Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To establish an objective basis for therapeutic decisions and follow-up programs in patients with follicular thyroid cancer, the authors developed a prognostic scoring system. The prognostic impact of nine clinical, histologic, and therapeutic parameters was quantified retrospectively based on a multivariate analysis covering 149 patients. The relative relapse risk in follicular thyroid cancer (RR) was 6.8-fold increased in the presence of a moderate when compared with a high degree of histologic tumor differentiation. The RR rose with increasing age of the patient at time of tumor diagnosis by a factor of 1.8 per 20 years. The RR was reduced by a factor of 4.3 after the performance of a neck dissection and by a factor of 2.3 after percutaneous radiation therapy of the neck. The relative mortality risk in follicular thyroid cancer (RM) rose in the absence of a tumor capsule by a factor of 10, in the presence of a moderate compared with a high degree of histologic tumor differentiation by a factor of 5.9, in the presence of distant metastases by a factor of 3.2, and with increasing age of the patient at the time of tumor diagnosis by a factor of 2.2 per 20 years. From these data prognostic indices denoting the individual risk for tumor relapse (IRR index) and tumor mortality (IMR index) were calculated. The indices categorize patients into low-risk, medium-risk, or high-risk groups with regard to tumor relapse and tumor-related death. Consequently, the IRR and IMR indices contribute to select patients with follicular thyroid cancer who need an aggressive form of treatment and an intensive follow-up program. The indices may also be used for risk stratification in prospective therapy trials.
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PMID:Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. 200 4

Expression of the wild-type RET proto-oncogene has been observed in non-medullary, follicular cell-derived tumors (FCDT), but the relation with the histopathological features has not been fully demonstrated. To assess the expression of RET and protein products in relation to morphological types of FCDT, including follicular adenoma (FA), papillary carcinoma (PTC), follicular carcinoma (FTC) and anaplastic carcinoma (AnC), 58 non-neoplastic and neoplastic samples using pathological paraffin sections by immunohistochemistry (IHC), reverse transcriptase-polymerase chain reaction (RT-PCR) and laser capture microdissection (LCM) methods were analyzed. Expression of RET proto-oncogene was detected in 27.3% of FCDT by IHC and 25.5% by RT-PCR using a primer set at a regular break point. The present study also found higher expression ratios of RET in FA (50.0%) and the follicular variant of PTC (50.0%), in contrast to FTC (20.0%), ordinary PTC (20.0%) and poorly differentiated or AnC (14.3%) by RT-PCR. One patient with PTC showed a discrepancy in the results by RT-PCR using a different primer set at the C-terminus of RET. The study found that the RET proto-oncogene is often stimulated in FCDT, not only in PTC but also in follicular tumors (FA and FTC), and may contribute to tumorigenesis of these tumors.
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PMID:Expression of RET in follicular cell-derived tumors of the thyroid gland: prevalence and implication of morphological type. 1260 95

Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyroid carcinoma (PTC). We report a high prevalence of BRAF(V599E) mutation in sporadic PTC and in PTC-derived cell lines. The BRAF(V599E) mutation was detected in 23 of 50 PTC (46%) and in three of four PTC-derived cell lines. The prevalence of the BRAF(V599E) mutation in PTC is the highest reported to date in human carcinomas, being only exceeded by melanoma. PTC with RET/PTC rearrangement as well as the TPC-1 cell line (the only one harboring RET/PTC rearrangement) did not show the BRAF(V599E) mutation. BRAF(V599E) mutation was not detected in any of 23 nodular goiters, 51 follicular adenomas and 18 follicular carcinomas. A distinct mutation in BRAF (codon K600E) was detected in a follicular adenoma. Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC. BRAF(V599E) mutation did not coexist with alterations in any of the RAS genes in any of the tumors. These results suggest that BRAF(V599E) mutation is frequent in the etiopathogenesis of PTC. The BRAF(V599E) mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF(V599E) may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation.
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PMID:BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. 1288 14

Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF--but not TSP-1--stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development.
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PMID:The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells. 1570 85

Differentiated thyroid cancers (papillary--PTC and follicular--FTC) are the most common endocrine malignancies. The recent progresses in the understanding of PTC and FTC pathogenesis are summarized in this review. In PTC, a single mutation of BRAF (the gene for the B-type Raf kinase) (V600E) is responsible for the disease in 40-50% of patients, especially in older people and is associated with a poorer clinicopathological outcome. Due to these characteristics, its use as a specific diagnostic and prognostic marker for PTC in cytological specimens is being implemented. Another important cause of PTC is rearrangements of the RET tyrosine kinase receptor (RET/PTC), which represent a recombination of the promoter and N-terminal domain of a partner gene with the C-terminal region of the RET gene, resulting in a chimeric gene with a protein product containing a constitutively activated RET tyrosine kinase, responsible for 20-30% patients, specially the younger or after radiation. The pathogenesis of FTC is less understood. A chromosomal translocation between the transcription factor PAX8 and the peroxisome proliferator-activated receptorgamma (PPARgamma) occurs in 30-50% of patients; however, the presence of PAX8-PPARgamma is also demonstrated in follicular adenomas. Therefore, there is no complete evidence that PAX8-PPARgamma is the cause of FTC. Another finding in FTC is mutations on the RAS gene, which excludes PAX8-PPARgamma rearrangements. Several genes, as TRgamma, PTEN, PKAR1A, DDIT3, ARG2, ITM1 and C1orf24--some discovered by techniques of differential gene expression--, have been recently implicated in the pathogenesis of FTC.
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PMID:[Pathogenesis of differentiated thyroid cancer (papillary and follicular)]. 1644 51

