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A repeat fine needle aspiration (FNA) is recommended for thyroid nodules diagnosed as atypia of undetermined significance (AUS) in a previous cytology. We evaluated the utility of NRAS codon 61 (NRAS61) mutation analysis and core needle biopsy (CNB) for the diagnosis of thyroid nodules previously diagnosed as AUS. This study enrolled 236 patients who underwent both NRAS61 mutation analysis and CNB of thyroid nodules previously diagnosed as AUS at cytology. The NRAS61 mutation was detected in 36 nodules and was more frequently detected in the AUS and follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN) categories, as determined by histological analysis of CNB, than in the benign group (p = 0.005). Sixty-one patients underwent surgery, and 29 nodules were finally diagnosed as malignant after surgery. Among 61 patients who underwent surgery, nodules with the NRAS61 mutation (42-65 %) had a significantly higher malignancy rate than nodules with wild-type NRAS61 (7-37 %, p = 0.038). The association between malignancy and the NRAS61 mutation was significant after adjusting for age, sex, nodule size, and histological diagnosis of CNB (p = 0.01). NRAS61 mutation analysis together with CNB could be helpful for arriving at a clinical decision in patients with thyroid nodules showing AUS in a previous cytology.

Type 2 diabetes is known to increase the risk and progression of certain types of cancer. Metformin treatment of diabetic patients is reported to have beneficial effects on some cancers. We evaluated the clinical outcome of diabetic patients with differentiated thyroid cancer (DTC) according to metformin treatment.We reviewed 943 patients diagnosed with DTC after total thyroidectomy between 1995 and 2005 in a tertiary hospital. The study involved 60 diabetic patients and 210 control patients matched for age, sex, body mass index (BMI), and tumor size.There were no differences in the clinicopathological features and disease-free survival (DFS) between diabetic patients and the control group over 8.9 years of follow-up. Of the diabetic patients with DTC, 35 patients (58%) were treated with metformin. There were no differences in age, sex, BMI, tumor size, antidiabetic medication, glycated hemoglobin, or C-peptide levels in metformin and nonmetformin groups. However, cervical lymph node (LN) metastasis was more prevalent in the metformin group than in the nonmetformin group (OR 3.52, p = 0.035). Among diabetic patients with cervical LN metastasis of DTC, the metformin subgroup (17.1 years) was associated with longer DFS than the nonmetformin subgroup (8.6 years) (HR 0.16, p = 0.021); metformin treatment was also associated with longer DFS in this subgroup in multivariate analysis after adjusting age, BMI, duration of diabetes, presence of tumor at resection margin, and serum thyroglobulin level at ablation (HR 0.03, p = 0.035).Metformin treatment is associated with low recurrence in diabetic patients with cervical LN metastasis of DTC.

Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg1 ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence.This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg.Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg1 ng/mL and 5 out of 37 patients with repeated sTg ≥ 1 ng/mL). Patients with repeated sTg ≥ 1 ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p0.001).About 1% of DTC patients who had sTg1 ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield.

Some patients with elevated serum thyroglobulin (Tg) but a negative diagnostic whole body scan (WBS) after initial therapy for differentiated thyroid carcinoma may benefit from empirical radioactive iodine (RAI) therapy. However, previous studies enrolled patients with negative diagnostic WBS, regardless of neck ultrasonography (USG) and/or (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET), which have become the preferred diagnostic procedures in such patients.The aim of this study was to evaluate the usefulness of empirical RAI therapy in patients with elevated stimulated Tg level and negative USG/FDG-PET findings after initial therapy for papillary thyroid carcinoma (PTC).This comparative study enrolled 39 patients with elevated stimulated Tg, negative diagnostic WBS, and negative USG/FDG-PET 1 yr after initial treatment. Empirical RAI therapy was performed in 14 patients (treatment group), whereas 25 patients were followed up without therapy (control group).There was no significant between-group difference in basal clinicopathological parameters. None of the 14 patients in the treatment group showed iodine uptake on posttreatment WBS. Five of 14 patients (36%) in the treatment group and eight of 25 (32%) in the control group had recurrence during the median 37 months of follow-up (P = 0.99). Changes in serum stimulated Tg concentrations did not differ between the two groups.Empirical RAI therapy and posttreatment WBS were not useful diagnostically or therapeutically in patients with positive serum stimulated Tg if such patients had negative USG and negative FDG-PET findings after initial treatment of PTC.

