Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormones are important regulators of differentiation, growth, metabolism, and physiological function of virtually all tissues. Active thyroid hormone T(3) affects expression of genes that encode for angiogenic proteins like adrenomedullin or vascular endothelial growth factor and erythropoietin, as well as for glucose transporters and phospho fructokinase that determine glucose use. Interestingly, those target genes are also hypoxia inducible and under the control of the oxygen-dependent transcription factor hypoxia-inducible factor (HIF)-1). We and others have reported that T(3) stimulates HIF-1 activation, which intimately links T(3) and HIF-1 induced gene expression. Here, we studied intracellular pathways that mediate HIF-1alpha regulation by T(3). We found that T(3)-dependent HIF-1 activation is not limited to hepatoma cells but is also observed in primary human hepatocytes, kidney and lung carcinoma cells. T(3) increased the HIF-1alpha subunit mRNA and protein within a few hours through activation of the thyroid hormone receptor beta retinoid X receptor alpha heterodimer because knockdown of each of the partners abrogated the stimulation by T(3). However, T(3) had no direct effect on transcription of HIF-1alpha, but activation of the thyroid hormone receptor beta/retinoid X receptor alpha heterodimer by T(3) stimulated expression of the hepatic leukemia factor, which increases HIF-1alpha gene expression.
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PMID:Thyroid hormone induces hypoxia-inducible factor 1alpha gene expression through thyroid hormone receptor beta/retinoid x receptor alpha-dependent activation of hepatic leukemia factor. 1823 67

Thyroid hormone (T3) regulates growth, development and differentiation. These activities are mediated by nuclear thyroid hormone receptors (TRs), which belong to the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. In an effort to study the mechanism of target genes regulation and their physiological significance after T3 treatment in a TR alpha-overexpressing hepatoma cell line (HepG2-TR alpha), c-DNA microarrays were performed. The data demonstrated that approximately 149 genes represented were positively regulated by T3, including fibrinogen, transferrin, fibronectin (FN), androgen receptor (AR)-associated protein (ARA70), and dehydroepiandrosterone sulfotransferase family 1A member 2 (SULT2A1). To further confirm the microarray results, a quantitative-reverse transcription polymerase chain reaction (Q-RT-PCR) was applied. The protein synthesis inhibitor, cycloheximide was used to determine whether the regulation was direct or indirect. A promoter assay further showed that T3 regulation was largely at the level of transcription. Although those genes were isolated from a human tumor cell line, they are regulated similarly in rats and humans. These results indicate that T3 might play an important role in the process of blood coagulation, inflammation, metabolism and cell proliferation. This may help to explain the association between thyroid diseases and the mis-regulation of the inflammatory and clotting profiles evident in the circulatory systems of these patients.
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PMID:Thyroid hormone dependent regulation of target genes and their physiological significance. 1893 90

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus-negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.
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PMID:Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. 1957 55

Thyroid hormones regulate critical developmental processes and key metabolic pathways. A number of natural and synthetic substances have been identified which adversely interfere with the endocrine system. These so-called endocrine disrupters (ED) have mainly been studied for their impact on the gonadal hormone axis. The aim of this work was to develop a novel sensitive and convenient in vitro screening assay for the detection and characterization of potential ED of thyroid hormone (TH)-dependent transactivation of gene transcription and to apply this tool to test relevant environmental and nutritive ED compounds. We constructed a TH-responsive luciferase-based reporter plasmid and established a reporter gene assay in a 96 well microplate format using the human hepatocarcinoma cell line HepG2 as host system. Both the synthetic TH receptor (TR) agonist GC-1 and the antagonist NH-3 were used to evaluate the assay. Concentration-response data of test compounds (food constituents, isoflavones, ultraviolet-absorbers, pesticides, industrial chemicals) were recorded in activation assays. In addition, interference with TH-mediated transactivation was tested by coincubation of the ED with triiodothyronine (T(3)) in competition assays. Most ED tested affected T(3) reporter gene activity at concentrations of 1 microM or higher and displayed either agonistic or mixed agonistic/antagonistic activities. Effects of relevant ED occurred only at relatively high concentrations compared with the endogenous TR ligand T(3). However, on basis of their high production volumes and potential bioaccumulation of some fat-soluble ED our data indicate the need to carefully monitor certain ED for potential disruption of the TH system in intact organisms and humans.
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PMID:Interference of endocrine disrupters with thyroid hormone receptor-dependent transactivation. 1940 56

Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of normal physiology and development. Mutations in TRs have been identified at high frequency in certain cancers, including human hepatocellular carcinomas (HCCs). The majority of HCC-TR mutants bear lesions within their DNA recognition domains, and we have hypothesized that these lesions change the mutant receptors' target gene repertoire in a way crucial to their function as oncoproteins. Using stable cell transformants and expression array analysis, we determined that mutant TRs isolated from two different HCCs do, as hypothesized, display a target gene repertoire distinct from that of their normal TR progenitors. Only a subset of genes regulated by wild-type TRs was regulated by the corresponding HCC-TR mutants. More surprisingly, the HCC-TR mutants also gained the ability to regulate additional target genes not recognized by the wild-type receptors, and were not simply restricted to repression, but could also activate a subset of their target genes. We conclude that the TR mutants isolated from HCC have sustained multiple alterations from their normal progenitors that include not only changes in their transcriptional outputs, but also changes in the genes they target; both are likely to contribute to neoplasia.
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PMID:Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire. 1974 97

Thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T(3)), mediates cell growth, development and differentiation by binding to its nuclear receptors (TRs). The role of TRs in cancer is still undefined. Notably, hyperthyroxinemia has been reported to influence the rate of colon cancer in an experimental model of carcinogenesis in rats. Previous microarray analysis revealed that cathepsin H (CTSH) is upregulated by T(3) in HepG2-TR cells. We verified that mRNA and protein expression of CTSH are induced by T(3) in HepG2-TR cells and in thyroidectomized rats following administration of T(3). The possible thyroid hormone-responsive elements of the CTSH promoter localized to the nucleotides -2038 to -1966 and -1565 to -1501 regions. An in vitro functional assay showed that CTSH can increase metastasis. J7 cells overexpressing CTSH were inoculated into severe combined immune-deficient mice and these J7-CTSH mice displayed a greater metastatic potential than did J7-control mice. The clinicopathologic significance of CTSH expression in hepatocellular carcinoma (HCC) was also investigated. The CTSH overexpressing in HCC was associated with the presence of microvascular invasion (P=0.037). The microvascular invasion characteristic is closely related to our in vitro characterization of CTSH function. Our results show that T(3)-mediated upregulation of CTSH led to matrix metallopeptidase or extracellular signal-regulated kinase activation and increased cell migration. This study demonstrated that CTSH overexpression in a subset hepatoma may be TR dependent and suggests that this overexpression has an important role in hepatoma progression.
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PMID:Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells. 2121 76

Thyroid metastases from hepatocellular carcinoma (HCC) seldom occur and are often difficult to diagnose because of their asymptomatic clinical course. We evaluated a very rare case of solitary thyroid metastasis from HCC that showed high uptake of fluorine-18 fluorodeoxyglucose (FDG), when imaged using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). The patient was a 74-year-old man and presented with a remarkably elevated des-gamma-carboxy prothrombin level of 1,157 mAU/ml 22 months after hepatic lobectomy. FDG-PET/CT imaging revealed a hypodense tumor with high FDG uptake, with a maximum standardized uptake value of 5.2 in the thyroid left lobe. Solitary thyroid metastasis from HCC was suspected and subsequent fine needle aspiration did indeed reveal HCC. The patient received left thyroidectomy with left regional lymph node dissection. Two months after left thyroidectomy, contrast-enhanced computed tomography showed local recurrence, and the patient received ongoing radiotherapy treatment. To our knowledge, the present study is the first to demonstrate the feasibility of FDG-PET/CT in the diagnosis and management of clinically diagnosed, asymptomatic, solitary thyroid metastasis from HCC.
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PMID:Solitary Asymptomatic Thyroid Metastasis from Hepatocellular Carcinoma Detected by FDG-PET/CT. 2138 51

Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that regulate a diverse array of biological activities, including metabolism, homeostasis, and development. TRs also serve as tumor suppressors, and aberrant TR function (via mutation, deletion, or altered expression) is associated with a spectrum of both neoplastic and endocrine diseases. A particularly high frequency of TR mutations has been reported in renal clear cell carcinoma (RCCC) and in hepatocellular carcinoma (HCC). We have shown that HCC-TR mutants regulate only a fraction of the genes targeted by wild-type TRs but have gained the ability to regulate other, unique, targets. We have suggested that this altered gene recognition may contribute to the neoplastic phenotype. Here, to determine the generality of this phenomenon, we examined a distinct set of TR mutants associated with RCCC. We report that two different TR mutants, isolated from independent RCCC tumors, possess greatly expanded target gene specificities that extensively overlap one another, but only minimally overlap that of the wild-type TRs, or those of two HCC-TR mutants. Many of the genes targeted by either or both RCCC-TR mutants have been previously implicated in RCCC and include a series of metallothioneins, solute carriers, and genes involved in glycolysis and energy metabolism. We propose as a hypothesis that TR mutations from RCCC and HCC may play tissue-specific roles in carcinogenesis, and that the divergent target gene recognition patterns of TR mutants isolated from the two different types of tumors may arise from different selective pressures during development of RCCC vs. HCC.
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PMID:Mutant thyroid hormone receptors (TRs) isolated from distinct cancer types display distinct target gene specificities: a unique regulatory repertoire associated with two renal clear cell carcinomas. 2162 34

Thyroid hormone, operating through its receptors, plays crucial roles in the control of normal human physiology and development; deviations from the norm can give rise to disease. Clinical endocrinologists often must confront and correct the consequences of inappropriately high or low thyroid hormone synthesis. Although more rare, disruptions in thyroid hormone endocrinology due to aberrations in the receptor also have severe medical consequences. This review will focus on the afflictions that are caused by, or are closely associated with, mutated thyroid hormone receptors. These include Resistance to Thyroid Hormone Syndrome, erythroleukemia, hepatocellular carcinoma, renal clear cell carcinoma, and thyroid cancer. We will describe current views on the molecular bases of these diseases, and what distinguishes the neoplastic from the non-neoplastic. We will also touch on studies that implicate alterations in receptor expression, and thyroid hormone levels, in certain oncogenic processes.
J Thyroid Res 2011
PMID:Thyroid hormone receptor mutations in cancer and resistance to thyroid hormone: perspective and prognosis. 2176 Sep 78

Chronic hepatitis C (CHC) is one of the commonest infectious diseases of the liver and may lead to cirrhosis or hepatocellular carcinoma. Combination therapy with pegylated interferon (PEG-IFN) and Ribavirin is the treatment of choice for CHC. Combination therapy is thought to act by means of antiviral mechanisms and immunomodulation. Thyroid dysfunction is the most common autoimmune adverse effect associated with combination therapy; hypothyroidism is more common than hyperthyroidism. Antithyroid antibodies and female sex have a predictive value in the development of interferon induced thyroid disease (IITD). Patients with CHC should be informed of the possibility of side effects on the thyroid gland. Screening for antithyroid antibodies and thyroid function tests should be performed in patients with CHC before the commencement of antiviral treatment, and during and after it. This article reviews different aspects of IITD, including its pathogenesis, clinical manifestations, association with treatment regimens and treatment response and the outcome of thyroid dysfunction.
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PMID:Interferon-alpha induced and ribavirin induced thyroid dysfunction in patients with chronic hepatitis C. 2231 86


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