Role In Thyroid Cancer Research Articles

Association of thyroid carcinoma with pregnancy: A meta-analysis.

A number of scholars reported that reproductive factors play a significant role in thyroid cancer and the correlation between the two may affect the diagnosis and treatment of thyroid carcinoma during pregnancy. To determine whether pregnancy reproductive factors affect thyroid carcinoma, we conducted a meta-analysis of studies that investigated the association between pregnancy factors and thyroid carcinoma. PubMed, OVID and the Cochrane Library were searched from their inception to April 1st, 2013. The searched publications mainly investigated reproductive factors and the morbidity or prognosis of female thyroid carcinoma. The studies were filtered by predetermined standards and the quality of the included studies was evaluated by the Newcastle-Ottawa scale inventory. Two researchers independently extracted information on first author, year of publication, study design (case-control or prospective cohort), compared populations, inclusion and exclusion criteria and total sample size. Other researchers assessed the studies for publication bias and performed statistical analyses. Discrepancies were resolved by consensus. A total of 21 studies were selected for the meta-analysis, including 406,329 cases in total. Compared to the control group, the risk of thyroid carcinoma in women with a history of pregnancy was not significantly discrepant, [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.91-1.11]. However, the risk of thyroid carcinoma in women with a history of ≥ 3 pregnancies was significantly increased (OR=1.39, 95% CI: 1.21-1.59). Furthermore, an interval of ≤ 5 years since the last pregnancy was closely associated with thyroid carcinoma (OR=1.53, 95% CI: 1.29-1.81). The patients developed thyroid carcinoma during pregnancy did not exhibit an increased risk of lymphatic metastasis (OR=0.94, 95% CI: 0.53-1.67); the risk of distant metastasis also did not increase significantly (OR=1.03, 95% CI: 0.86-1.24). Therefore, multiple pregnancies and a ≤ 5-year interval between pregnancies were identified as high-risk factors for thyroid carcinoma, whereas thyroid carcinoma during pregnancy was not associated with a significant risk of lymphatic and distant metastasis.

Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer.

Studies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in other malignancies. Nevertheless, scanty data were available on the possible impact on the outcome of the disease. We demonstrated that FCM has a positive effect on thyroid cancer presentation and outcome. We also excluded that the better clinical features observed were due to the effect of pregnancy per se. In conclusion, FCM may have not only a protective role toward the onset of thyroid cancer, but also a positive effect on its progression. These findings give novel insights into the identification of the role of FCM in oncology and, consequently, in the potential therapeutic application of this physiological phenomenon.

Estrogen and its role in thyroid cancer.

Proliferative thyroid diseases are more prevalent in females than in males. Upon the onset of puberty, the incidence of thyroid cancer increases in females only and declines again after menopause. Estrogen is a potent growth factor both for benign and malignant thyroid cells that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. It exerts its growth-promoting effect through a classical genomic and a non-genomic pathway, mediated via a membrane-bound estrogen receptor. This receptor is linked to the tyrosine kinase signaling pathways MAPK and PI3K. In papillary thyroid carcinomas, these pathways may be activated either by a chromosomal rearrangement of the tyrosine receptor kinase TRKA, by RET/PTC genes, or by a BRAF mutation and, in addition, in females they may be stimulated by high levels of estrogen. Furthermore, estrogen is involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer. In contrast to other carcinomas, however, detailed knowledge on this regulation is still missing for thyroid cancer.

Epigenetic silencing of TSHR gene in thyroid cancer patients in relation to their BRAF V600E mutation status.

Promoter hypermethylation of multiple genes have been identified to play a role in thyroid cancers and most prominent among them is TSHR gene promoter hypermethylation in particular showing a close association with BRAF gene-altered status. Thus, the aim of this study was to analyze the TSHR gene promoter hypermethylation in a series of thyroid tumor tissues in the backdrop of their BRAF gene mutational status. Methylation-specific PCR (MS-PCR) was used for detection of promoter methylation while BRAF gene mutational status was analyzed by PCR followed by DNA sequencing in the same series of 60 thyroid tumor tissues. The promoter region of TSHR gene was found to be methylated in 25 % (15 of 60) of the thyroid cancer patients. Patients having elevated TSH levels showed strong association with methylation (OR = 4.0, P = 0.02). BRAF V600E mutation was found in 25 % (15 of 60) patients and among them TSHR promoter was methylated in 73.3 % (11 of 15) patients and only 26.7 % (4 of 15) patients with mutated BRAF showed the absence of TSHR promoter methylation. We found a significant association between the presence of methylation in TSHR with the BRAF V600E mutation-positive cases (P < 0.05). In conclusion, our study showed a high implication of TSHR gene methylation and its significant association with BRAF V600E mutation in thyroid tumors, depicting a positive connection between TSHR pathway and MAP Kinase pathway.

