Endocrinology, doi:10.1210/en.2006-0927
Endocrinology Vol. 148, No. 3 948-953
Copyright © 2007 by The Endocrine Society
Gene Methylation in Thyroid Tumorigenesis
Mingzhao Xing
Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
Address all correspondence and requests for reprints to: Michael Mingzhao Xing, M.D., Ph.D., Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287. E-mail: mxing1{at}jhmi.edu.
 |
Abstract
|
|---|
Aberrant gene methylation plays an important role in human tumorigenesis, including thyroid tumorigenesis. Many tumor suppressor genes are aberrantly methylated in thyroid cancer, and some even in benign thyroid tumors, suggesting a role of this epigenetic event in early thyroid tumorigenesis. Methylation of some of these genes tends to occur in certain types of thyroid cancer and is related to specific signaling pathways. For example, methylation of PTEN and RASSF1A genes occurs mostly in follicular thyroid cancer, and its tumorigenic role may be related to the phosphatidylinositol 3-kinase/Akt signaling pathway, whereas methylation of genes for tissue inhibitor of metalloproteinase-3, SLC5A8, and death-associated protein kinase occurs in papillary thyroid cancer and is related to the BRAF/MAPK kinase/MAPK pathway. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter and thyroid-stimulating hormone receptor, is also common in thyroid cancer. Although its tumorigenic role is not clear, methylation, and hence silencing, of these thyroid-specific genes is a cause for the failure of clinical radioiodine treatment of thyroid cancer. Unlike gene methylation, histone modifications have been relatively poorly investigated in thyroid tumors. Future studies need to emphasize the mechanistic aspects of these two types of epigenetic alterations to uncover new molecular mechanisms in thyroid tumorigenesis and to provide novel therapeutic targets for thyroid cancer.
|
Introduction
|
|---|
EPIGENETIC ALTERATIONS, changes around a gene that alter gene expression without affecting the nucleotide sequence of the gene, play a fundamental role in the regulation of human gene expression. Two epigenetic mechanisms are commonly used by cells to regulate gene expression: DNA methylation and histone modifications (1, 2). DNA methylation is an epigenetic event in which a methyl group is added to the fifth carbon position of the cytosine residue in a CpG dinucleotide. The regions rich in CpG dinucleotides are termed CpG islands and are usually located in the 5'-flanking promoter areas of genes. Gene promoter methylation, particularly near the transcription start site, occurs in close association with chromatin remodeling and is usually associated with silencing of the gene (1, 2). This methylation-induced gene silencing occurs through recruitment of DNA methyl-binding transcription repressors or through blockage of DNA binding of transcriptional factors.
|
Overview of Epigenetic Regulation of Genes
|
|---|
DNA methylation is an important physiological mechanism in the regulation of gene expression, particularly during embryogenesis, and is normally present in genes on the inactive X chromosome and imprinted genes. In contrast, normally expressed genes, such as the housekeeping genes, are protected from methylation in normal cells. This protection is critical because methylation of CpG islands in the promoter is associated with loss of gene expression. Aberrant gene methylation occurs frequently in pathological conditions, particularly in cancers, leading to inappropriate silencing of genes. Such methylation in human cancers has been frequently found in tumor suppressor genes that are silenced and plays a fundamental role in human tumorigenesis. In fact, like genetic alterations, gene methylation has long been known to be a hallmark of human cancer (3, 4).
Histone modification, including acetylation and methylation, is another important epigenetic event in gene regulation. There is an intricate interplay between DNA methylation and histone modification in gene regulation during chromatin remodeling (5, 6). In eukaryotes, genetic DNA is organized into chromatin. The basic structural unit of chromatin, the nucleosome, consists of a DNA fragment (about 146 bp) wrapped around a complex of histone octamer comprised of pairs of the core histones H2A, H2B, H3, and H4. The dynamics of acetylation-deacetylation of the N termini of histone is balanced by histone acetyltransferase and histone deacetylase (HDAC). Acetylation occurs to the lysine residues, and histone deacetylation frees these positively charged residues, which facilitates the binding of histone to the negatively charged DNA and tightly compacts the chromatin. This prevents the access of transcription machinery to gene promoter and represses expression of the gene (7, 8). It has been well known that DNA methyltransferases interact with HDAC (5), and HDACs are recruited by methyl-CpG-binding proteins (9, 10, 11). Therefore, DNA methylation and histone modifications are two closely associated epigenetic events that occur in a coordinated manner in the regulation of gene expression. Not surprisingly, aberrant epigenetic alterations lead to disrupted regulation of important genes and play a critical role in the tumorigenesis of human cancers, including thyroid cancer.
