteosarcoma Cell ◽  
Protein Levels ◽  
Normal Bone ◽  
U2os Cells ◽  
Proliferation And Invasion

TRAF4, or tumor necrosis factor receptor-associated factor 4, is overexpressed in several cancers, suggesting a specific role in cancer progression. However, its functions in osteosarcoma are unclear. This study aimed to explore the expression of TRAF4 in osteosarcoma tissues and cells, the correlation of TRAF4 to clinical pathology of osteosarcoma, as well as the role and mechanism of TRAF4 in osteosarcoma metastasis. The protein expression levels of TRAF4 in osteosarcoma tissues and three osteosarcoma cell lines, MG-63, HOS, and U2OS, were assessed. Constructed TRAF4 overexpression vectors and established TRAF4 overexpression of the U2OS cell line. Cell proliferation, cell invasion, protein levels, and TRAF4 phosphorylations were assessed following TRAF4 transfection, as well as the effects of TRAF4 siRNA on cell proliferation and invasion. The results show that TRAF4 protein levels in osteosarcoma tissues were significantly higher than that in normal bone tissues. Importantly, an obvious upregulation of TRAF4 was found in carcinoma tissues from patients with lung metastasis compared with patients without lung metastasis. Consistently, a similar increase in TRAF4 mRNA and protein was also demonstrated in the osteosarcoma cell lines MG-63, HOS, and U2OS compared to normal bone cells, hFOB1.19. When TRAF4 was overexpressed in U2OS cells, cell proliferation was significantly enhanced, accompanied by an increase in Ki67 expression and colony formation. Compared with the control and vector-treated groups, TRAF4 transfection increased the invasion potential of U2OS cells (p<0.05). Interestingly, TRAF4 transfection significantly enhanced the phosphorylation of Akt. After blocking Akt with its specific siRNA, TRAF4-induced cell proliferation and invasion were dramatically attenuated. In summary, our findings demonstrated that TRAF4 enhances osteosarcoma cell proliferation and invasion partially by the Akt pathway. This work suggests that TRAF4 might be an important target in osteosarcoma.

scholarly journals Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2548
Author(s):  
Athanasios Bikas ◽  
Kirk Jensen ◽  
Aneeta Patel ◽  
John Costello ◽  
Sarah Reynolds ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cell Lines ◽  
Cancer Progression ◽  
Mitochondrial Respiration ◽  
Thyroid Tissue ◽  
Human Thyroid ◽  
Atp Production ◽  
Tt Cells

The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC.

Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11505-11505 ◽  
Author(s):  
Katie Streicher ◽  
Brandon W. Higgs ◽  
Song Wu ◽  
Karen Coffman ◽  
Gautam Damera ◽  
...  
Keyword(s):  
Cell Lines ◽  
Phase 1 ◽  
Underlying Mechanism ◽  
Protein Levels ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Dependent Inhibition ◽  
Cd73 Expression ◽  
Egfr Mutant ◽  
Egfr Tkis

11505 Background: Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood. We investigated the relationship between Methods: Flow cytometry and/or quantitative PCR were used to evaluate genes and proteins in five NSCLC EGFR mt cell lines and 6 wt lines. Anti-EGFR TKIs gefitinib and osimertinib were used at concentrations ranging from 0.001-100uM; EGF was used at 50 ng/mL. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 previously treated patients in CP1108 were enrolled. RNA sequencing was conducted on available tumor specimens from 97 patients in CP1108. CP1108 and TCGA were separated by EGFR status for genomic comparisons. Results: Median CD73 expression was increased 10-fold in EGFR mt NSCLC cell lines (n = 5) compared to wt cell lines (n = 6). EGF induced CD73 protein levels 5-40-fold in 3/6 EGFR wt lines. There was dose-dependent inhibition of CD73 expression (45-70 fold maximum) following treatment with gefitinib or osimertinib in 3/5 mt cell lines and 4/6 wt lines, suggesting a causal relationship between the EGFR pathway and CD73 expression. Consistent with these observations, EGFR mutant tumors had ≥2 fold increased expression of CD73 compared to wt (p < 0.05) in TCGA and CP1108 NSCLC adenocarcinoma patients. These EGFR mutants had significantly lower levels of IFNg signature, previously reported to be associated with enhanced benefit from durvalumab. Conclusions: Our findings identify a novel relationship in NSCLC between EGFR pathway activation, expression of the immunosuppressive molecule CD73 and reduced expression of IFNg mRNA signature. These results prompt the hypothesis that over-expression of CD73 in EGFR-mt NSCLC may explain, at least in part, the reduced benefit from anti-PD-1(L1) in this subset of NSCLC, and suggest evaluating anti-CD73 in combination with EGFR TKIs or anti-PD-L1 in EGFR-mt NSCLC.

scholarly journals The Long Non-Coding RNA Prader Willi/Angelman Region RNA5 (PAR5) Is Downregulated in Anaplastic Thyroid Carcinomas Where It Acts as a Tumor Suppressor by Reducing EZH2 Activity

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 235 ◽  
Author(s):  
Simona Pellecchia ◽  
Romina Sepe ◽  
Myriam Decaussin-Petrucci ◽  
Cristina Ivan ◽  
Masayoshi Shimizu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Progression ◽  
P Value ◽  
Thyroid Carcinomas ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
E Cadherin