Radioiodine (I-131) therapy is of proven efficacy for treatment of differentiated thyroid carcinoma (DTC). However, loss of differentiation in recurrent or metastatic DTC which decrease I-131 uptake may decrease the efficacy of I-131 therapy. Therefore, strategies to improve I-131 uptake are mandatory. This study is an open label clinical study to evaluate the effectiveness of 13-cis retinoic acid (13-cis RA) for improving I-131 uptake in recurrent or metastatic of DTC with defective I-131 uptake. Eleven patients (Age 27-66 years, M : F=4 : 7) were given 13-cis RA (1.5 mg/kg daily for 5 weeks), followed by 200 mCi (7.4 GBq) I-131 treatment. The differences of serum thyroglobulin (Tg) level and I-131 uptake on the post-treatment whole body scan (RxWBS) were compared before and after 13-cis RA therapy. Six out of 11 patients showed significantly increased (above 50%) Tg levels just after RA therapy. However, Tg levels a year after I-131 therapy were increased, stable and decreased in 7, 2 and 1 patients, respectively. Iodine uptake on RxWBS showed marginal improvement in only 2 patients and their Tg levels after one year follow-up increased. Most frequent adverse events were dry skin and lips. 13-cis RA partially restores I-131 uptake in few patients with recurrent or metastatic DTC. The use of 13-cis RA in current protocol has only limited usefulness and is not routinely recommended as currently used protocol.

Introduction The technique of selective embolization has been applied for years in the treatment of vascular anomalies, severe hemorrhage, and for benign and malignant tumors. Some hypervascular skeletal metastases are prone to massive hemorrhage. Case presentation We describe the cases of two patients with thyroid carcinoma presenting with neuromuscular symptoms due to large skeletal metastases in the shoulder and sternum respectively. Pre-operative percutaneous selective catheterizations of the arteries feeding the metastatic tumors were performed, followed by infusion of gelfoam. The procedures were technically successful in both patients without adverse effects or bleeding. Complete resections of the skeletal metastases were then performed without substantial bleeding. Conclusion Selective embolization is an effective treatment for bony metastases from thyroid cancer.

Serum thyroglobulin (Tg) is the most sensitive biomarker for recurrence of differentiated thyroid cancer (DTC). We have assessed the changing pattern of stimulated Tg (sTg) and the clinical course of patients with no structural evidence of disease (NSED), based on imaging studies such as neck ultrasonography (US), fluorodeoxyglucose positron emission tomography, and/or chest computed tomogram (CT). We sought to determine if, in patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine, sTg 1 year (sTg1) after initial treatment and repeated sTg measurements, 1-2 years after sTg1, helped predict the long-term outcome with respect to structural recurrence and biochemical remission (BR), which is defined as sTg1 ng/mL.We retrospectively assessed the records of patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine between 1995 and 2004. The study included 186 patients who had NSED with sTg1 ≥2 ng/mL and subsequent sTg measurements (sTg2) without additional treatment. Patients were classified into three groups based on their sTg1 measurements: Group A, 2-4.9 ng/mL; Group B, 5-19.9 ng/mL; and Group C, ≥20 ng/mL. Patients were also classified into two groups based on whether sTg2, 1-2 years after sTg1, had decreased by ≥50% (Group 1) or had either decreased by50% or increased (Group 2). sTg was measured every 1-2 years until structural recurrence or BR.Patients remaining in NSED showed a decrease in serial sTg. Of patients in Groups A, B, and C, 41%, 17%, and 1%, respectively, achieved BR, and there was a significant difference in the BR rate between Groups 1 and 2 (p0.001). In patients with structural recurrence, serial sTg generally did not decrease from sTg1. There was a significant difference in the recurrence rate among Groups A, B, and C (p=0.005) and between Groups 1 and 2 (p0.001).We found that 41% of patients with sTg1 in the range 2-5 ng/mL achieved BR, and that sTg1 and percent change of subsequent sTg were predictive of BR. Repeated sTg measurements are useful for predicting patient prognosis in patients with DTC.

