Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid cancer is common, occurring in 1% of the general population. The relative frequencies of two of the most common subtypes of thyroid carcinoma, follicular (FTC) and papillary (PTC), vary depending on the regional prevalence of iodine deficiency. Although PTC has been more extensively studied, the etiology of sporadic FTC is poorly understood. To further elucidate this, we conducted microarray expression comparison of FTC tumors and normal thyroid tissue. Three commonly down-regulated genes, caveolin-1, caveolin-2, and GDF10/BMP3b, were chosen for further study on the basis of their localization to two chromosomal regions, 7q31.1 and 10q11.1, that commonly show loss of heterozygosity in FTC. Two additional genes, glypican-3 and a novel chordin-like gene, were also analyzed in view of their involvement in bone morphogenetic protein signaling and possible interaction with GDF10. Each of these five genes was down-regulated in >or=15 of 19 FTC tumors (79%) by semiquantitative reverse transcription-PCR. Caveolin-1 showed preferential down-regulation of its beta-isoform at both the mRNA and protein level, suggesting a distinct function for this isoform. Caveolin-1 is of particular functional interest because it has been shown to interact with PTEN, the tumor suppressor gene mutated in Cowden syndrome, an inherited multiple hamartoma syndrome that includes predisposition to FTC. Immunohistochemical analysis of 141 thyroid tumors of various histological types showed significantly fewer caveolin-1-positive tumors in FTCs, including insular type tumors, and Hurthle cell carcinomas in comparison with normal thyroid. PTC and anaplastic thyroid carcinomas did not show significant down-regulation, and thus, caveolin-1 may become a useful molecular marker to differentiate the various histologies of thyroid malignancies.
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PMID:Caveolin-1 and caveolin-2,together with three bone morphogenetic protein-related genes, may encode novel tumor suppressors down-regulated in sporadic follicular thyroid carcinogenesis. 1278 92

Maspin (mammary serpin) is a serine protease inhibitor member of the serpin family and a class II tumor suppressor, whose expression is lost in many advanced cancers. Maspin has been shown to inhibit cell motility, invasion, and metastasis; however, its precise role still remains to be verified. Altough the expression of maspin mRNA is low or absent in most human cancer cells, the maspin gene is rarely re-arranged or deleted. We hypothesized that aberrant promoter methylation of the maspin promoter participates in the silencing of maspin expression during neoplastic progression. In thyroid and thyroid neoplasms the effects of maspin are still unknown. To clarify the role of maspin in thyroid carcinogenesis, we searched for mRNA and protein expression, as well as for promoter methylation in 30 normal (tumor-free) thyroid tissues (NT), 35 follicular adenomas (FAD), 42 papillary carcinomas (PTC), 38 follicular carcinomas (FTC), 25 poorly differentiated carcinomas (PDTC), and 34 undifferentiated carcinomas (UTC). Maspin mRNA expression in combination with protein expression was not found in any of the NT cases, nor in FAD, FTC, PDTC, and UTC. In contrast, mRNA and protein expressions were noted in 71 and 69% of PTC, respectively. Maspin promoter methylation was found in 93% of NT, in 89% of FAD, in 92% of FTC and PDTC, and in 100% of UTC. In contrast to these high methylation rates, only 29% were methylated in PTC. In conclusion, we hypothesize that maspin mRNA expression in combination with protein expression represents a special feature in the cascade of PTC genesis. Our data suggest that promoter methylation-caused maspin repression plays a major role in gene balance and in the process of tumor determination and dedifferentiation in thyroids. We presume that methylation of the maspin gene promoter is a common, a likely, and an early event during the development of papillary thyroid carcinomas.
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PMID:Silencing of the maspin gene by promoter hypermethylation in thyroid cancer. 1296 23