|
Aberrant Methylation of Tumor Suppressor Genes in Thyroid Tumors
|
|---|
Follicular epithelial cell-derived thyroid cancer can be classified histologically into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC), which account for about 80, 15, and 2–5% of all thyroid malignancies, respectively (12). Follicular epithelial cell-derived benign thyroid neoplasms (BTN), including adenoma and hyperplasia, are more common than thyroid cancer. As in other human tumors, aberrant methylation, and hence inappropriate silencing, of tumor suppressor genes are common in thyroid tumors. Examples of these genes include PTEN (13), RASSF1A (14, 15), tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK), and retinoic acid receptor ß2 (RARß2) (16, 17). These tumor suppressor genes have well-established, tumor-suppressing function through various mechanisms. It is therefore conceivable that silencing of these genes through methylation has serious consequences and plays an important role in thyroid tumorigenesis.
Aberrant methylation of some tumor suppressor genes are seen in both thyroid cancer and BTN, albeit usually more common and extensive in the former, suggesting its role early in thyroid tumorigenesis. PTEN and RASSF1A genes represent two such examples. PTEN gene encodes a phosphatase that dephosphorylates phosphatidylinositol-3,4,5-trisphosphate and hence terminates the signaling of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (18). Germline inactivating mutations and deletions of this gene are the cause of Cowden’s syndrome, which is associated with development of BTN and FTC. This gene was recently found to be aberrantly methylated in both BTN and thyroid cancer, including PTC and FTC (13). Similarly, the RASSF1A gene, which encodes a signaling protein that may function through a pathway involving Ras, is methylated in many human tumors (19) as well as BTN and thyroid cancers, including PTC, FTC, and ATC (14, 15). Interestingly, these studies showed that, among different thyroid tumors, methylation of RASSF1A and PTEN occurred most frequently and extensively in FTC, suggesting a unique and specific role of silencing of the two genes in this cancer. Aberrant signaling of the PI3K/Akt pathway plays an important role in the tumorigenesis of thyroid cancer, particularly FTC (20, 21). Because RASSF1A signaling may involve Ras and the latter is a component of the PI3K/Akt pathway, it remains an interesting question as to whether methylation-mediated silencing of RASSF1A contributes to thyroid tumorigenesis through alteration of the PI3K/Akt pathway. Although aberrant methylation of RASSF1A occurred frequently in both BTN and FTC, a level of more than 50% of allelic methylation was seen only in the latter but not in the former, suggesting that methylation, and therefore silencing, of both RASSF1A alleles may be required for the pathogenesis and development of FTC (15). It remains to be explored whether this is a critical epigenetic event that can convert BTN to FTC. Interestingly, Ras mutations are also common in BTN and FTC, more so in the latter (22). These genetic and epigenetic data are consistent with the conventional belief that FTC can derive from BTN.
Based on recent evidence in other human cancers that epigenetic alterations may addict the tumor cell to altered signaling pathways early in tumorigenesis, it is proposed that dependence of cell proliferation and survival on these signaling pathways may lead to acquirement of genetic alterations in the same pathway, conferring the cell with selective advantages for tumor progression (23). It remains to be investigated whether this is the case with the relationship of RASSF1A methylation and Ras mutations in early thyroid tumorigenesis. A small fraction of PTC also harbored RASSF1A methylation involving both alleles and in a mutually exclusive manner with BRAF mutation, suggesting that loss of RASSF1A expression in some PTC, as in FTC, is an important event in tumorigenesis independently of BRAF/MAPK kinase (MEK)/MAPK pathway (15).