Summary Objectives To evaluate the clinical outcomes of persistent radioiodine uptake (RAIU) in the neck by diagnostic whole body scan (DxWBS) after initial therapy and the efficacy of the second ablation in patients with differentiated thyroid carcinoma (DTC). Design Patients with DTC who underwent bilateral surgery and high-dose remnant ablation between 2000 and 2004 were included. Patients with elevated serum stimulated thyroglobulin (sTg) or extensive lateral neck lymph node involvement at initial surgery underwent a second ablation, and patients with undetectable sTg or in very low-risk groups were observed. Results Among 572 patients, 25 had persistent RAIU in the neck at first DxWBS. After a median 65·7 months of follow-up, five of these patients (20%) had persistent disease, whereas another 20 patients had no abnormal findings by ultrasonography (US) or other imaging modalities. Seven of 20 patients underwent second ablation and 13 were observed. RAIU disappeared spontaneously in about half of the patients in the observation group. There were no significant between-group differences in change of RAIU at follow-up DxWBS (P = 0·62). Serum sTg decreased and eventually disappeared over a few years in both groups. Ablation failure was not an independent risk factor for recurrence (P = 0·169). Conclusions Neck US and serum sTg, but not DxWBS, were useful diagnostic tools during follow-up of patients with persistent uptake in the neck at DxWBS. A second ablation was not necessary when neck US showed no evidence of disease, especially in patients with very low sTg concentration.

The aim of the study was to evaluate the usefulness of the antithyroglobulin autoantibody (TgAb) value at 6-12 months after remnant ablation in predicting recurrence in differentiated thyroid carcinoma patients who had undetectable thyroglobulin (Tg) values. The change in TgAb concentration measured between the time of remnant ablation (TgAb1) and 6-12 months thereafter (TgAb2) was also evaluated as a possible prognostic indicator.Patients with differentiated thyroid carcinoma who underwent total thyroidectomy followed by (131)I remnant ablation between 1995 and 2003 at the Asan Medical Center (Seoul, Korea) were enrolled. Of these, 824 patients with undetectable Tg at 6-12 months after remnant ablation during thyroid hormone withdrawal were the subjects of this study.TgAb2 was positive in 56 patients. Ten of 56 patients (18%) with positive TgAb2 had recurrence, whereas only 10 of 768 patients (1%) with negative TgAb2 had recurrence during 73.6 months of follow-up (P0.001). The change between TgAb1 and TgAb2 levels was evaluated in patients with positive TgAb2. TgAb concentration decreased by more than 50% in 21 patients (group 1) and by less than 50% in 16 patients (group 2), and it increased in 19 patients (group 3). The recurrence rates in groups 1, 2, and 3 were 0, 19, and 37%, respectively (P = 0.016).Serum TgAb levels measured at 6-12 months after remnant ablation could predict recurrence in patients with undetectable Tg values. In patients with undetectable Tg and positive TgAb values, a change in TgAb concentration during the early postoperative period may be a prognostic indicator of recurrence.

Reactive oxygen species (ROS) are recently known as a contributor to tumor progression and metastasis through several mechanisms including induction of epithelial-mesenchymal transition (EMT), invasion, and tumor angiogenesis. In this study, we investigated the role of alpha-Lipoic acid (ALA), a potential antioxidant, on EMT in thyroid cancer cell lines. Human thyroid cancer-derived cell lines, BCPAP (BRAF V600E), HTH83 (HRAS Q61R), CAL62 (KRAS G12R), BHT101 (BRAF V600E), and FTC133 (PTEN null) were treated with ALA, and changes in ROS generation were measured by DCFH-DA. The expression of E-cadherin, vimentin and Twist were determined by immunoblot analysis. Cell migration and invasion were evaluated by scratch assay and by Boyden chamber assay. ALA significantly decreased intracellular ROS generation in most cell lines. The total amount of E-cadherin increased and those of vimentin and Twist decreased after ALA treatment in 4 thyroid cancer cell lines (BCPAP, HTH83, BHT101 and CAL62) in a dose-dependent manner (0.2∼1.0 mM). But, the changes in E-cadherin, vimentin and Twist were opposite in FTC133 cells. The cell migration and invasion ability decreased after treatment with ALA in all cell lines except FTC133 (PTEN null cell). These results suggest that ALA is a potential agent to inhibit EMT resulting in suppression of migration and of invasiveness in thyroid cancer cell lines with RAS or BRAF mutation, probably through reducing cellular amount of Twist. We suggest that it might be caused by antioxidant effects of ALA, but the exact mechanism of action of ALA is not clear yet. ALA could be a novel, potential agent to suppress metastasis of tumors in patients with thyroid cancer. Citation Format: Ji Min Han, Hyun-Jeung Choi, Ji Hye Yim, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Eui Young Kim, Won Bae Kim. Alpha-Lipoic acid suppresses migration and invasiveness of thyroid cancer cells through inhibition of epithelial-mesenchymal transition . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1498. doi:10.1158/1538-7445.AM2013-1498