Mutations of genes coding effectors of signaling pathway RET/PTC-RAS-RAF-MEK-ERK, involved in cell growth and proliferation, are important in papillary thyroid cancer development. To earlier discovered mutations of RAS and RET/PTC genes, BRAF gene mutation has been recently added. Mutation of BRAF gene appears in various types of carcinomas, but most frequently in malignant melanomas (66%) and papillary thyroid cancer (average 44%). The BRAF gene protein product belongs to the serine-threonine kinase family and to the RAF proteins subfamily, among which it is the strongest activator of MAP kinases cascade. The most frequently mutation of BRAF gene is thymine to adenine transversion at nucleotide position 1796 (T1796A). This point mutation causes valine to glutamic acid substitution at residue 599 (V599E), that results in constitutive and oncogenic activation of BRAF kinase. The relation between mutations of BRAF, RAS and RET/PTC genes has not been found, although they together exist in two thirds of papillary thyroid cancers. BRAF(TI796A) oncogene appears in papillary thyroid cancer, whereas it has not been found in follicular thyroid cancer and benign thyroid adenomas. For this reason mutated BRAF gene could be specific molecular marker, with relatively high sensitivity in diagnostics of papillary thyroid cancer. In addition, BRAF gene has been demonstrated as a novel prognostic biomarker, which correlates with unfavorable clinicopathological factors, such as extrathyroidal invasion and distant metastasis.
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PMID:[BRAF gene mutation in thyroid cancer]. 1670 43

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.
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PMID:The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer. 1712 11

Thyroid cancer is the most common endocrine malignancy; it accounts for approximately 1% of all new case of cancer each year, and its incidence has increased significantly over the last few decades. The majority of thyroid tumors originate from follicular epithelial cells. Among them, papillary (PTC) and follicular carcinomas (FTC) represent the most common forms of differentiated thyroid cancer and account for approximately 80% and 15% of all cases, respectively. Specific genetic lesions are associated to each thyroid tumor histotype: BRAF mutations and RET/PTC and TRK oncogenes have been detected in PTC, whereas FTC is characterized by PAX8/PPARgamma rearrangements and RAS mutations. In this review we summarize studies on the molecular biology of the differentiated thyroid tumors, with particular interest in the associated genetic lesions and their role in thyroid carcinogenesis. We also report recent findings on gene expression and miRNA profiles of PTC and FTC.
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PMID:Molecular pathology of differentiated thyroid cancer. 1991 Aug 97

Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.
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PMID:The role of oestrogen receptor {alpha} in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2. 2003 8

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, accounting for 85-90% of all thyroid cancers. Genetic alternations involving the mitogen-activated protein kinase (MAPK) pathway are frequently demonstrated in PTC, such as RET/PTC, RAS, and B-type Raf kinase (BRAF) mutations. Over 90% of BRAF mutations are T1799A, resulting in a BRAF(V600E) mutation. BRAF(V600E) is present in approximately 50% of PTC and also found in aggressive histologic variants and PTC-derived anaplastic thyroid cancer, but is rare in follicular variants, and not found in follicular thyroid cancer. The tumorigenic role of BRAF(V600E) in the development of PTC was documented in thyroid-targeted BRAF(V600E) transgenic mice, and rat thyroid cells overexpressed with BRAF(V600E) suggested that BRAF(V600E) is an initiator of tumorigenesis and is required for tumor progression in PTC. Most clinical studies have demonstrated an association of BRAF(V600E) mutation with aggressive clinicopathologic characteristics and high tumor recurrence, although the results are controversial. The association is also observed in patients with papillary thyroid microcarcinomas and low-risk PTC. As a highly specific and unique mutation in PTC, testing for BRAF(V600E) in fine-needle aspiration specimens has been shown to refine the diagnostic accuracy of PTC in indeterminate cytology. Preoperative BRAF(V600E) analysis in low-risk patients may provide important value for prognostication, and these patients might benefit from receiving more intensive management and frequent follow-up. BRAF-targeted therapies have been developed to treat various human cancers including advanced thyroid cancers. Preclinical results are encouraging, but the anticancer effects of clinical trials are disappointing. Studies of multi-kinase inhibitors and/or combination with other regimens are underway in the treatment of advanced thyroid cancers. In this article, we review the pathogenesis of PTC, and the clinical implications of BRAF(V600E) mutation in the diagnosis, prognosis and potential targeted therapeutic strategies for thyroid cancers.
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PMID:BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. 2023 Sep 95


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