Methylation of several tumor suppressor genes may play an important role also in PTC tumorigenesis, including TIMP3, SLC5A8, and DAPK, because it is associated with poor pathological characteristics of PTC (17). TIMP3 is a tissue inhibitor of metalloproteinase, which has been demonstrated to inhibit growth, angiogenesis, invasion, and metastasis of several cancers (24, 25). This gene was found to be hypermethylated in many human cancers (26, 27, 28, 29), including thyroid cancer (16, 17). A close association of TIMP3 methylation with extrathyroidal invasion, lymph node metastasis, and multifocality of the tumor was observed in our recent study on a large series of PTC (17). This is consistent with the loss of the function of TIMP3 as an inhibitor of metalloproteinase, which promotes cancer spread by degrading interstitial matrix substance, and as an antagonist of angiogenesis by blocking vascular endothelial growth factor (VEGF) binding to VEGF receptor-2 (25). SLC5A8 is a member of the sodium solute symporter family (SLC5) and is widely expressed in human tissues, including thyroid tissue (30, 31, 32). Its tumor suppressor function, through proapoptosis, has been well documented and its gene is frequently methylated in human cancers (33, 34, 35, 36), including thyroid cancer (32, 17). Methylation of this gene was shown to be associated with extrathyroidal invasion, multifocality, and advanced tumor stages of PTC (17), strongly supporting a role of silencing of this gene in the progression of PTC. DAPK is a calcium/calmodulin-dependent serine threonine kinase that plays a tumor suppressing role through its proapoptotic function (37). This gene is frequently hypermethylated and silenced in human cancers (37), including thyroid cancer (16, 17). Methylation of this gene was associated with multifocality of PTC (17). In thyroid tumor cell lines, methylation of these tumor suppressor genes was shown to be associated with gene silencing, which could be reversed by treatment of cells with demethylating agents (17). Although further mechanistic studies are needed, demonstration of association of methylation of these tumor suppressor genes with aggressiveness of PTC provides strong evidence supporting an important role of methylation-induced silencing of these genes in PTC tumorigenesis.
|
Association of BRAF Mutation with Aberrant Methylation of Tumor Suppressor Genes in Papillary Thyroid Cancer
|
|---|
The T1799A BRAF mutation occurs commonly in PTC (38). This mutation causes a V600E amino acid change in the BRAF kinase, with constitutive activation of the kinase. The BRAF mutation was able to initiate the development of PTC with aggressive behaviors in transgenic mice (39). Several clinicopathological studies also suggested an important role of the BRAF mutation in the progression of PTC by showing the correlation of this mutation with aggressive clinicopathological characteristics and recurrence of this cancer (40, 41, 42, 43, 44). The molecular mechanism involved in tumor aggressiveness of PTC harboring the BRAF mutation is not clear, however. The recent demonstration of association of BRAF mutation with aberrant methylation of several tumor suppressor genes in PTC seems to shed light on this issue. These include TIMP3, SLC5A8, DAPK, and RARß2 genes (17). Because methylation of these genes was also associated with aggressive pathological characteristics of PTC, it is conceivable that silencing of these genes is an important mechanism mediating BRAF mutation-promoted progression of PTC. Interestingly, BRAF mutation was recently shown to be associated with overexpression of VEGF (45). In addition to being a metalloproteinase inhibitor, TIMP3 is also a VEGF receptor antagonist (25). Therefore, the dual effects of mutant BRAF on methylation-induced TIMP3 silencing and VEGF overexpression may be a particularly effective mechanism for BRAF mutation-promoted PTC progression and aggressiveness, particularly in the form of extrathyroidal invasion, metastasis, and recurrence of this cancer.
