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)

Many studies suggest that hepatocellular carcinoma (HCC) is an androgen-dependent tumor with an incidence five times higher in males, but few data are available on the androgen receptor (AR) mRNA levels in different physiological classes of human liver specimens. In this study 108 human hepatic samples have been analyzed for AR mRNA expression by a comparative RT-PCR assay. These consisted of 35 non-tumoral hepatic samples (3 normal parenchymas, 4 steatosis, 10 hepatitis, 18 cirrhosis), 38 tumoral specimens derived from uninodular and multinodular HCCs and 35 peritumoral hepatic tissues. Normalized AR mRNA levels in tumoral and peritumoral liver tissues spanned from 0 to 146% and from 7 to 125% respectively. Only in a relatively small percentage of HCCs, the levels of expression of AR mRNA were higher than in the corresponding peritumoral tissues (16% of total HCCs). Although extremely variable, the AR mRNA levels were related to histological tumoral differentiation and proved to be lower in the highly dedifferentiated HCCs as compared to the well differentiated ones. Therefore, the evaluation of AR expression in HCC patients might be relevant for the planning of clinical studies on anti-androgen therapies, which might be useful only in the cases in which a high level of AR mRNA is detected, considering the high heterogeneity of AR mRNA levels which characterizes HCC samples. It is likely that the HCCs, expressing low or undetectable levels of AR mRNA, would not benefit by the anti-androgen therapy.
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PMID:Androgen receptor mRNA under-expression in poorly differentiated human hepatocellular carcinoma. 1237 Nov 39

Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals.
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PMID:Interaction of organophosphate pesticides and related compounds with the androgen receptor. 1267 13

The transforming growth factor-beta (TGF-beta) and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathologic processes. We previously reported that liganded glucocorticoid receptor (GR) repressed TGF-beta induction of human plasminogen activator inhibitor-1 gene transcription by directly targeting the transcriptional activation function of Smad3. To identify the domain(s) in the glucocorticoid receptor involved in this repression, we have examined the ability of various GR truncation, deletion, and substitution mutants to repress TGF-beta transactivation in Hep3B human hepatoma cells that lack functional endogenous GR. Partial deletions in the ligand-binding domain (LBD), including the tau2 and tauc regions, greatly reduced or eliminated GR repression, whereas deletion of the N-terminal AF1 (tau1) domain and substitution mutations in the DNA-binding domain had little or no effect. Liganded androgen receptor repressed TGF-beta transactivation, whereas mineralocorticoid receptor did not, and studies with rat GR-mineralocorticoid receptor chimeras confirmed that the GR C-terminal domains were required for repression. RU486, a strong antagonist of transactivation by GR, partially reversed repression by wild type GR. Co-immunoprecipitation experiments in Hep3B cells indicated that physical interaction between GR and Smad3 is necessary but not sufficient for repression. Physical interaction required activation of Smad3 by TGF-beta but not dexamethasone binding to GR. Glutathione S-transferase pull-down assays demonstrated that several regions of the LBD could mediate GR-Smad3 physical interaction. We conclude that the LBD of GR, but not the DNA-binding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF-beta transactivation.
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PMID:Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. 1290 38

This report describes a hepatocellular carcinoma (HCC) with concomitant focal nodular hyperplasia (FNH) in a 56 year old Chinese man. There were two well circumscribed tumours measuring 3 x 2.5 x 2 cm and 2 x 1.5 x 1.5 cm. The larger mass was grey and soft with a small area of bleeding and necrosis and an intact capsule. The smaller mass was yellow and had no capsule. Clonal analysis was carried out to clarify the relation between the HCC and the adjacent FNH. The clonal analysis was based on the methylation pattern of the polymorphic X chromosome linked androgen receptor gene (HUMARA). In FNH, after HpaII digestion, the allelic bands showed two well defined peaks. The intensity of the two peaks in the DNA from cirrhotic tissue did not differ significantly, consistent with a random pattern of X chromosome inactivation. However, in HCC, after HpaII digestion, the allelic bands differed significantly in intensity. Therefore, there was a typical polyclonal pattern of inactivation in FNH but the HCC was interpreted as being monoclonal.
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PMID:Focal nodular hyperplasia with concomitant hepatocellular carcinoma: a case report and clonal analysis. 1511 71

Chronic hepatitis B is the most common cause of hepatocellular carcinoma (HCC) in Asia. Integration of hepatitis B virus (HBV) genome is likely an early event of carcinogenesis. The integrated HBV genome may activate neighboring cellular genes directly to offer a selective growth advantage to the liver cells. Production of hepatitis B X protein can act as a transactivator on various cellular genes for tumor development. Hepatic inflammation and cirrhosis also favors the process of carcinogenesis. Various viral factors associated with hepatocellular carcinoma development include HBV genotype, basal core promoter mutations, and high viral load. Polymorphisms at the androgen receptor-regulating genes and cytokine genes are possible host factors associated with HCC. This review article summarizes the pathogenesis of HBV-related carcinogenesis and the viral and host factors that may increase the risk of HCC development.
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PMID:Hepatocellular carcinoma and hepatitis B virus. 1667 93