Assessment of Risk Factors For Patients With Thyroid Cancer in Mosul Teaching Hospitals

Background and Objectives: Thyroid cancer is the most common endocrine malignancy. Several riskfactors were found to play a role in thyroid cancer. The aim of the study was to identify risk factors forthyroid cancer in Mosul city and to assess the relationship between some types of food and thyroidcancer.Materials and Methods: The Non-experimental Quantitative design (a Case – Control approach) wasused in this study. The study was conducted at AL-Jamhori Teaching Hospital, Al-Salam TeachingHospital, and Nuclear Medicine and Oncology Hospital in Mosul city. The period from 18th. October,2012 to 20th, August, 2013. A formal consent was taken from all participants (case group and controlgroup) in questionnaire . A non probability purposive sample was selected that consisted (172) clientsdivided into two groups, a case group (86) clients with thyroid cancer and a control group (86) clientswithout goiter and thyroid cancer.Results: According to the age, the highest percentage was in the age group (50-59 years),constituted(34%)for the case group. The majority of the case group are female who were accounted (78.0%) femaleto male ratio 4:1. The incidence of differentiated thyroid carcinoma according to histopathology wasincreased for women compared with men specially papillary thyroid carcinoma.Conclusion: The statistical analysis shows that there are significant relationship in previous history forgoiter, family history for thyroid cancer, and exposure to radio active iodine items with respect to the riskfactors of thyroid cancer.Keywords: Assessment, Risk Factors, Thyroid Cancer.

ZIC1 Is a Putative Tumor Suppressor in Thyroid Cancer by Modulating Major Signaling Pathways and Transcription Factor FOXO3a

ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown. The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis. Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays. ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity. Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.

Identification of RASAL1 as a Major Tumor Suppressor Gene in Thyroid Cancer

RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer. By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer. Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship. We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.

Activation of the two microRNA clusters C19MC and miR-371-3 does not play prominent role in thyroid cancer

Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.

STAT3 negatively regulates thyroid tumorigenesis

Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.

Abstract 943: Characterization of RET and integrin signaling in thyroid tumors

Abstract The REarranged in Transfection (RET) tyrosine kinase is important during development of neural crest derived tissues such as the enteric and sympathetic nervous systems, but is also activated in multiple human tumour types. Activating mutations of RET play an important role in thyroid cancers including both papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). More broadly, recent studies have also shown that RET may be active in other tumour types such as pancreatic and breast cancers, and that the overexpression and activation of RET may be linked to more aggressive disease. In order to explore this link, we have investigated the expression of RET in a large cohort of over 400 thyroid tumour samples of multiple histologies, ranging from benign lesions through to aggressive, metastatic disease by immunhistochemistry using a thyroid tissue microarray. Our data suggest that RET expression may correlate with more aggressive phenotype across a broader spectrum of tumours than previously predicted. We are currently investigating this association further; first by examining the expression of two major RET protein isoforms, RET9 and RET51, in this panel of tumours, and second, by investigating the coexpression of RET with another group of proteins associated with tumour progression, the integrin family. In preliminary studies, we have evaluated RET coexpression with two integrin subunits, ITGB1 and ITGB3. Our data suggest correlation between tumour aggressiveness and coexpression of RET with these integrin subunits. Together, our data provides insight on the role of RET in increasing aggressiveness over a range of tumours. 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 943. doi:1538-7445.AM2012-943

The pituitary tumor transforming gene in thyroid cancer.

The pituitary tumor transforming gene (PTTG) is a multifunctional proto-oncogene that is over-expressed in various tumors including thyroid carcinomas, where it is a prognostic indicator of tumor recurrence. PTTG has potent transforming capabilities in vitro and in vivo, and many studies have investigated the potential mechanisms by which PTTG contributes to tumorigenesis. As the human securin, PTTG is involved in critical mechanisms of cell cycle regulation, whereby aberrant expression induces aneuploidy. PTTG may further contribute to tumorigenesis through its role in DNA damage response pathways and via complex interactions with hormones and growth factors. Furthermore, PTTG over-expression negatively impacts upon the efficacy of radioiodine therapy in thyroid cancer, through repression of expression and function of the sodium iodide symporter. Given its various roles at all disease stages, PTTG appears to be an important oncogene in thyroid cancer. This review discusses the current knowledge of PTTG with particular focus on its role in thyroid cancer.

