Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated integrin-linked kinase (ILK), a focal adhesion serine-threonine protein kinase, as a new molecular target for treating anaplastic thyroid cancer. ILK mediates cell growth and survival signals and is overexpressed in a number of cancers. Therefore, we hypothesized that inhibition of ILK leads to growth arrest and apoptosis of thyroid cancer cells. According to Western blotting, the level of ILK protein was highly expressed in one papillary (NPA187) and four of five (Hth74, DRO, ARO, KAT4, and K4) anaplastic thyroid cancer cell lines. Immunohistochemical analysis of a human tissue microarray revealed that ILK was highly expressed in anaplastic thyroid cancer but not in normal human thyroid tissue. Treating thyroid cancer cell lines with a new ILK inhibitor, QLT0267, inhibited epidermal growth factor-induced phosphorylation of AKT, inhibited cell growth, and induced apoptosis in the NPA187, DRO, and K4 cell lines. QLT0267 also inhibited the kinase activity of immunoprecipitated ILK in four of five cell lines. Tumor volumes in mice treated with QLT0267 were significantly reduced compared with those in untreated mice. In immunohistochemical studies, QLT0267 suppressed phosphorylated p-AKT and angiogenesis (i.e., reduced mean vascular density) and induced apoptosis in both tumor cells and tumor-associated endothelial cells of the thyroid DRO xenografts. In summary, we found that ILK expression and activity were elevated in human anaplastic thyroid cancer and ILK inhibition led to growth arrest and apoptosis in vitro and in vivo. Our results provide preliminary evidence that ILK is a potential therapeutic target for treating anaplastic thyroid cancer.
Mol Cancer Ther 2005 Aug
PMID:Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. 1609 30

Thyroid nodules are common. It would very helpful if genetic markers that can diagnose malignancy from fine needle aspiration samples were available. Few such markers has been thus identified and none are specific. Large panels of potential markers can be screened by microarray technology. Studies done to date have concentrated on single tumor types and thus provide no help in identifying tumor subtype specific markers. To that end we have studied gene profiles of 5 types of benign and malignant thyroid nodular tissue (multinodular goiter, follicular adenoma, papillary and follicular carcinomas). We have identified 195 genes whose differential expression clustered into clinically relevant groups. Twenty-eight genes were selected for further confirmation using real time quantitative polymerase chain reaction. Despite the differences in the microarray panels used, we confirmed the differential regulation of 12 genes previously reported in thyroid cancer, although we found the expression of several genes to be regulated in other histological tumor subtypes than originally described. We found, PCSK2, TRIB1, RAP1 GA1 to be specifically overexpressed in follicular cancer and S100A4 and GK2 in papillary carcinoma. SERP1, RNASE 2 and STATA5 were suppressed in papillary thyroid cancer. We have thus identified new potential markers specific to malignant thyroid tumors. It is apparent that a range of nodular thyroid tissue using large tumor sample numbers is necessary to establish robust markers for malignancy and to categorize tumors on the basis of small tumor samples.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 05
PMID:Gene profiling identifies genes specific for well-differentiated epithelial thyroid tumors. 1617 53

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with an incidence of approximately 22,000 cases in 2004 in the USA. Incidence is increasing, with a global estimate of half a million new cases this year. PTC is found in a variety of morphologic variants, usually grows slowly and is clinically indolent, although rare, aggressive forms with local invasion or distant metastases can occur. In recent years, thyroid cancer has been at the forefront of molecular pathology as a result of the consequences of the Chernobyl disaster and the recognition of the role of Ret/PTC rearrangements in PTC. Nonetheless, the molecular pathogenesis of this disease remains poorly characterized. In the clinical setting, benign thyroid nodules are far more frequent, and distinguishing between them and malignant nodules is a common diagnostic problem. It is estimated that 5-10% of people will develop a clinically significant thyroid nodule during their lifetime. Although the introduction of fine-needle aspiration has made PTC identification more reliable, clinicians often have to make decisions regarding patient care on the basis of equivocal information. Thus, the existing diagnostic tools available to distinguish benign from malignant neoplasms are not always reliable. This article will critically evaluate recently described putative biomarkers and their potential future role for diagnostic purposes in fine-needle aspiration cytology samples. It will highlight the evolution of our understanding of the molecular biology of PTC, from a narrow focus on specific molecular lesions such as Ret/PTC rearrangements to a pan-genomic approach.
Expert Rev Mol Diagn 2005 Nov
PMID:Molecular classification and biomarker discovery in papillary thyroid carcinoma. 1625 34

