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Tae Hyuk Kim, Young-Eun Kim, Soomin Ahn, Ji-Youn Kim, Chang-Seok Ki, Young Lyun Oh, Kyunga Kim, Jae Won Yun, Woong-Yang Park, Jun-Ho Choe, Jung-Han Kim, Jee Soo Kim, Sun Wook Kim, and Jae Hoon Chung

TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16–81 years) and median follow-up of 13 years (interquartile range 11–16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77–18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03–66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85–17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

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Kyoungjune Pak, Seong-Jang Kim, In Joo Kim, Bo Hyun Kim, Sang Soo Kim, and Yun Kyung Jeon

The incidence of thyroid cancer in both men and women is increasing faster than that of any other cancer. Although positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has received much attention, the use of FDG PET for the management of thyroid cancer is limited primarily to postoperative follow-up. However, it might have a role in selected, more aggressive pathologies, and so patients at a high risk of distant metastasis may benefit from PET before surgery. As less FDG-avid thyroid cancers may lower the diagnostic accuracy of PET in preoperative assessment, an understanding of FDG avidity is important for the evaluation of thyroid cancer. FDG avidity has been shown to be associated with tumor size, lymph node metastasis, and glucose transporter expression and differentiation. As PET is commonly used in clinical practice, the detection of incidentalomas by PET is increasing. However, incidentalomas detected by PET have a high risk of malignancy. Clinicians handling cytologically indeterminate nodules face a dilemma regarding a procedure for a definitive diagnosis, usually lobectomy. With ‘nondiagnostic (ND)’ fine-needle biopsy (FNA), PET has shown a negative predictive value (NPV) of 100%, which indicates that negative uptake in a ND FNA procedure accurately excludes malignancy. With ‘atypia of undetermined significance’ or ‘follicular neoplasm’, the sensitivity and NPV of PET are 84 and 88%. PET does not provide additional information for the preoperative assessment of thyroid cancer. However, factors associated with FDG positivity are related to a poor prognosis; therefore, FDG PET scans before surgery may facilitate the prediction of the prognosis of differentiated thyroid cancer.

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Sunmi Park, Mark C Willingham, Jun Qi, and Sheue-Yann Cheng

Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (Thrb PV/PV Pten +/ mice). The Thrb PV/PV Pten +/ mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. The Thrb PV/PV Pten +/ mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese Thrb PV/PV Pten +/ mice (HFD-Thrb PV/PV Pten +/ mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-Thrb PV/PV Pten +/ mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-Thrb PV/PV Pten +/ with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

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Thomas A Werner, Inga Nolten, Levent Dizdar, Jasmin C Riemer, Sina C Schütte, Pablo E Verde, Katharina Raba, Matthias Schott, Wolfram T Knoefel, and Andreas Krieg

Follicular thyroid cancer’s (FTC) excellent long-term prognosis is mainly dependent on postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes refractory, the 10-year disease-specific survival rate drops below 10%. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small-molecule-mediated antagonisation of inhibitor of apoptosis proteins (IAPs) on TRAIL sensitivity in vitro. Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data and overall as well as recurrence-free survival. Non-iodine-retaining FTC cell lines TT2609-bib2 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence-free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95% CI: 1.144–1.826; P < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL-sensitised FTC cell lines for TRAIL-induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis as well as earlier recurrence. The specific degradation of cIAP1/2 sensitises FTC cells to TRAIL-induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.

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Sonja Balthasar, Nina Bergelin, Christoffer Löf, Minna Vainio, Sture Andersson, and Kid Törnquist

Sphingosine-1-phosphate (S1P) induces migration of human ML-1 thyroid follicular cancer cells and inhibits migration of human FRO anaplastic thyroid cancer cells. As tumour cells often secrete vascular endothelial growth factor (VEGF), we investigated a possible interaction between S1P and VEGF signalling in the regulation of thyroid tumour cell migration. We found that both ML-1 and FRO cells secreted VEGF-A (∼3.6 and <0.1 ng/106 cells/day respectively) and VEGF-C (∼3.0 and 0.14 ng/106 cells/day respectively). S1P stimulated VEGF-A secretion in both cell lines, and blocking S1P receptors 1, 2 and 3 attenuated the S1P-evoked secretion of VEGF-A. Neither TSH nor insulin affected the amount of secreted VEGF-A or -C in ML-1 cells, while simultaneous stimulation with insulin and S1P increased VEGF-C secretion in FRO cells. Both cell lines expressed VEGF receptor 2 (VEGFR-2) mRNA and proteins. Serum-evoked migration of both ML-1 and FRO cells was attenuated when VEGFR-2 was inhibited. Moreover, inhibiting VEGFR-2 in ML-1 cells resulted in a rapid downregulation of S1P1 mRNA expression and S1P1 protein levels, suppression of S1P-induced migration and a decrease in S1P-induced Akt phosphorylation. A VEGF-neutralizing antibody also reduced S1P-induced migration. In ML-1 cells, S1P phosphorylated VEGFR-2. In addition, VEGFR-2 inhibition resulted in the upregulation of S1P3 mRNA within 24 h, but a significant increase in S1P3 protein levels was not observed. VEGFR-2 inhibition, but not a VEGF-neutralizing antibody, reduced ML-1 cell proliferation independently of S1P stimulation. The results indicate a complex interaction between S1P and VEGFR-2 in ML-1 cells, particularly in regulating migratory responses.