RET TKI: Potential Role in Thyroid Cancers

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (RET/PTC) or signaling kinases (vascular endothelial growth factor receptor [VEGFR]) involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies able to inhibit RET(sorafenib, imatinib, vandetanib) in stabilizing the course of the disease. The aim of the introduction of these targeted therapies is to extend life duration assuring a good quality of life; however, further studies are needed to reach these goals.

BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy

BRAF(V600E) is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-κB have been shown to play an important role in thyroid cancer. In particular, TIMP-1 binds its receptor CD63 on cell surface membrane and activates Akt signaling pathway, which is eventually responsible for its anti-apoptotic activity. The aim of our study was to evaluate whether interplay among these three factors exists and exerts a functional role in PTCs. To this purpose, 56 PTC specimens were analyzed for BRAF(V600E) mutation, TIMP-1 expression, and NF-κB activation. We found that BRAF(V600E) mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-κB and upregulation of both TIMP-1 and its receptor CD63. To assess the functional relationship among these factors, we first silenced BRAF gene in BCPAP cells, harboring BRAF(V600E) mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-κB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IκB-α and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAF(V600E) activates NF-κB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAF(V600E) causes upregulation of TIMP-1 via NF-κB. TIMP-1 binds then its surface receptor CD63, leading eventually to Akt activation, which in turn confers antiapoptotic behavior and promotion of cell invasion. The recognition of this functional trilogy provides insight on how BRAF(V600E) determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.

Abstract 1075: STAT3 signaling in thyroid cancer

Abstract Here, we examined the contribution of STAT3 activation in papillary thyroid carcinoma (PTC), which constitutes 80% of all thyroid malignancies. We initially examined STAT3 activation (i.e. Y705 phosphorylation) by IHC in 80 primary PTCs. Approximately 50% of the tumors expressed nuclear pSTAT3. In general, positive cancer cells were found on the edge of the tumor and in association with the stroma (also strongly pSTAT3 positive). The inner part of the tumor was generally negative, as well as all solid PTCs. Additionally, we examined human thyroid cancer derived cell lines and determined that STAT3 was phosphorylated in ∼50% and was regulated by the IL-6/gp130/JAK pathway, similarly to what has been described in breast and lung cancers. To assess STAT3's role in thyroid cancer, we evaluated the effects of STAT3 under-expression in two models: thyroid cancer derived cell lines where STAT3 levels were reduced using a short hairpin and a transgenic model of PTC lacking STAT3. We observed no significant effects on in vitro growth, migration and invasion as a consequence of reduced STAT3 levels in cancer cell lines. However, in vivo (xenografts in nude mice) the tumors with low STAT3 were significantly larger compared to control (STAT3 expressing) tumors. Similarly, in a transgenic model of PTC lacking STAT3, tumors were larger, more cellular with evidence of increased proliferation compared to the STAT3 expressing cancers. RNA expression analysis of the human xenografts suggested that tumors deficient in STAT3 have downregulated death-promoting genes. In conclusion, our data suggests that in thyroid cancer STAT3 can function as a tumor suppressor, contrary to the current dogma where STAT3 is considered to be oncogenic. We are currently determining whether STAT3's effect on tumorigenesis is dependent on “activated” or total STAT3 and hope to identify the specific molecular pathways involved. 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 1075. doi:10.1158/1538-7445.AM2011-1075