Hepatic angiomyolipoma (HAML) is an unusual mesenchymal lesion that can be misdiagnosed as hepatocellular carcinoma or sarcoma. We sought to better define the morphological variations and immunohistochemical and molecular features of this unusual tumor. Forty-nine sporadic HAMLs were investigated for immunopathologic characteristics with EnVision Plus. The clonal analysis was based on the methylation pattern of the polymorphic X chromosome-linked human androgen receptor gene, loss of heterozygosity (LOH), and microsatellite instability (MSI) detected with polymerase chain reaction using the MegaBACE 500 automatic system on microdissected tissues. Histologically, HAML is composed of a heterogeneous mixture of blood vessels, smooth muscle, and adipose cells. The myomatous or myoid cells were the most variable. Most of the tumor cells were positive for HMB-45 (100%) and SMA (100%). There was a typical monoclonal pattern in 35 of the 40 tumors. No LOH or MSI was found. Hepatic AML is a benign neoplasm with varied morphology and monoclonal growth. HMB-45 is the best marker available for diagnosis. Neither LOH nor MSI appears to play an important role in the pathogenesis of this tumor.
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PMID:Pathological and molecular analysis of sporadic hepatic angiomyolipoma. 1673 15

Cirrhosis is a heterogeneous tissue composed of polyclonal regenerative and monoclonal neoplastic, potentially malignant nodules from which hepatocellular carcinoma (HCC) might develop. The aim of this study was to investigate proteomic profile changes associated with clonal expansion of cirrhotic nodules and malignant transformation of monoclonal nodules. Seventy-one cirrhotic nodules from 10 female patients with six HCC were dissected from liver surgical specimen by laser capture microdissection. Clonal status of each nodule was assessed by the study of X-chromosome inactivation pattern using the human androgen receptor. Protein profiles were determined by surface-enhanced laser desorption ionisation-time-of-flight technology using Q10 arrays (Cyphergen ProteinChip). Molecular weight of differentially expressed protein peaks was assessed. An average of 50 protein peaks was obtained for each nodule's profile. Comparison of protein profiles in polyclonal (n=45) and monoclonal cirrhotic nodules (n=26) identified three differentially expressed protein peaks (10,092, 54,025 and 62,133 Da). All were upregulated in monoclonal nodules. Twelve peaks were differentially expressed between monoclonal nodules and HCC with nine proteins upregulated in cancer samples. This study confirms that proteome analysis can be achieved from a limited number of microdissected cells, and provides further insight into the process of clonal expansion and malignant transformation of cirrhotic nodules.
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PMID:Global proteomic analysis of microdissected cirrhotic nodules reveals significant biomarkers associated with clonal expansion. 1684 32

Expression of estrogen receptors (ER)-alpha and -beta, as well as androgen receptor (AR), in hepatocellular carcinoma (HCC) is thought to be correlated with prognosis, survival, and male prevalence of HCC. These hypotheses are based on investigations of European patients; however the expression patterns of these receptors in Asian patients are largely unknown. In this study, we collected liver carcinoma and peritumor tissues from 32 patients (9 females and 23 males) in South Korea. The expression of ERs and ARs was studied using RT-PCR. Wild-type ER-alpha and AR were expressed in all of the samples investigated, and their expression was independent of the causal virus or patient sex. Expression of the ER-alpha variant was independent of sex (100% female vs. 91.3% male) and HCV and HBV status (91.3% vs. 100%). Wild-type ER-beta was expressed more often in HCV patients than in HBV patients (95.7% vs. 44.4%; p < 0.05). In conclusion, the stronger ER-alpha variant expression in HCC tissues implies that this variant has an important role in HCC development. However, at least in Korean patients, expression of the ER-alpha variant (vER-alpha) is not related to male HCC prevalence. In addition, the predominant expression of ER-beta in HCV patients suggests that it plays an important role in HCV-induced liver disease.
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PMID:The expression of estrogen receptors in hepatocellular carcinoma in Korean patients. 1719 10

Androgen and androgen receptor (AR) have long been implicated in liver carcinogenesis, especially for the male dominance feature. However, whether AR gene could occur in somatic mutations that might contribute to this process has not yet been studied. DNA sequencing and genotyping were conducted for detecting the genetic aberrations of AR gene in 257 primary hepatocellular carcinomas (HCCs) and also the dysplastic nodules (DN) from another 11 patients. Twenty-one AR somatic mutations causing amino acid changes were identified in HCC and even in the precancerous DN. The missense somatic mutations of AR were rare in HCC (2 cases) but the trinucleotide repeat (TNR) changes, both at (CAG)n and (GGC)n, was a more common one (19 cases). Notably, all these mutations occurred in male patients and most TNR changes belonged to the contraction type (15 out of 19 cases, 78.9%), which has been reported to associate with increased AR transcriptional activity. Most samples with TNR changes did not show microsatellite instability, suggesting a different cause for these TNR mutations. Although no significant correlation was identified between AR mutations and the clinicopathologic parameters, we found the (CAG)n length significantly shorter in hepatitis B virus (HBV)(+) HCCs than in HBV(-) HCCs and the (GGC)n length significantly correlates with the overall survival. In conclusion, the mis-sense somatic mutations of AR were rare in HCC but the TNR change was a more common one, which exclusively occurred in males. Moreover, the length of TNR carried clinical significance in special HCC group.
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PMID:Somatic mutations at the trinucleotide repeats of androgen receptor gene in male hepatocellular carcinoma. 1723 May 29

Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBV-related HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.
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PMID:Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. 1725 6


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