Methylation of TIMP3, SLC5A8, DAPK, and RARß2 in association with BRAF mutation seemed to be selective in PTC because methylation of many other tumor suppressor genes was found to be uncommon in this cancer (17). Methylation occurred concurrently in these genes and was associated with BRAF mutation both individually and in various combinations of these genes (17). In colorectal cancer and other cancer cells, it is often observed that specific groups of CpG islands are hypermethylated with gene silencing, leading to the proposal that these cells acquired a hypermethylator phenotype (46). The types or subtypes of cancer with this gene methylation patterns are thought to be distinct and are defined as CpG island methylator phenotype (CIMP). A recent study (47) demonstrated that this CIMP is tightly associated with BRAF mutation in colorectal cancers. It would thus be interesting to use the CIMP concept to consider the subset of PTC that uniquely harbors BRAF mutation-associated cluster methylation of tumor suppressor genes. This seems to be a meaningful consideration, particularly given the common association of methylation-induced silencing of these genes with increased cancer invasion and aggressiveness that seems to define a subgroup of PTC as a unique hypermethylator phenotype. Two fundamental questions remain unanswered as to whether BRAF mutation occurs first or cluster methylation of these genes occurs first and whether there is a causal relationship between these genetic and epigenetic alterations in PTC. If BRAF mutation is the initiator of methylation of these genes, it remains to be investigated whether molecular alterations occur at the DNA methyltransferase level or at the chromatin microenvironmental level around the gene promoter that, as a consequence of aberrant BRAF/MEK/MAPK signaling, lead to hypermethylation of these genes. It also remains an interesting question why these genes are selective in methylation in association with the BRAF/MEK/MAPK pathway in PTC.
|
Aberrant Methylation of Thyroid-Specific Genes in Thyroid Cancer
|
|---|
A unique physiological function of thyroid gland is its ability to uptake, concentrate, and use iodide to synthesize thyroid hormones to meet the normal metabolism of the body. This process involves several key protein molecules that are specifically expressed in follicular epithelial cells of the thyroid gland (48). Iodide is transported from the blood into thyroid cell through the sodium/iodide symporter (NIS) in the basal membrane, followed by transportation presumably through pendrin (also called SLC26A4) in the apical membrane of the cell into the follicular lumen in which, through thyroid peroxidase, iodide is oxidized and organified into thyroglobulin (Tg) on tyrosine residues for the formation of thyroid hormones. The entire process is coordinated by hormonal regulation, in which TSH, acting by binding to the TSH receptor (TSHR), plays a central role. Expression of these thyroidal iodide-metabolizing molecules is frequently lost in thyroid cancer (e.g. Refs. 49, 50, 51, 52) and aberrant localization or dysfunction of NIS may also occur, resulting in loss of the ability of cancer cells to concentrate radioiodine. Consequently, these thyroid cancer patients may fail radioiodine therapy, the mainstay of medical treatment for this cancer. This is a major cause of thyroid cancer-related morbidity and mortality (53, 54).
Although the molecular mechanism underlying silencing of thyroid-specific genes in thyroid cancer is unclear, aberrant gene methylation is conceivably an important mechanism. Many of these thyroid-specific genes are methylated in the promoter areas in thyroid tumors, including NIS (50, 55), TSHR (56), the genes for the putative thyroid follicular cell apical iodide transporters SLC26A4 (57) and SLC5A8 gene (17, 32). Methylation of thyroid-specific genes was also found in thyroid cell lines. For example, aberrant methylation and associated silencing of NIS gene was demonstrated in human thyroid tumor cell lines, which could be reversed by treatment of cells with demethylating agents (50). We reported similar findings for TSHR gene in human thyroid tumor cell lines (56). In rat thyroid cells, Tg promoter became methylated on transformation of the cell (58). Also in rat thyroid cells, TSHR promoter methylation was shown to block the binding of a transcription factor GA-binding protein with TSHR promoter with consequent silencing of the gene (59). Interestingly, several thyroid-specific genes were shown to be silenced on activation of the BRAF/MEK/MAPK pathway with induced expression of BRAF V600E in rat and human thyroid cell lines (43, 60). Suppression of MAPK pathway could restore the expression of these genes and, at least in the case of TSHR gene, demethylation of the gene associated with its expression occurred with suppression of the BRAF/MEK/MAPK pathway (60). The SLC5A8 tumor suppressor gene is also a putative iodide transporter in the apical membrane of follicular thyroid cells (30, 31). Methylation and silencing of this gene was closely associated with BRAF mutation in PTC (17, 32). Therefore, aberrant methylation and hence silencing of thyroid-specific genes are common in thyroid cancer. An important question remains unanswered as to whether silencing of these thyroid-specific genes, which are not classical tumor suppressor genes, plays some primary role in driving thyroid tumorigenesis or is simply a secondary event of aberrant activation of other signaling pathways, such as the BRAF/MEK/MAPK pathway in PTC. Silencing of thyroid-specific genes often occurs with progression and dedifferentiation of thyroid cancer. In this sense, methylation, and hence silencing, of these genes might be a driving force for thyroid cancer pathogenesis and progression, albeit through an undefined mechanism. Regardless of its biological mechanism and relevance in thyroid tumorigenesis, methylation-mediated silencing of thyroid-specific genes is clearly clinically relevant because it is a cause of the loss of radioiodine avidity and hence radioiodine treatment failure and consequent progression of thyroid cancer.