Several genes control cell growth, differentiation and apoptosis. Any alteration in the sequence or expression of these genes can cause an uncontrolled growth of the tissue and produce a tumor. Quantitative and qualitative gene expression studies using genes as tumor markers are essential for the diagnosis and prognosis of the tumor and its behavior. Oncogenes are genes that stimulate cell growth and have an increased expression. On the contrary, tumor suppressor genes are genes that inhibit cell growth and have a decreased expression in tumor cells. To study these tumor markers we apply simple and random molecular biology techniques such as polymerase chain reaction (PCR), reverse transcription and genomic sequencing. In the case of thyroid epithelial neoplasia, tumor markers such as PTEN/MMAC1/TEP1, telomerase, RET/PTC, b-catenine, PAX8/PPAR(1, ciclooxygenase, thyroid stimulating hormonal receptor (TSHR), and thyro-globulin are being investigated. These markers are analyzed for somatic mutations in the genetic sequence, chromosomical rearrangements, alterations in the promoter zone that affect gene expression, regulation and studies of genes at mRNA level. A deeper study of these markers is deemed to help improve the accuracy of tumor diagnosis, behavior and prognosis. Hence, more effective therapeutic options will be adapted to each individual, eventually reducing hospital costs.
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PMID:[Thyroid carcinomas of the follicular epithelium: tumor markers and oncogenes]. 1297 39

This study aimed at investigating new mechanisms of carcinogenesis in thyroid cancer at the molecular level and at finding potential protein markers involved in the initiation of the different histological subtypes. For this, we performed differential proteome analysis on primary cultured thyrocytes (PT) and transformed thyrocytes (TT) derived from 238Pu alpha-particle irradiation using 2-dimensional electrophoresis (2-DE) and peptide mass fingerprinting (PMF) with matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS). Image analysis showed that one protein was very strongly expressed in TT; 55 proteins were weaker, different in intensity, including 26 spots that were increased in PT, and 29 spots were decreased. The hot spot was identified as maspin, a unique member of the serpin family considered to be a class II tumor suppressor gene. To clarify the role of maspin in thyroid carcinogenesis we searched for protein expression in 20 normal (tumor-free) tissues, as well as in 20 follicular adenomas (FAD), 20 papillary carcinomas (PTC), 20 follicular carcinomas (FTC), 20 poorly differentiated carcinomas (PDTC), and 20 undifferentiated carcinomas (UTC). Maspin protein expression was detectable in none of the cases of normal tumor-free thyroid tissue, nor in FAD, FTC, PDTC and UTC. In contrast 14 of 20 PTC (70%) showed a moderate or strong cytoplasmic staining; 4 of these 14 cases had a moderate cytoplasmic and nuclear staining. In conclusion, we hypothesize that maspin protein expression is a special feature in the cascade of PTC genesis and that the way of initiating PTC is different from other thyroid carcinoma types.
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PMID:Proteome analysis identified maspin as a special feature of papillary thyroid carcinoma. 1453 72

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E2 synthase-1 (mPGES-1) as a RET/PTC-inducible gene through subtraction hybridization cloning and expression profiling with custom microarrays. The inducible prostaglandin E2 (PGE2) biosynthetic enzymes cyclooxygenase-2 (COX-2) and mPGES-1 are up-regulated in many cancers. COX-2 is overexpressed in thyroid malignancies compared with benign nodules and normal thyroid tissues. Eicosanoids may promote tumorigenesis through effects on tumor cell growth, immune surveillance, and angiogenesis. Conditional RET/PTC1 or RET/PTC3 expression in PCCL3 thyroid cells markedly induced mPGES-1 and COX-2. PGE2 was the principal prostanoid and up-regulated (by approximately 60-fold), whereas hydroxyeicosatetraenoic acid metabolites were decreased, consistent with shunting of prostanoid biosynthesis toward PGE2 by coactivation of the two enzymes. RET/PTC activated mPGES-1 gene transcription. Based on experiments with kinase inhibitors, with PCCL3 cell lines with doxycycline-inducible expression of RET/PTC mutants with substitutions of critical tyrosine residues in the kinase domain, and lines with inducible expression of activated mutants of H-RAS and MEK1, RET/PTC was found to regulate mPGES-1 through Shc-RAS-MEK-ERK. These data show a direct relationship between activation of a tyrosine kinase receptor oncogene and regulation of PGE2 biosynthesis. As enzymes involved in prostanoid biosynthesis can be targeted with pharmacological inhibitors, these findings may have therapeutic implications.
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PMID:Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway. 1455 60