Tenascin-C (Tn-C) is a matricellular protein involved in the initial and intermediate stages of cell adhesion. The present study is the first undertaken to comparatively investigate Tn-C in neoplastic, non-neoplastic thyroid lesions and normal thyroid tissues. Forty-eight thyroid specimens were studied immunohistochemically using a monoclonal antibody against Tn-C. Immunohistochemistry was supplemented by RT-PCR analysis of the two Tn-C mRNA splice variants in 13 thyroid cancer cell lines. Normal and non-neoplastic tissues were devoid of Tn-C, as well as follicular neoplasms, Huerthle-cell and anaplastic carcinomas. Most papillary carcinomas showed a focally intensive extracellular staining, localized in the connective tissue stroma, whereas most medullary carcinomas showed a staining in the connective tissue but also in intracellular location mainly. RT-PCR analysis detected Tn-C mRNA in all thyroid cancer cell lines with prevalence of the large splice variant in all but the medullary line, characterized by a higher Tn-Csmall:Tn-Clarge ratio. In conclusion, Tn-C re-expression has been observed in papillary and medullary thyroid carcinomas with different staining patterns accompanied by the prevalence of different mRNA splice variants in cell cultures. It seems possible that Tn-C is rather synthesized by tumor cells than by activated stromal cells.
Exp Mol Pathol 2006 Apr
PMID:Tenascin-C protein expression and mRNA splice variants in thyroid carcinoma. 1625 77

PTEN, a dual-phosphatase tumor suppressor, is inactivated in Cowden syndrome (CS), characterized by high risk of breast and thyroid cancer, and in variety of sporadic cancers. Despite the importance of alternative splicing, very limited information on its role in PTEN and associated cancers is available. We identified eight novel PTEN splice variants (SVs) that retained intron 3 regions (3a, 3b, 3c); intron 5 regions (5a, 5b, 5c); excluded part of exon 5 (DelE5) or all of exon 6 (DelE6), respectively. Analysis of SVs in 12 sporadic breast cancers revealed full-length (FL)-PTEN transcript reduction in 10; SVs 3b, 3c and 5c not expressed in 7, 6 and 4, respectively, and under-expressed in the rest. In contrast, SV-5b was over-expressed in breast cancers. PTEN SV analysis in 16 CS/CS-like patients and eight controls revealed that SV-5a is under-expressed and SV-3a over-expressed in the germline of CS/CS-like individuals when compared with controls. Although SV-5a expression decreased P-Akt level and cyclin D1 promoter activity, SVs 5b and 5c increased cyclin D1 promoter activity. Thus, SV-5a behaving like FL-PTEN corroborates our observation that SV-5a is under-expressed in CS when compared with controls. Similarly, SV-5b functionally counters PTEN's action and is over-expressed in sporadic breast cancers. Furthermore, we demonstrate that expression of these SVs is under the regulation of p53. Our observations suggest that differential expression of PTEN and its SVs could play a role in the pathogenesis of sporadic breast cancers and CS, and may lend a novel way of making a rapid molecular diagnosis of CS without mutation analysis.
Hum Mol Genet 2006 Mar 01
PMID:Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer. 1643 56

The sodium/iodide symporter (NIS) mediates a remarkably effective targeted radioiodide therapy in thyroid cancer; this approach is an emerging candidate for treating other cancers that express NIS, whether endogenously or by exogenous gene transfer. Thus far, the only extrathyroidal malignancy known to express functional NIS endogenously is breast cancer. Therapeutic efficacy in thyroid cancer requires that radioiodide uptake be maximized in tumor cells by manipulating well-known regulatory factors of NIS expression in thyroid cells, such as TSH, which stimulates NIS expression via cAMP. Similarly, therapeutic efficacy in breast cancer will likely depend on manipulating NIS regulation in mammary cells, which differs from that in the thyroid. Human breast adenocarcinoma MCF-7 cells modestly express endogenous NIS when treated with all-trans-retinoic acid (tRa). We report here that hydrocortisone and ATP each markedly stimulates tRa-induced NIS protein expression and plasma membrane targeting in MCF-7 cells, leading to at least a 100% increase in iodide uptake. Surprisingly, the adenyl cyclase activator forskolin, which promotes NIS expression in thyroid cells, markedly decreases tRa-induced NIS protein expression in MCF-7 cells. Isobutylmethylxanthine increases tRa-induced NIS expression in MCF-7 cells, probably through a purinergic signaling system independent of isobutylmethylxanthine's action as a phosphodiesterase inhibitor. We also observed that neither iodide, which at high concentrations down-regulates NIS in the thyroid, nor cAMP has a significant effect on NIS expression in MCF-7 cells. Our findings may open new strategies for breast-selective pharmacological modulation of functional NIS expression, thus improving the feasibility of using radioiodide to effectively treat breast cancer.
Mol Endocrinol 2006 May
PMID:Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in breast cancer cells. 1643 63