|
Histone Modification of Genes in Thyroid Tumorigenesis
|
|---|
Unlike gene methylation, fewer in-depth studies have been conducted to investigate the role of histone modifications in thyroid tumorigenesis. A previous study demonstrated that HDAC inhibitors could promote apoptosis and cell cycle arrest in ATC cell lines (61). This probably involved increased P53 transcriptional activity (62, 63). Other mechanisms may include the modulation of cell cycle-related molecules, such as the p27 protein (64). Several studies showed that histone modifications, particularly acetylation/deacetylation, also played a role in the regulation of thyroid-specific genes in thyroid tumorigenesis. For example, a previous study tested the effect of the HDAC inhibitor depsipeptide on expression of NIS and Tg and showed reexpression of these genes with increased iodine uptake and histone acetylation in poorly differentiated thyroid cancer cell lines (65). Similar results of other HDAC inhibitors on iodine uptake were reported in poorly differentiated and ATC cell lines with reexpression of NIS, thyroid peroxidase, and Tg (66). A recent study demonstrated that inhibitors of HDAC could increase NIS expression in thyroid tumor cell lines with increased promoter activity of NIS through promoter acetylation in a transcription factor-independent manner (67). Although mechanistic data are lacking, the results from these studies do suggest the involvement and importance of histone modifications in gene regulation in thyroid tumorigenesis, a research area that needs to be further explored.
|
Conclusions
|
|---|
As in other human cancers, aberrant gene methylation plays an important role in thyroid tumorigenesis. The genes known to be aberrantly methylated in thyroid tumors include both tumor suppressor genes and thyroid-specific genes. Methylation of some of the tumor suppressor genes may play its tumorigenic role in association with aberration of well-known signaling pathways such as the PI3K/Akt pathway in FTC and the BRAF/MEK/MAPK pathway in PTC. Whether aberrant methylation-induced silencing of thyroid-specific genes plays a primary role in thyroid tumorigenesis is not clear, but it is an important cause of radioiodine treatment failure and hence clinical progression of thyroid cancer. Data on histone modifications in thyroid tumorigenesis are relatively limited. Future studies should emphasize mechanistic exploration on these epigenetic alterations to uncover new molecular mechanisms in thyroid tumorigenesis that may provide novel therapeutic targets for thyroid cancer.
|
Footnotes
|
|---|
This work was supported by an American Cancer Society Research Scholar Grant (RSG-05-199-01-CCE) and a Flight Attendant Medical Research Institute Clinical Innovator Award (to M.M.X.).
Disclosure Summary: The author has nothing to declare.
First Published Online August 31, 2006
Abbreviations: ATC, Anaplastic thyroid cancer; BTN, benign thyroid neoplasm; CIMP, CpG island methylator phenotype; DAPK, death-associated protein kinase; FTC, follicular thyroid cancer; HDAC, histone deacetylase; MEK, MAPK kinase; NIS, sodium/iodide symporter; PI3K, phosphatidylinositol 3-kinase; PTC, papillary thyroid cancer; RARß2, retinoic acid receptor ß2; Tg, thyroglobulin; TIMP3, tissue inhibitor of metalloproteinase-3; TSHR, TSH receptor; VEGF, vascular endothelial growth factor.
Received July 20, 2006.