X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis (IAP) protein family that selectively blocks caspases-3, -7, -9 and inhibits cell death. Embelin, a XIAP inhibitor, is known to exhibit anti-inflammatory and apoptotic activities. Recent reports suggest that embelin interferes the signal transducer and activator of transcription 3 (STAT3) pathway and nuclear factor-kB (NF-kB) signal pathway. In this study, we investigated the anti-cancer efficacy of embelin by measuring its effects on apoptosis of thyroid cancer cell lines. We also explored the mechanism underlying these effects. We found that embelin induced the apoptosis of human thyroid cancer cell lines, such as FTC-133, CAL-62, KTC-1, and 8505C. The effect was stronger in BRAF V600E-mutant thyroid cancer cell lines (KTC-1 and 8505C) than wild-type cell lines (FTC-133 and CAL-62). The effect of embelin on cell apoptosis was associated with increased phosphorylation of p38. SB203580 inhibited the embelin mediated induction of cleaved caspase-3 activity in V600E mutant thyroid cancer cell lines. Interestingly, embelin induced apoptosis in BRAF wild type cancer cell lines, even after treatment of SB203580. These results indicated that another signaling pathway, not a p38 pathway, might be existed for embelin induced apoptosis in BRAF wild type thyroid cancer cell. In conclusion, embelin-induced XIAP suppression resulted in an increase of apoptosis via phosphorylation of p38 in BRAF V600E-mutant thyroid cancer cell lines. Regulation of XIAP activity may be potentially useful as a treatment of thyroid cancer, especially in BRAF V600E-mutant thyroid cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1709. doi:1538-7445.AM2012-1709

Background : Anaplastic thyroid carcinoma is one of the most aggressive human cancers with a median survival of only 6 months. Local surgical tumor debulking and combined with radio-chemotherapy is conventionally used but low success rate urges the search for new therapeutic targets. 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of the 5’ AMP-activated protein kinase (AMPK), which plays a role in cellular energy homeostasis. Activated AMPK is inhibits the protein kinase mammalian target of rapamycin, thereby reducing protein translation and suppressing cell growth and cell cycle entry. Recently, AMPK was reported to be mediated by RAF-MEK-ERK pathway in melanoma cells harboring the B-RAF(V600E) mutation. Methods: We investigated the anti-tumor effect of AICAR on the proliferation of thyroid cancer cell lines with BRAF(V600E) mutation or wild type BRAF. We were to see the effect of AICAR on cell proliferation, apoptosis and cell cycle of thyroid cancer cell and reveal the mechanism of these changes. Methods: The proliferation of thyroid cancer cell lines with BRAF(V600E) mutations was more significantly inhibited by administration of AICAR in comparison with cell lines with wild type BRAF. The suppressive effect of AICAR on cell proliferation of BRAF(V600E) mutated thyroid cancer cell lines was related with increased phosphorylation of AMPK, S-phase cell cycle arrest, and increased apoptosis. Interestingly, the AICAR suppressed phosphorylation of ERK and p70S6K in B-RAF V600E mutated thyroid cancer cells compared to B-RAF wild type cells. Conclusion: In BRAF(V600E) mutation harboring thyroid cancer cell lines, AICAR induced AMPK activation resulted in decrease of cell growth, apoptosis, and increased cell cycle arrest via down-regulation of ERK and p70S6K activity. These results suggest that regulation of AMPK activity may be a potential target for cancer therapy in thyroid cancer with BRAF V600E mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4471. doi:10.1158/1538-7445.AM2011-4471