Thyroid Function and Growth Regulation under Normal and Abnormal Conditions

The thyroid gland exerts a major control on the physiology of the whole body, and it raises fundamental questions about molecular physiological processes. Moreover, an increased proliferation of thyroid cells is associated with several pathologies, and several mechanisms may be involved. Thyroid disorders are very common, affecting millions of people. These include hypothyroidism, hyperthyroidism, thyroid nodules, thyroid cancer, and so forth, but they are also associated with other nonthyroid disorders. This special issue is devoted to illustrate the particular richness of current investigations in the field of thyroid function and growth regulation under normal and abnormal conditions. Although thyroid gland function is mainly under the control of pituitary TSH in normal conditions, other factors may also play a role in this process. Thyroid disease is more common in women than in men. Tania Weber Furlanetto and Ana Paula Santin reviewed the direct effects of estrogens on thyroid function and growth regulation in the paper titled “Role of estrogen in thyroid function and growth regulation.” Thyroid cancer is the most common endocrine malignancy, and its incidence has significantly risen in the last decades in the world. The knowledge how thyroid cancer develops is expanding rapidly. The sequential acquisition of mutations which arise as a consequence of damage to the genome is required in order to transform a normal cell into a malignant one. The understanding of the process of thyroid carcinogenesis at the molecular level will improve not only the diagnostic but also the treatment of this pathology. Ioannis Legakis and Konstantinos Syrigos describe the molecular events associated with the progression and dedifferentiation of thyroid carcinoma in the paper titled “Recent advances in molecular diagnosis of thyroid cancer.” Thyroid-specific transcription factors regulate thyroid-specific gene expression and organogenesis. Their possible role in thyroid cancer as well as in the maintenance and/or activity of stem cells is discussed by Shioko Kimura in the paper titled “Thyroid-specific transcription factors and their roles in thyroid cancer.” MicroRNAs (miRNAs) are short ribonucleic acid molecules (around 22 nucleotides) found in eukaryotic cells. miRNAs are posttranscriptional regulators that bind to complementary sequences on messenger RNA transcripts inducing the translational repression or messenger RNA degradation. Several miRNAs have been found to have links with some types of cancer. Francesca Marini, Ettore Luzi, and Maria Luisa Brandi reviewed the role of miRNAs in thyroid cancer development in the paper titled “MicroRNA role in thyroid cancer development.” Growth factors play a role in thyroid proliferation and function, while EGF acts as a mitogen for thyroid cells inhibiting also thyroid differentiation. TGF-β is a potent inhibitor of thyroid cell growth. However, in some transformed thyroid cells this inhibition is lost. The role of TGF-β and EGF on thyroid carcinogenesis and the crosstalk between these growth factors are discussed by Gabriella Mincione Maria Carmela Di Marcantonio, Chiara Tarantelli, Sonia D'Inzeo, Arianna Nicolussi, Francesco Nardi, Caterina Francesca Donini, and Anna Coppa in the paper titled “EGF and TGF-β1 effects on thyroid function.” Grave's disease and Hashimoto's thyroiditis are the two main types of autoimmune thyroid disease. Occasionally they are also associated with other autoimmune diseases. Emina Kasumagic-Halilovic, Asja Prohic, Begler Begovic, and Nermina Ovcina-Kurtovic bring additional support to the existence of a significant association between vitiligo and thyroid autoimmunity in the paper titled “Association between vitiligo and thyroid autoimmunity.” Although some authors have found an association between an abnormal thyroid condition and bipolar disorder, little is known about the implication of the hypothalamo-pituitary-thyroid in neuropsychological deficits. Subho Chakrabarti review the last findings on this topic including genetic and neuroimaging investigations (Thyroid Functions and Bipolar Affective Disorder). Guillermo Juvenal Daniel Christophe Pierre Roger Mario Pisarev

Thyroid-Specific Transcription Factors and Their Roles in Thyroid Cancer

Homeodomain, forkhead domain, and paired domain-containing transcription factors play a major role in development, tissue-specific gene expression, and tissue homeostasis in organs where they are expressed. Recently, their roles in stem cell and cancer biology are emerging. In the thyroid, NKX2-1, FOXE1, and PAX8 transcription factors are responsible for thyroid organogenesis and expression of thyroid-specific genes critical for thyroid hormone synthesis. In contrast to their known roles in gene regulation, thyroid development and homeostasis, their involvement in stem cell, and/or cancer biology are still elusive. In order to further understand the nature of thyroid cancer, it is critical to determine their roles in thyroid cancer.

PPARγPromotes Growth and Invasion of Thyroid Cancer Cells

Undifferentiated (anaplastic) thyroid cancer (ATC) is one of the most aggressive human malignancies and no effective therapy is currently available. We show here that PPARγ levels are elevated in cells derived from ATC. Depletion of PPARγ in HTh74 ATC cells resulted in decreased cell growth, cell cycle arrest and a reduction in pRb and cyclin A and B1 levels. We further showed that both flank and orthotopic thyroid tumors derived from PPARγ-depleted cells grew more slowly than PPARγ-expressing cells. When PPARγ was overexpressed in more differentiated thyroid cancer BCPAP cells which lack PPARγ, there was increased growth and raised pRb and cyclin A and B1 levels. Finally, PPARγ depletion in ATC cells decreased their invasive capacity whereas overexpression in PTC cells increased invasiveness. These data suggest that PPARγ may play a detrimental role in thyroid cancer and that targeting it therapeutically may lead to improved treatment of advanced thyroid cancer.

