Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The essential micronutrient selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins which exert various effects, while maintaining the cell reduction-oxidation balance. The discovery that all three deiodinases that convert thyroxine (T4) into triiodothyronine (T3) contain selenocysteine illustrates how the production of the active thyroid hormone is dependent on Se status. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage. Se supplementation in patients with autoimmune thyroiditis seems to modify the immune response, probably by enhancing plasma GPx activity and decreasing excess levels of hydrogen peroxide. However, the enhancement of immunocompetence may also be the result of the synergistic action of various selenoproteins and not exclusively of GPx. There is evidence supporting considerable oxidative stress in Graves' disease where Se supplementation, because of its free radical scavenging properties, may increase the enzymatic antioxidant activity. TRx has been found significantly elevated in GD revealing its involvement in the pathogenesis of this condition and representing a potential future target for therapeutical intervention. Low Se serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis. It is noteworthy, that the Food and Drug Administration has recently determined that there is sufficient evidence to warrant a qualified health claim for Se and cancer. Furthermore, the recent discovery that defects in the SECIS-binding protein 2 (SBP2), which is an indispensable protein for the incorporation of Se into the selenoproteins, result in thyroid dysfunction, together with the recognition of the many roles of selenoprotein P in Se distribution and storage in the human body, reveal not only the indispensability of Se and the selenoproteins as essential factors in thyroid metabolism and pathogenesis, but open up new prospects for enhanced treatment.
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PMID:The role of selenium in thyroid autoimmunity and cancer. 1726 Apr 47

The preoperative evaluation of thyroid nodules currently relies on a clinical assessment of risk factors and an algorithm based on imprecise tests. With serum TSH, thyroid ultrasound and fine-needle aspiration (FNA) with or without ultrasound guide, accounting for the routine initial evaluation, indeterminate aspirates remain the major obstacle for confidently advising patients whether to have surgery or not. Recent clinical guidelines have attempted to settle various controversies but many inherent errors of clinical testing result in delayed diagnosis and unnecessary surgery. A better solution may ultimately involve the use of molecular markers of thyroid carcinogenesis but further research is still needed regarding the basic biology of thyroid cancer.
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PMID:Progress in the preoperative diagnosis of thyroid nodules: managing uncertainties and the ultimate role for molecular investigation. 1690 60

There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells, which are characterized by their self-renewing capacity and differentiation ability. Cancer could be regarded as an abnormal organ initiated by cancer stem cells, and cancer stem cells might play a decisive role in tumor initiation and progression. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer, and stem cells seem more likely to be the transformed target cells in carcinogenesis. This cancer stem cell model has great implications for understanding of oncogenesis and treatment for cancer. Abundant evidence suggests that, parallel to other solid tumors, cancer stem cells also exist in thyroid cancer, although their characteristics are largely unknown to date. The present review will discuss the potential traits of cancer stem cells in thyroid cancer and their transformation targets: stem cells in the thyroid gland.
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PMID:Cancer stem cell hypothesis in thyroid cancer. 1693 Mar 27

Overexpression of pituitary tumor-transforming 1 (PTTG1) is associated with thyroid cancer. We found elevated PTTG1 levels in the thyroid tumors of a mouse model of follicular thyroid carcinoma (TRbeta(PV/PV) mice). Here we examined the molecular mechanisms underlying elevated PTTG1 levels and the contribution of increased PTTG1 to thyroid carcinogenesis. We showed that PTTG1 was physically associated with thyroid hormone beta receptor (TRbeta) as well as its mutant, designated PV. Concomitant with thyroid hormone-induced (T3-induced) degradation of TRbeta, PTTG1 proteins were degraded by the proteasomal machinery, but no such degradation occurred when PTTG1 was associated with PV. The degradation of PTTG1/TRbeta was activated by the direct interaction of the liganded TRbeta with steroid receptor coactivator 3 (SRC-3), which recruits proteasome activator PA28gamma. PV, which does not bind T3, could not interact directly with SRC-3/PA28gamma to activate proteasome degradation, resulting in elevated PTTG1 levels. The accumulated PTTG1 impeded mitotic progression in cells expressing PV. Our results unveil what we believe to be a novel mechanism by which PTTG1, an oncogene, is regulated by the liganded TRbeta. The loss of this regulatory function in PV led to an aberrant accumulation of PTTG1 disrupting mitotic progression that could contribute to thyroid carcinogenesis.
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PMID:Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. 1703 56

Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TRbetaPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRbetaPV mice with mice lacking PTTG (PTTG(-/-) mice). The thyroids of TRbeta(PV/PV) PTTG(-/-) mice were significantly smaller than TRbeta(PV/PV) mice. Ki-67 staining showed a decrease in thyroid proliferation in TRbeta(PV/PV) PTTG(-/-) mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TRbeta(PV/PV) PTTG(-/-) mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRbeta(PV/PV) and TRbeta(PV/PV) PTTG(-/-) mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRbeta(PV/PV) PTTG(-/-) mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TRbeta(PV/PV) PTTG(-/-) versus TRbeta(PV/PV) thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription-polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.
Carcinogenesis 2007 May
PMID:The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer. 1712 11

Follicular thyroid cancer (FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mouse) that spontaneously develops thyroid cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TRbeta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TRbeta(PV/PV) mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor (trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TRbeta1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of thyroid carcinogenesis.
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PMID:Gelsolin: a novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer. 1717 Jan 1

Thyroid carcinomas are the most common endocrine neoplasms in humans, with a globally increasing incidence. Thyroid follicular cells and neuroendocrine (parafollicular) C cells are each susceptible to neoplastic transformation, resulting in thyroid cancers of differing phenotypes with unique associated genetic mutations and clinical outcomes. Over the past 15 years, several sophisticated genetically engineered mouse models of thyroid cancer have been created to further our understanding of the genetic events leading to thyroid carcinogenesis in vivo. The most significant mouse models of papillary, follicular, anaplastic, and medullary thyroid carcinoma are highlighted, with particular emphasis on the relationship between the relevant oncogenes in these models and genetic events in the naturally occurring human disease. Limitations of each model are presented, and the need for additional models to better recapitulate certain aspects of the human disease is discussed.
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PMID:Genetic alterations in thyroid cancer: the role of mouse models. 1719 19

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor beta (THRB)(PV) mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7-10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.
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PMID:Thyroid hormone receptor beta mutations in the 'hot-spot region' are rare events in thyroid carcinomas. 1721 Jul 45

A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.
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PMID:RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. 1727 Feb 45

The process of carcinogenesis is permanently one of the most interesting and significant issues for researchers in different fields of medicine. Therefore, we attempted to bring closer the problem of neoplastic transformation in the thyroid gland. This article covers the latest data about genetic factors, involved in thyroid carcinogenesis. We have presented results of the most recent studies referred to molecular biology of thyroid neoplasms. We have demonstrated not only the genetic background of cancers, derived from the thyroid follicular cell, but also genetic aspects related to medullary thyroid carcinoma and some benign thyroid lesions. The review describes DNA methylation disturbances and the mutations in thyrotropin receptor and G protein genes. Furthermore, we introduce the results of studies performed at our laboratory, concerning mutations in the following protooncogenes: RAS, RET, Trk, MET, and BRAF. Also, we present our data, regarding the loss of heterozygosity (LOH) in the short arm of chromosome 3. Additionally, we discuss overexpression of cyclin D1 gene in benign and malignant thyroid lesions. Previous studies performed at our laboratory indicate the role of IGF-I in the pathogenesis and invasiveness of thyroid cancers. The review indicates that progress in genetics of the thyroid cancer is extremely rapid.
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PMID:Genetic background of carcinogenesis in the thyroid gland. 1743 80


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