Background: Various staging systems for thyroid cancer that focus on cancer specific death have been suggested, but this approach had a limitation due to the relatively long clinical course and very low rate of cancer death. This study was performed to evaluate the staging systems and to determine the most predictive staging system for predicting recurrence. Methods: The patients who underwent first total or near total thyroidectomy due to papillary thyroid cancer (PTC) at Asan Medical Center between January 1995 and December 2001 were the subjects of this study. The commonly used 8 staging systems were applied to these subjects. Disease free survival (DFS) and the relative importance of each staging system were determined by the Kaplan-Meier method, the Cox-proportional hazards model and the proportion of variation in the survival time explained (PVE). Results: A total of 952 patients (M = 117, F = 835) were enrolled and their mean age was 45 years. During a median of 10 years of follow-up, 146 (15.3%) of 952 patients had recurred tumor. The independent prognostic factors were male gender, tumor size, extrathyroidal invasion and cervical lymph node metastasis. Risk stratification according to the American thyroid association (ATA) guideline was the most predictive staging system for recurrence of PTC (PVE 88.6%). The staging systems from EORTC (PVE 79.5%), and MACIS (PVE 68.4%) had significant values for predicting recurrence of PTC. The stage of NTCTCS could not predict recurrence (PVE 4.5%, P = 0.11). Conclusion: Risk stratification according to the ATA was most predictive staging system for predicting recurrence of PTC. The MACIS and EORTC staging systems have good value for predicting recurrence of PTC. (Endocrinol Metab 26:53-61, 2011)

Background: Follicular neoplasm (FN) or Hurthle cell neoplasm (HN) is a less well understood pitfall when evaluating thyroid nodule with fine-needle aspiration (FNA). This study aimed to determine the rates of malignancy and the predictive factors for malignancy in thyroid nodules with a cytological diagnosis of FN or HN. Methods: The patients who were cytologically diagnosed as having FN or HN after FNA between 1995 and 2004 at Asan Medical Center were included in this study. We collected the pathology data until 2009 and we analyzed the clinical characteristics associated with malignancy. Results: A total 478 patients were cytologically diagnosed as having FN or HN during the study period and 327 (68%) among them underwent thyroid surgery. Thyroid malignancy was confirmed in 157 (48%) of 327 patients. Malignancy was confirmed in 124 patients with FN (124/253, 49%). They were 48 papillary, 65 follicular, 7 Hurthle cell and 3 medullary carcinomas and 1 anaplastic carcinoma. The malignancy in the cases of HN (33/71, 44.6%) was 9 papillary, 4 follicular and 20 Hurthle cell carcinomas. The risk of malignancy was not associated with male gender, a larger tumor size (> 4 cm) or the diagnosis of HN. However, an age below 20 years (RR 3.6, P = 0.03) and above 60 years (RR 2.3, P = 0.04) was associated with an increased risk of malignancy. Conclusion: About half of the patients with FN or HN on FNA cytology were diagnosed as having thyroid cancer after surgery. The malignancy rate for the cytologic diagnosis of HN was similar to that for FN. Thyroid surgery should be recommended for this situation, and especially for patients younger than 20 years or older than 60 years.

Background: Induction of re-differentiation is necessary for the proper treatment of patients with recurrent or metastatic differentiated thyroid cancer (DTC) because cancer cells show de-differentiation in about 30% of these patients. In this study, we evaluated the expression of thyroid specific genes after treatment with various agents to induce re-differentiation in the follicular thyroid cancer cell line FTC-133. Methods: FTC-133 cells were treated with U0126, LY294002, trichostatin A, retinoic acid (RA), 5'-azacytidine and α-lipoic acid (ALA). We evaluated mRNA expression of thyroid specific genes, thyroglobulin (Tg), sodium iodine symporter (NIS), PAX-8 and TTF-1 by reverse transcriptase polymerase chain reaction (PCR). Quantified expression of Tg mRNA was also evaluated by real-time PCR. Results: The expression of Tg mRNA increased after 48 h of treatment with 0.1 uM RA and the expression of Tg mRNA and TTF-1 mRNA increased after 48-72 h of treatment with ALA (10~100 uM). There was no change in thyroid specific gene expression by the other agents. Increased expression of Tg mRNA was confirmed by real-time PCR (1.3 times by 10 uM ALA and 3.6 times by 100 uM ALA). There was no basal NIS mRNA expression in FTC-133 cells and none of the tested agents induced expression of NIS mRNA. There was no change in phosphorylation of AMPK1-α after ALA treatment of FTC-133 cells. Conclusion: ALA increases mRNA expression of Tg and TTF-1 of FTC-133 thyroid cancer cells and these effects are not mediated by activation of AMP kinase. The finding that ALA could be a potential re-differentiation inducing agent in thyroid cancer cells is novel. Further studies are needed to elucidate the mechanism of induction of re-differentiation. Furthermore, the effect of ALA on NIS expression and on iodine uptake should be evaluated using diverse thyroid cancer cell lines. (J Korean Endocr Soc 25:28~36, 2010)