Anaplastic thyroid carcinoma (ATC) represents one the most aggressive neoplasias in humans, and, nowadays, limited advances have been made to extend the survival and reduce the mortality of ATC. Thus, the identification of molecular mechanism underlying its progression is needed. Here, we evaluated the long non-coding RNA (lncRNA) expression profile of nine ATC in comparison with five normal thyroid tissues by a lncRNA microarray. By this analysis, we identified 19 upregulated and 28 downregulated lncRNAs with a fold change >1.1 or <−1.1 and p-value < 0.05, in ATC samples. Some of them were subsequently validated by qRT-PCR. Then, we investigated the role of the lncRNA Prader Willi/Angelman region RNA5 (PAR5), drastically and specifically downregulated in ATC. The restoration of PAR5 reduces proliferation and migration rates of ATC-derived cell lines indicating that its downregulation contributes to thyroid cancer progression. Our results suggest that PAR5 exerts its anti-oncogenic role by impairing Enhancer of Zeste Homolog 2 (EZH2) oncogenic activity since we demonstrated that PAR5 interacts with it in thyroid cancer cell lines, reducing EZH2 protein levels and its binding on the E-cadherin promoter, relieving E-cadherin from the negative regulation by EZH2. Consistently, EZH2 is overexpressed in ATC, but not in differentiated thyroid carcinomas. The results reported here define a tumor suppressor role for PAR5 in undifferentiated thyroid neoplasias, further highlighting the pivotal role of lncRNAs in thyroid carcinogenesis.

MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 193-193
Author(s):  
Foteini Kalofonou ◽  
Ailsa Sita-Lumsden ◽  
Damien Leach ◽  
Claire Fletcher ◽  
Jonathan Waxman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Target Genes ◽  
Tumour Suppressor ◽  
Mrna Levels ◽  
Protein Levels ◽  
Androgen Ablation ◽  
Castrate Resistant

193 Background: Prostate cancer (PCa) is an androgen dependent malignancy. PCa patients initially respond to androgen ablation but eventually the disease becomes castrate resistant. MicroRNAs (miRs) are considered to be master regulators of gene expression and could be potential biomarkers and therapeutic targets for PCa. We previously showed miR-27a-3p to be an androgen receptor (AR)-modulatory oncomiR, with a role in PCa progression. Methods: RNA sequencing was carried out on xenograft tumours treated with an inhibitory antisense oligonucleotide for miR-27a (ASO-27a), or control. Differentially expressed genes were cross-referenced with publicly available patient tissue datasets. ASO-27a was transfected in a panel of PCa cell lines mirroring disease progression, to verify changes in transcriptional and translational levels. Immunohistochemical analysis of encoded proteins was undertaken in a cohort of 46 PCa patients with Gleason 3+4 or 4+3 disease and compared with normal tissue-control. Results: Putative target genes tested included the tumour suppressor HIP2, the oncogenes SRC3, YAP, and PAX3, which can act both as oncogene and tumour suppressor. MRNA or protein levels of the majority of those genes tested were upregulated after ASO-27a treatment of PCa cell lines. In 22Rv1 cells, HIPK2 mRNA levels were significantly upregulated with ASO-27a (p = 0.0137), while protein levels were downregulated . PAX3 mRNA levels were significantly reduced by ASO-27a in 22Rv1 cells (p = 0.0364), while protein levels were significantly increased (p = 0.0112). Immunohistochemically, PAX3 protein was lower in Gleason 7 tumours than in normal tissue, while YAP expression was higher in patients with Gleason 4+3, relative to those with 3+4. SRC3 immunostaining was slightly, but not significantly, higher in patients with 3+4 compared to 4+3. Conclusions: MiR-27a-3p is an AR-modulatory oncomiR in PCa, with potential as a therapeutic target. MiR-27a interaction with its target genes and especially HIPK2, YAP, SRC3 and PAX3 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant disease, through ASO-27a inhibition.

scholarly journals mTOR Pathway Overactivation in BRAF Mutated Papillary Thyroid Carcinoma

2012 ◽  
Vol 97 (7) ◽  
pp. E1139-E1149 ◽  
Author(s):  
Alexandra Faustino ◽  
Joana P. Couto ◽  
Helena Pópulo ◽  
Ana Sofia Rocha ◽  
Fernando Pardal ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Expression Vectors ◽  
Papillary Thyroid ◽  
Brafv600e Mutation ◽  
Pathway Activation

Abstract Context: There are several genetic and molecular evidences suggesting dysregulation of the mammalian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphatidylinositol-3-kinase/AKT pathway by RET/PTC and mutant RAS has already been demonstrated, but no data have been reported for the BRAFV600E mutation. Objective: The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesions and whether it may be correlated with known genetic alterations, as well as to explore the mechanisms underlying mTOR pathway activation in these neoplasias. Results: We observed, by immunohistochemical evaluation, an up-regulation/activation of the mTOR pathway proteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAFV600E mutation. Transfection assays with BRAF expression vectors as well as BRAF knockdown by small interfering RNA revealed a positive association between BRAF expression and mTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAF mutation and mTOR pathway up-regulation. When we evaluated the rapamycin in the growth of thyroid cancer cell lines, we detected that cell lines with activating mutations in the MAPK pathway show a higher sensitivity to this drug. Conclusions: We determined that the AKT/mTOR pathway is particularly overactivated in human cPTC harboring the BRAFV600E mutation. Moreover, our results suggest that the mTOR pathway could be a good target to enhance therapy effects in certain types of thyroid carcinoma, namely in those harboring the BRAFV600E mutation.

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