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Yushan Mao and Mingzhao Xing

Abstract

The incidence rate of thyroid cancer has been rising rapidly in recent decades; however, its trend remains unclear. To investigate this, we analyzed the database of the Surveillance, Epidemiology and End Results (SEER) 13, 1992–2012 in the USA, particularly focusing on conventional papillary thyroid cancer (CPTC) and follicular variant of PTC (FVPTC). Of the 75,992 thyroid cancers, 61.3% were CPTC and 25.7% were FVPTC, and their incidence rates (IRs) were significantly increased from 1992 to 2012 (P all < 0.001), with CPTC being 2.4 times of FVPTC (P < 0.001) and the overall average annual percent change (AAPC) of incidence being 6.3% in the former and 5.3% in the latter. IRs were increased in all thyroid cancers, albeit most dramatically in PTC, in virtually all ethnic/demographic groups in recent two decades; however, the incidence trends varied among different thyroid cancers, particularly differentiable between CPTC and FVPTC. For example, Joinpoint analyses revealed that the APC of CPTC before 1996 was 1.5% (P > 0.05), which jumped to 6.8% (P < 0.05) after 1996, whereas the APC of FVPTC before 2000 was 6.6% (P < 0.05), which dropped to 4.8% (P < 0.05) after 2000. IRs and incidence trends of PTC were uneven among different ethnic/demographic groups, as exemplified by the lower IRs of both PTC variants in the Black females than in non-Hispanic White females but higher AAPCs of incidence in the former than in the latter. Interestingly, the data also suggest that the rise in the IRs of PTC is becoming plateaued in the most recent 2 years. These novel observations are helpful in understanding the incidence and incidence trends of thyroid cancer.

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Xuguang Zhu, Dong Wook Kim, Li Zhao, Mark C Willingham, and Sheue-yann Cheng

Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers. FDA approval of suberoylanilide hydroxamic acid (SAHA; vorinostat), an inhibitor of histone deacetylase, for the treatment of hematological malignancies led to the clinical trials of vorinostat for advanced thyroid cancer. However, patients were resistant to vorinostat treatment. To understand the molecular basis of resistance, we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer: ThrbPV/PV and ThrbPV/PVPten+/− mice. In both, thyroid cancer is driven by overactivation of PI3K-AKT signaling. However, the latter exhibit more aggressive cancer progression due to haplodeficiency of the tumor suppressor, the Pten gene. SAHA had no effects on thyroid cancer progression in ThrbPV/PV mice, indicative of resistance to SAHA. Unexpectedly, thyroid cancer progressed in SAHA-treated ThrbPV/PVPten+/− mice with accelerated occurrence of vascular invasion, anaplastic foci, and lung metastasis. Molecular analyses showed further activated PI3K-AKT in thyroid tumors of SAHA-treated ThrbPV/PVPten+/− mice, resulting in the activated effectors, p-Rb, CDK6, p21Cip1, p-cSrc, ezrin, and matrix metalloproteinases, to increase proliferation and invasion of tumor cells. Single-molecule DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost, whereas carcinogenesis progressed in SAHA-treated ThrbPV/PVPten+/− mice. Thus, this study has uncovered a novel mechanism by which SAHA-induced loss of the tumor suppressor Pten gene to promote thyroid cancer progression. Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of thyroid cancer to SAHA.

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Muhammad Yasir Asghar, Tero Viitanen, Kati Kemppainen, and Kid Törnquist

Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a′-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P1–3 receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P1,3 inhibitor VPC-23019, the S1P2 inhibitor JTE-013, and the S1P2 receptor siRNA, we showed that the effect was mediated through S1P2. Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P2 and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein.

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Xiulong Xu, Helen Ding, Geetha Rao, Shalini Arora, Constantine P Saclarides, Joseph Esparaz, Paolo Gattuso, Carmen C Solorzano, and Richard A Prinz

The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status of BRAF gene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown of SHH and GLI expression by miRNA constructs that target SHH or GLI mRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

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Maria Rosaria Sapio, Anna Guerra, Daniela Posca, Paolo Piero Limone, Maurilio Deandrea, Manuela Motta, Giancarlo Troncone, Alessia Caleo, Pasquale Vallefuoco, Guido Rossi, Gianfranco Fenzi, and Mario Vitale

Ten to fifteen percent of fine-needle aspiration biopsy (FNAB) of thyroid nodules are indeterminate. Galectin-3 (Gal-3) and the oncogene BRAF V600E are markers of malignancy useful to improve FNAB accuracy. The objective of this study was to determine whether the combined analysis of Gal-3 and BRAF V600E expression in thyroid aspirates could improve the diagnosis in FNAB with suspicious cytological findings. Two hundred and sixty-one surgical thyroid tissues and one hundred and forty-four thyroid aspirates were analyzed for the presence of the two markers. In surgical specimens, Gal-3 expression was present in 27.4% benign nodules, 91.9% papillary (PTC) and 75% follicular (FTC) thyroid carcinomas. BRAF V600E was not detected in 127 benign nodules, as well as in 32 FTCs, while was found in 42.9% PTC. No correlation was found between BRAF mutation and Gal-3 expression. Forty-seven consecutive FNAB suspicious for PTC were analyzed for the presence of the two markers. Of these nodules, 23 were benign at histology, 6 were positive for Gal-3, none displayed BRAF V600E, and 17 were negative for both the markers. Twenty suspicious nodules were diagnosed as PTC and four FTCs at histology. Of these 24 carcinomas, 9 resulted positive for BRAF V600E, 17 for Gal-3, and 22 for one or both the markers. The sensitivity, specificity, and accuracy for the presence of Gal-3 and/or BRAFV600E were significantly higher than those obtained for the two markers alone. Notably, the negative predictive value increased from 70.8 to 89.5%. In conclusion, the combined detection of Gal-3 and BRAF V600E improves the diagnosis in FNAB with cytological findings suspicious for PTC and finds clinical application in selected cases.