Clinical relevance and stage correlation of telomerase activity in well-differentiated papillary thyroid carcinoma (WD PTC) has not been well determined, as its reported activity could be due to the analysis of tumors with lymphocytic infiltrates or aggressive variants of papillary carcinomas. We conducted a prospective study of telomerase activity in WD PTC without inflammatory infiltrates and correlated it with clinical stage. Fifty WD PTCs were analyzed for telomerase activity by PCR-based TRAP (telomeric repeat amplification protocol) assay. Results were correlated with stage and other clinicopathologic variables. Twenty-one (42%) WD PTCs demonstrated telomerase activity. The enzyme was detected more frequently in stage III/IVa WD PTCs (p = 0.02) and in tumors with extra thyroidal extension (p = 0.04). The risk of presenting advanced disease (stage III/IVa) and extrathyroidal growth was significantly increased in telomerase-positive tumors (p = 0.01; odds ratio [OR] 4.4 [95%CI 1.3-14.7]) and (p = 0.04; OR 3.6 [95%CI 1.1-11.7]), respectively. Also, a correlation was found between telomerase activity and age. There was no correlation of telomerase activity with gender, histologic variant, tumor size, or cervical lymph node metastasis. Telomerase activity was observed in 42% of WD PTC and was detected more frequently in AJCC TNM stage III/IVa cases. This finding suggests that telomerase deregulation could be involved in tumor progression.
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PMID:Telomerase activity in well-differentiated papillary thyroid carcinoma correlates with advanced clinical stage of the disease. 1458 66

Recently, studies on endocrine tumors revealed a potential role of telomerase in the dedifferentiation and/or malignant transition of these tumors. Telomerase is a ribonucleoprotein complex that includes the telomerase RNA component (hTR), the telomerase-associated protein (TP1), and the telomerase catalytic subunit (hTERT). Previously, the chaperones p23 and HSP90 have been described as additional telomerase regulators. To test whether the interactions of these genes are reflected in the dedifferentiation of thyroid tumors, we determined their mRNA and/or protein expression in 30 normal (tumor-free) thyroid tissues (NT), 35 follicular adenomas (FAD), 42 papillary carcinomas (PTC), 38 follicular carcinomas (FTC), 25 poorly differentiated carcinomas (PDTC), and 34 undifferentiated carcinomas (UTC). We then compared the results with telomerase activity. RT-PCR analysis revealed that TP1 was ubiquitously expressed. hTR was found in 50-94% of malignant tumors, in contrast to 7% of NT and 26% of FAD. hTERT was clearly associated with aggressive biological behavior. Ninety-two to 100% of the malignant tumors were positive for hTERT protein, whereas NT and FAD were negative in 100% and 94%, respectively. HSP90 mRNA and protein showed a close relationship to hTERT. p23 protein was negative in NT and positive in 3% of FAD, 39% of FTC, 40% of PTC, 44% of PDTC and 47% of UTC. High telomerase activity was measurable in hTERT and HSP90-positive tissues only. Our data show that the common expression of hTERT and HSP90 regulates telomerase activity in thyroid carcinomas. Chaperone p23 is involved in the telomeric complex to a lesser extent, but its expression is stronger in carcinomas than in non-malignant thyroid tissues. The expression profile of telomerase components represents an additional prognostic marker that may identify more aggressive thyroid tumors.
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PMID:Function of HSP90 and p23 in the telomerase complex of thyroid tumors. 1462 Nov 92