Role of dietary iodine and cruciferous vegetables in thyroid cancer: a countrywide case–control study in New Caledonia

Exceptionally high incidence rates of thyroid cancer have been reported in New Caledonia, particularly in Melanesian women. To clarify the reasons of this elevated incidence, we conducted a countrywide population-based case-control study in the multiethnic population of Caledonian women. The study included 293 cases of thyroid cancer and 354 population controls. Based on a food frequency questionnaire, we investigated the role in thyroid cancer of food items rich in iodine-such as seafood-and of vegetables containing goitrogens-such as cruciferous vegetables. A measure of total daily iodine intake based on a food composition table was also used. Our findings provided little support for an association between thyroid cancer and consumption of fish and seafood. We found that high consumption of cruciferous vegetables was associated with thyroid cancer among women with low iodine intake (OR = 1.86; 95% CI: 1.01-3.43 for iodine intake <96 microg/day). The high consumption of cruciferous vegetables among Melanesian women, a group with mild iodine deficiency, may contribute to explain the exceptionally high incidence of thyroid cancer in this group.

Cyclooxygenase-2 is Involved in the Progression of Thyroid Cancer

Although the inducible form of cyclooxygenase (COX), COX-2, is highly expressed in various cancers and it is also involved in cancer progression, its role in thyroid cancer is not fully understood. We assessed in the situ cyclooxygenase expression in normal thyroids (n=6), Graves' thyroids (n=6), thyroid adenomas (n=12), thyroid follicular (n=15) and papillary carcinomas (n=30). In comparison to the constitutive expression of COX-1, COX-2 was highly expressed in thyroid cancers (90.0% of thyroid papillary carcinomas and 73.3% of thyroid follicular carcinomas) and moderately in thyroid adenomas (25.5%), but barely expressed in normal and Graves' thyroid tissues. This quantitative assessment employed immunohistochemical methods. Thereafter we compared the effect of COX-2 inhibition on a human follicular thyroid carcinoma cell line (WRO), and a human papillary carcinoma cell line (NPA), using selective COX-2 inhibitor(NS-398). The treatment with 50 M NS-398 suppressed the growth of the COX-2 expressing cells, NPA cells (37.7%;p<0.01) and WRO cells (10.1%;p<0.05). Moreover, at concentrations 100 M, NS-398 induced cell death a mitochondrial dysfunction. In addition, 50 M of NS-398 inhibited the activation of extracellular signalregulated kinase in NPA cells after the stimulation with fetal bovine serum. Our results indicate that COX-2 is involved in the progression of thyroid cancer. ACTA MEDICA NAGASAKIENSIA 54: 9－14, 2009

Strong Association of Chromosome 1p12 Loci with Thyroid Cancer Susceptibility

Several genes directly related to thyroid cancer development have been described; nevertheless, the genetic pathways of this tumorigenesis process are unknown. Together with environmental factors, susceptibility genes could have an important role in thyroid cancer. Our previous studies suggest that the chromosome 1p12-13 is related to thyroid cancer incidence. Here, we extend the analysis with a case-control association study in a Spanish population. Thus, six single-nucleotide polymorphisms were genotyped, covering 2.4 Mb of the 1p12-13 region. A statistically significant association between thyroid cancer incidence and the rs2145418 and rs4658973 polymorphisms was found (P < 0.0001). No association was detected for the other four polymorphisms studied. The rs2145418 marker showed a significant odds ratio of 5.0 [95% confidence interval (95% CI), 2.85-8.83] and 9.2 (95% CI, 4.50-21.6) for heterozygous and homozygous G-variant alleles, respectively. For rs4658973, the odds ratios were 0.40 (95% CI, 0.26-0.62) and 0.07 (95% CI, 0.03-0.18) for heterozygous and homozygous G-variant alleles, respectively. These markers map into the 1p12 region, and no linkage disequilibrium was found between them, indicating an independent relation of these polymorphisms with thyroid cancer susceptibility. Our data provide evidence of a strong association of the chromosome 1p12 with thyroid cancer risk, and it is the first study describing susceptibility loci for thyroid cancer in this region.