Well differentiated (follicular and papillary) thyroid cancer (DTC) is characterized by rare occurrence and a good prognosis. However, up to 20% of patients with DTC develop locoregional recurrences, whereas even 8% of patients with such recurrences will eventually die from disease. In some of these patients it is related to incomplete initial treatment, whereas in others it indicates the presence of an aggressive tumor. In this latter case, dedifferentiation may occur with negative I-131 whole body scintigraphy (WBS) results and unreliable Tg measurements. In patients with thyroid cancer metastases that lost the capability of I-131 uptake, other imaging techniques are required to depict the non-functioning metastases, irrespective of the Tg-levels and irrespective of the site of recurrent disease. In this respect, some reports have discussed the value of ultrasonography of the head and neck region with good results for the detection of locoregional disease. We have assessed the role of FDG-PET in patients with I-131 negative WBS and its relation with Tg values and TSH-stimulation based on data that have appeared in the literature. In this review article, a discussion is given on the results published so far.
Q J Nucl Med Mol Imaging 2006 Mar
PMID:The value of FDG-PET in the follow-up of differentiated thyroid cancer: a review of the literature. 1655 7

A global gene expression profiling of TSH stimulation on differentiated (FRTL5) and partially dedifferentiated [FRT/TSHR (TSH receptor)] rat thyroid cells was performed. A total of 123 TSH-regulated genes (95 newly described) were identified in FRTL5, whereas no significant transcriptional modifications were seen in FRT/TSHR cells. Because regulatory subunit IIbeta (RIIbeta) of protein kinase A (PKA), a key element downstream of cAMP, was expressed in FRTL5 but not in cAMP-refractory FRT/TSHR cells, we hypothesized that this gene may play an important role in TSH signaling. We therefore performed a series of experiments to investigate the involvement of RIIbeta and the different PKA isoforms. A positive effect of PKA II- but not of PKA I-selective activation on gene transcription and proliferation in FRTL5 cells, as well as an impairment of TSH nuclear effects after RIIbeta silencing were observed, suggesting that PKA II plays an essential role in TSH signaling. This view was supported by the restoration of TSH nuclear effects after reexpression of RIIbeta in FRT/TSHR cells. Because PKA I stimulation could increase iodide uptake in FRTL5 cells without affecting gene transcription, PKA I may mediate TSH actions at posttranscriptional levels. Analyses on three human cancer cell lines confirmed the possible loss of RIIbeta expression and antiproliferative activity of PKA I-selective cAMP analogs ( approximately 60% at 200 microm in BRAF-mutated cells). The inhibitory effect of PKA I apparently required constitutive MAPK activation and was associated with an inhibition of ERK phosphorylation. These findings may open new therapeutic perspectives in patients with thyroid cancer.
Mol Endocrinol 2006 Dec
PMID:Selective modulation of protein kinase A I and II reveals distinct roles in thyroid cell gene expression and growth. 1688 86

Serum peptidomics is a special form of functional proteomics. The small number of blood proteins that are the source of most prominent peptides in human serum serve as a substrate pool for commonly occurring and/or cancer-derived proteases. Exoprotease activities in particular, when superimposed on the ex vivo coagulation and complement degradation pathways, contribute to generation of not only cancer-specific but also "cancer type"-specific serum peptides. Following development of a unique, semiautomated serum peptide profiling platform and after completing investigations to eliminate common experimental bias, we have now studied possible effects of gender and age on serum peptidomes of 200 healthy men and women, ages 20-80, and of 60 patients (30 men and 30 women) with metastatic thyroid carcinomas. Extensive MALDI-TOF MS and data analysis suggested negligible contributions of both age and gender to the serum peptidome patterns except that healthy men and women under 35 years, but not older individuals, could be distinguished with approximately 70% accuracy. Considering the more advanced age of most patients, this finding is unlikely to interfere with peptidomics analysis of most cancers. By examining patient samples and age/gender-matched controls followed by variability analysis of either demographic or disease (versus control) groups, we could conclusively rule out demographic bias. An optimized, 12-peptide ion thyroid cancer signature was then developed, enabling classification of an independent validation set with 95% sensitivity and 95% specificity (binomial confidence intervals, 75.1-99.9%). Ten of these peptides had previously been assigned to signature patterns of other solid tumor cancers. One of the two newly discovered peptides was dehydro-Ala(3)-fibrinopeptide A. As we expand this study to include hundreds of thyroid cancer patients, the peptide signature will be adjusted, further validated, and then evaluated in a clinical setting used either independently or in combination with existing markers.
Mol Cell Proteomics 2006 Oct
PMID:Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age. 1689 61

The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer. Moreover, a direct anti-proliferative effect of RA on human endothelial cells is suggested.
Mol Cell Endocrinol 2007 Jan 29
PMID:Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. 1710 Dec 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>