Background: Peroxisome proliferator-activated receptor delta (PPAR-δ) is a ligand-activated nuclear transcription factor that is associated with many diseases, such as diabetes, obesity, metabolic syndrome, and cancer. However, the function of PPAR-δ is controversial in carcinogenesis since its ligands may inhibit or promote the growth of cancer cells. The purpose of this study was to determine the effect of GW501516, the specific agonist of PPAR-δ, in the growth and invasiveness of thyroid cancer cell lines by modulation of the target genes, ANGPTL-4 and MCP-1. Methods: Three kinds of human cancer cell lines, FRO (thyroid anaplastic carcinoma), NPA (melanoma), and ARO (colon cancer) were treated with GW501516 in serum-free media. Cell viability was assayed using a colorimetric cell counting kit-8 assay. The changes in the level of expression of PPAR-δ and its target genes, angiopoietin-like protein-4 (ANGPTL-4) and monocyte chemotactic protein-1 (MCP-1), were determined by RT-PCR analysis and invasiveness was assessed by a cell invasion assay kit. Results: GW501516 inhibited the cell growth of cancer cell lines in a dose-dependent manner and modulated the stimulation of ANGPTL-4, as well as inhibition of MCP-1. These effects were more prominent in NPA and ARO, but less effective in the thyroid cancer cell l ine, which had higher PPAR-δ and lower ANGPTL-4 mRNA levels. The inhibitory effects of GW501516 on cancer invasiveness had a similar pattern. Conclusion: The activation of PPAR-δ by GW501516 reduced the cell growth and invasiveness of the thyroid cancer cell line. This effect of GW501516 was associated with a stimulatory effect of ANGPTL4 and an inhibitory effect of MCP-1 in cancer cell lines. GW501516 was less effective in the thyroid cancer cell line, which had a low basal ANGPTL-4 mRNA level. The findings of our study serve as an impetus for further studies to elucidate the precise role of ANGPTL-4 and PPAR-δ in carcinogenesis. (J Korean Endocr

Background: Anaplastic thyroid carcinoma has grave prognosis with most patient dying within 6 months of diagnosis. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been reported to have an anticancer effect in experimental and clinical studies. In this study, we investigated the effect of HMG-CoA reductase inhibitors on cell growth, invasiveness, adherence and signal transduction to evaluate the possibility of simvastatin as an agent for treatment of thyroid cancer. Methods: The viability of simvastatin treated 3 thyroid cancer cell lines (FRO, WRO, and ARO) were determined. We evaluated the cell migration, anchorage-independent growth and invasion ability in anaplastic thyroid cell line. The expression and phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regurated kinase (ERK) were determined by immunoblot analysis. Results: Three thyroid cancer cell lines showed concentration dependent decrease of viability after treatment with 100~200 mM of simvastatin. Anaplastic ARO cell line showed the most predominant decrease in viability. In ARO cell lines, cell migration was decreased by concentration dependent manner after treatment with simvastatin (concentration ≥ 5 mM). Anchorage independent colony formation also decreased after simvastatin (≥ 10 mM). Finally, immunoblot analysis revealed that the phosphorylation status of FAK and ERK decreased in time dependent manner following treatment with 10 mM of simvastatin. Conclusion: The results of this study suggest that simvstatin exerts a favorable effect on the progression and metastasis of thyroid cancer. However, further studies are needed to elucidate the related mechanisms and signal transductions prior to its therapeutic application. (J Korean Endocr Soc 23:238~244, 2008)