Accepted for publication August 24, 2006.
|
References
|
|---|
- Bird A 2002 DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21[Free Full Text]
- Yoo CB, Jones PA 2006 Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50[CrossRef][Medline]
- Bird AP 1996 The relationship of DNA methylation to cancer. Cancer Surv 28:87–101[Medline]
- Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP 1998 Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196[Medline]
- Robertson KD 2002 DNA methylation and chromatin-unraveling the tangled web. Oncogene 21:5361–5379[CrossRef][Medline]
- Hashimshony T, Zhang J, Keshet I, Bustin M, Cedar H 2003 The role of DNA methylation in setting up chromatin structure during development. Nat Genet 34:187–192[CrossRef][Medline]
- Grunstein M 1997 Histone acetylation in chromatin structure and transcription. Nature 389:349–352[CrossRef][Medline]
- Jenuwein T, Allis CD 2001 Translating the histone code. Science 293:1074–1080[Abstract/Free Full Text]
- Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A 1998 Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389[CrossRef][Medline]
- Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A 1999 MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 23:58–61[Medline]
- Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP 1999 Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23:62–66[Medline]
- Hundahl SA, Fleming ID, Fremgen AM, Menck HR 1998 A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 83:2638–2648[CrossRef][Medline]
- Alvarez-Nunez F, Bussaglia E, Mauricio D, Ybarra J, Vilar M, Lerma E, de Leiva A, Matias-Guiu X 2006 Thyroid Neoplasia Study Group. PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid 16:17–23[CrossRef][Medline]
- Schagdarsurengin U, Gimm O, Hoang-Vu C, Dralle H, Pfeifer GP, Dammann R 2002 Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma. Cancer Res 62:3698–3701[Abstract/Free Full Text]
- Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, Sidransky D 2004 Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res 64:1664–1668[Abstract/Free Full Text]
- Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, Sidransky D, Umbricht CB 2005 Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab 90:4011–4018[Abstract/Free Full Text]
- Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M 2006 Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF Mutation in papillary thyroid cancer. Int J Cancer 119:2322–2329[CrossRef][Medline]
- Cantley LC, Neel BG 1999 New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245[Abstract/Free Full Text]
- Pfeifer GP, Dammann R 2005 Methylation of the tumor suppressor gene RASSF1A in human tumors. Biochemistry (Mosc) 70:576–583[CrossRef][Medline]
- Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, Bernet V, Burman KD, Kohn LD, Saji M 2001 Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res 61:6105–6111[Abstract/Free Full Text]
- Hou P, Liu D, Shan Y, Hu S, Studeman K, Condouris S, Wang Y, El-Naggar AK, Xing M, Genetic alterations and their relationship in the PI3K/Akt pathway in thyroid cancer: implications for this pathway as a major therapeutic target. Clin Cancer Res, in press
- Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C 2003 Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab 88:2745–2752[Abstract/Free Full Text]
- Baylin SB, Ohm JE 2006 Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116[CrossRef][Medline]
- Anand-Apte B, Bao L, Smith R, Iwata K, Olsen BR, Zetter B, Apte SS 1996 A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 74:853–862[Medline]
- Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B 2003 A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9:407–415[CrossRef][Medline]
- van der Velden PA, Zuidervaart W, Hurks MH, Pavey S, Ksander BR, Krijgsman E, Frants RR, Tensen CP, Willemze R, Jager MJ, Gruis NA 2003 Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer 106:472–479[CrossRef][Medline]
- Feng H, Cheung AN, Xue WC, Wang Y, Wang X, Fu S, Wang Q, Ngan HY, Tsao SW 2004 Down-regulation and promoter methylation of tissue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol 94:375–382[CrossRef][Medline]
- Brueckl WM, Grombach J, Wein A, Ruckert S, Porzner M, Dietmaier W, Rummele P, Croner RS, Boxberger F, Kirchner T, Hohenberger W, Hahn EG 2005 Alterations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) are found frequently in human colorectal tumours displaying either microsatellite stability (MSS) or instability (MSI). Cancer Lett 223:137–142[CrossRef][Medline]