Basal cell carcinoma (BCC), the most common form of human cancer, is understood to be associated with activation of the sonic hedgehog pathway, through loss-of-function mutations of tumor suppressor PTCH1 or gain-of-function mutations of smoothened. Interferon (IFN)-based therapy is quite effective in BCC treatment, but the molecular basis is not well understood. Here we report a novel mechanism by which IFNalpha mediates apoptosis in BCCs. In the presence of IFNalpha, we observed increased apoptosis in a BCC cell line ASZ001, in which PTC is null, and therefore with constitutive activation of the sonic hedgehog pathway. We demonstrate that SMO agonist Ag-1.4 mediates activation of extracellular signal-regulated kinase (Erk) phosphorylation, which is abrogated by IFNalpha in sonic hedgehog responsive C3H10T1/2 cells. In transient transfection experiments, we demonstrate that IFNalpha inhibits Erk phosphorylation and serum response element activation induced by expression of SMO, Gli1, PDGFRalpha and activated Raf, but not activated mitogen-activated Erk-regulating kinase (Mek), suggesting that IFNalpha targets mainly on Mek function. We further show that IFNalpha induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in IFNalpha-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFNalpha-mediated apoptosis. Thus, our data indicate that IFNalpha-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function.
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PMID:IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. 1464 22

Papillary (PTC) and follicular thyroid carcinoma (FTC) are known as differentiated thyroid carcinoma (DTC). Nevertheless, according to the UICC/AJCC (TNM) classification PTC and FTC are frequently analyzed as one cancer. The aim of this study is to show differences in outcome and specific prognostic factors in an iodine-replete endemic goiter region. Six hundred and three patients with DTC treated within a 35-year-period were retrospectively analyzed with respect to carcinoma-specific survival. Prognostic factors were tested for their significance using univariate and multivariate analysis. The histological type (PTC versus FTC) was found to be a highly significant factor - carcinoma-specific survival both in univariate (P<0.001) and multivariate analyses (P=0.003) was significantly different. Univariate analysis revealed patients' age, extra-thyroid tumor spread, lymph node and distant metastases, increasing tumor size, and the tall cell variant to be significant prognostic factors for PTC patients. Age > or =45 years, positive lymph nodes and increasing tumor size were confirmed as independent prognostic factors. Univariate analysis of FTC patients revealed age at presentation, gender, extrathyroidal tumor spread, lymph node and distant metastases, increasing tumor size, multifocality, widely invasive tumor growth and oxyphilic variant to be factors bearing prognostic significance. The presence of distant metastases and increasing tumor size could be identified as independent prognostic factors for FTC patients. This study shows distinctive differences in prognostic factors of PTC and FTC: independent factors predicting poor prognosis are age > or =45 years, positive lymph nodes and increasing tumor size for PTC, and distant metastases and increasing tumor size for FTC. PTC and FTC patients should be analyzed and reported separately.
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PMID:Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine-replete endemic goiter region. 1502 90

Ionizing radiation is the strongest risk factor known for the development of thyroid neoplasia. Although ret/PTC rearrangements have been identified in both spontaneous and radiation-induced papillary thyroid cancer, they seem more frequent among radiation-associated tumors. We studied the frequency of ret/PTC activation in a group of sporadic and radiation-induced thyroid carcinomas (n = 49) and adenomas (n = 13) among 44 individuals treated for Tinea Capitis with low-dose external irradiation as well as in 18 nonirradiated subjects. Total RNA recovered from paraffin-embedded thyroid cancer surgical specimens was analyzed for ret/PTC 1, 2, and 3 mutations using RT-PCR with Southern blotting to maximize detection sensitivity. Ret/PTC rearrangements were identified in 42.9% of thyroid carcinoma and 46.2% of adenoma subjects. Among the positive carcinoma specimens, three were follicular carcinomas. Ret/PTC 1, the predominant rearrangement, was more prevalent in nonirradiated compared with irradiated carcinomas (66.7 vs. 27.0%; P = 0.04). Ret/PTC activation was associated with male gender. The strengths of this study included analysis of age-, gender-, and ethnicity-matched groups; molecular analysis using two techniques; and a complete blinding of laboratory analysis from clinical features. The differences seen between these and other published results may be related to differences in radiation doses to the thyroid, latency period between time of radiation exposure and development of clinically apparent thyroid cancer, and ethnic background of the study populations.
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PMID:Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose external-beam irradiation in childhood. 1512 54


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