- Darnton SJ, Hardie LJ, Muc RS, Wild CP, Casson AG 2005 Tissue inhibitor of metalloproteinase-3 (TIMP-3) gene is methylated in the development of esophageal adenocarcinoma: loss of expression correlates with poor prognosis. Int J Cancer 115:351–358[CrossRef][Medline]
- Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T 2002 Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab 87:3500–3503[Abstract/Free Full Text]
- Lacroix L, Pourcher T, Magnon C, Bellon N, Talbot M, Intaraphairot T, Caillou B, Schlumberger M, Bidart JM 2004 Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters. J Clin Endocrinol Metab 89:1423–1428[Abstract/Free Full Text]
- Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, Borson-Chazot F, Dante R, Rousset B 2005 Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab 90:3028–3035[Abstract/Free Full Text]
- Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD 2003 SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA 100:8412–8417[Abstract/Free Full Text]
- Ueno M, Toyota M, Akino K, Suzuki H, Kusano M, Satoh A, Mita H, Sasaki Y, Nojima M, Yanagihara K, Hinoda Y, Tokino T, Imai K 2004 Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol 25:134–140[CrossRef][Medline]
- Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF 2005 Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res 65:3617–3623[Abstract/Free Full Text]
- Ganapathy V, Gopal E, Miyauchi S, Prasad PD 2005 Biological functions of SLC5A8, a candidate tumour suppressor. Biochem Soc Trans 33:237–240[CrossRef][Medline]
- Schneider-Stock R, Roessner A, Ullrich O 2005 DAP-kinase—protector or enemy in apoptotic cell death. Int J Biochem Cell Biol 37:1763–1767[CrossRef][Medline]
- Xing M 2005 BRAF mutation in thyroid cancer. Endocr Relat Cancer 12:245–262[Medline]
- Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao XH, Refetoff S, Nikiforov YE, Fagin JA 2005 Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 65:4238–4245[Abstract/Free Full Text]
- Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE 2003 BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 88:5399–5404[Abstract/Free Full Text]
- Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S 2003 Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397[Abstract/Free Full Text]
- Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW 2005 BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373–6379[Abstract/Free Full Text]
- Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M, Santisteban P 2006 The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I– targeting to the membrane. Endocr Relat Cancer 13:257–269[Abstract/Free Full Text]
- Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC, Hong SJ, Shong YK 2006 The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf) 65:364–368[CrossRef][Medline]
- Jo YS, Li S, Song JH, Kwon KH, Lee JH, Rha SY, Lee HJ, Sul JY, Kweon GR, Ro H-K, Kim J-M, Shong M 2006 Influence of the BRAF V600E mutation on expression of VEGF in papillary thyroid cancer. J Clin Endocrinol Metab 91:3667–3670[Abstract/Free Full Text]
- Issa JP 2004 CpG island methylator phenotype in cancer. Nat Rev Cancer 4:988–993[CrossRef][Medline]
- Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW 2006 CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793[CrossRef][Medline]
- Nilsson M 2001 Iodide handling by the thyroid epithelial cell. Exp Clin Endocrinol Diabetes 109:13–17[CrossRef][Medline]
- Sheils OM, Sweeney EC 1999 TSH receptor status of thyroid neoplasms-TaqMan RT-PCR analysis of archival material. J Pathol 188:87–92[CrossRef][Medline]
- Venkataraman GM, Yatin M, Marcinek R, Ain KB 1999 Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I– symporter gene methylation status. J Clin Endocrinol Metab 84:2449–2457[Abstract/Free Full Text]
- Ringel MD, Anderson J, Souza SL, Burch HB, Tambascia M, Shriver CD, Tuttle RM 2001 Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol 14: 289–296
- Arturi F, Russo D, Bidart JM, Scarpelli D, Schlumberger M, Filetti S 2001 Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors. Eur J Endocrinol 145:129–135[Abstract]
- Ain KB 2000 Management of undifferentiated thyroid cancer. Baillieres Best Pract Res. Clin Endocrinol Metab 14: 615–629
- Sherman SI 2003 Thyroid carcinoma. Lancet 361:501–511[CrossRef][Medline]
- Neumann S, Schuchardt K, Reske A, Reske A, Emmrich P, Paschke R 2004 Lack of correlation for sodium iodide symporter mRNA and protein expression and analysis of sodium iodide symporter promoter methylation in benign cold thyroid nodules. Thyroid 14:99–111[CrossRef][Medline]
- Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, Tong BC, Tallini G, Udelsman R, Califano JA, Ladenson PW, Sidransky D 2003 Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res 63:2316–2321[Abstract/Free Full Text]
- Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D 2003 Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. Cancer Res 63:2312–2315[Abstract/Free Full Text]
- Berlingieri MT, Musti AM, Avvedimento VE, Di Lauro R, Di Fiore PP, Fusco A 1989 The block of thyroglobulin synthesis, which occurs upon transformation of rat thyroid epithelial cells, is at the transcriptional level and it is associated with methylation of the 5' flanking region of the gene. Exp Cell Res 183:277–283[CrossRef][Medline]
- Yokomori N, Tawata M, Saito T, Shimura H, Onaya T 1998 Regulation of the rat thyrotropin receptor gene by the methylation-sensitive transcription factor GA-binding protein. Mol Endocrinol 12:1241–1249[Abstract/Free Full Text]
- Liu D, Hu S, Hou P, Jing D, Condouris S, Xing M, Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res, in press
- Greenberg VL, Williams JM, Cogswell JP, Mendenhall M, Zimmer SG 2001 Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. Thyroid 11:315–325[CrossRef][Medline]
- Imanishi R, Ohtsuru A, Iwamatsu M, Iioka T, Namba H, Seto S, Yano K, Yamashita S 2002 A histone deacetylase inhibitor enhances killing of undifferentiated thyroid carcinoma cells by p53 gene therapy. J Clin Endocrinol Metab 87:4821–4824[Abstract]
- Kitazono M, Bates S, Fok P, Fojo T, Blagosklonny MV 2002 The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53. Cancer Biol Ther 1:665–668[Medline]
- Mitsiades CS, Poulaki V, McMullan C, Negri J, Fanourakis G, Goudopoulou A, Richon VM, Marks PA, Mitsiades N 2005 Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clin Cancer Res 11:3958–3965[Abstract/Free Full Text]
- Kitazono M, Robey R, Zhan Z, Sarlis NJ, Skarulis MC, Aikou T, Bates S, Fojo T 2001 Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(–) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab 86:3430–3435[Abstract/Free Full Text]
- Furuya F, Shimura H, Suzuki H, Taki K, Ohta K, Haraguchi K, Onaya T, Endo T, Kobayashi T 2004 Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology 145:2865–2875[Abstract/Free Full Text]
- Puppin C, D’Aurizio F, D’Elia AV, Cesaratto L, Tell G, Russo D, Filetti S, Ferretti E, Tosi E, Mattei T, Pianta A, Pellizzari L, Damante G 2005 Effects of histone acetylation on sodium iodide symporter promoter and expression of thyroid-specific transcription factors. Endocrinology 146:3967–3974[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Vargiolu, D. Fusco, I. Kurelac, D. Dirnberger, R. Baumeister, I. Morra, A. Melcarne, R. Rimondini, G. Romeo, and E. Bonora
The Tyrosine Kinase Receptor RET Interacts in Vivo with Aryl Hydrocarbon Receptor-Interacting Protein to Alter Survivin Availability
J. Clin. Endocrinol. Metab.,
July 1, 2009;
94(7):
2571 - 2578.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. C Smallridge, L. A Marlow, and J. A Copland
Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies
Endocr. Relat. Cancer,
March 1, 2009;
16(1):
17 - 44.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Xing
BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications
Endocr. Rev.,
December 1, 2007;
28(7):
742 - 762.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Smith, C.-Y. Fan, C. Zou, D. Bodenner, and M. S. Kokoska
Methylation Status of Genes in Papillary Thyroid Carcinoma
Arch Otolaryngol Head Neck Surg,
October 1, 2007;
133(10):
1006 - 1011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kondo, X. Zhu, S. L. Asa, and S. Ezzat
The Cancer/Testis Antigen Melanoma-Associated Antigen-A3/A6 Is a Novel Target of Fibroblast Growth Factor Receptor 2-IIIb through Histone H3 Modifications in Thyroid Cancer
Clin. Cancer Res.,
August 15, 2007;
13(16):
4713 - 4720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Durante, E. Puxeddu, E. Ferretti, R. Morisi, S. Moretti, R. Bruno, F. Barbi, N. Avenia, A. Scipioni, A. Verrienti, et al.
BRAF Mutations in Papillary Thyroid Carcinomas Inhibit Genes Involved in Iodine Metabolism
J. Clin. Endocrinol. Metab.,
July 1, 2007;
92(7):
2840 - 2843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kondo, L. Zheng, W. Liu, J. Kurebayashi, S. L. Asa, and S. Ezzat
Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/Mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression
Cancer Res.,
June 1, 2007;
67(11):
5461 - 5470.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
