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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and first-degree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P(trend) =.0216) and age at natural menopause (P(trend) =.0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age <or=50 during premenopausal years was also a risk factor (multivariate-adjusted OR, 2.57; 95% CI, 1.42-4.63). Use of hormone replacement therapy (HRT) (multivariate-adjusted OR, 0.46; 95% CI, 0.27-0.79) was associated with a lower risk of HCC, and there was a trend in the risk with increasing duration of HRT (P(trend) = 0.0013). All reproductive factors had a similar impact on HBsAg-positive and -negative women except for an early menarche (<or=12 vs. >or=16 years), which increased HCC risk in HBsAg carriers (multivariate-adjusted OR, 6.96; 95% CI, 2.52-19.18) but posed no increased risk in noncarriers (P(interaction) =.0053). In conclusion, increased exposure to estrogen during adulthood may provide a protective effect against HCC. Nevertheless, an early menarche, which results in early estrogen exposure, does not confer protection for HBsAg carriers.
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PMID:Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk. 1464 50

Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-alpha, ERbeta, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERbeta knockout mice but not in those lacking ERalpha or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides -1862 and -855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERalpha, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.
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PMID:Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro. 1531 56

Estrogen has been related to the development of hepatocellular carcinoma (HCC). In this molecular epidemiological study, we used logistic regression to compare the genotype frequencies of estrogen-metabolizing genes that are involved in estrogen biogenesis (CYP17), hydroxylation (CYP1A1) and inactivation of the reactive metabolites (catechol-O-methyltransferase, COMT) in HCC patients and control subjects, and determined their relationship with the risk of female HCC. The heterozygous or homozygous variants of high activity CYP17 (A2), high inducibility CYP1A1(m1), and low activity COMT (L) alleles were considered as high-risk genotypes. We found that the risk of HCC was elevated in women harboring either heterozygous or homozygous variants of the CYP1A1 gene and the respective OR (and 95% confidence interval) were 6.61 (1.35, 32.43) and 12.00 (1.73, 83.46). Moreover, we found that the risk of HCC was increased in the female subjects harboring higher numbers of high-risk genotypes, but not in male subjects. The OR for female HCC associated with two putative high-risk genotypes was 12.63 (1.50, 106.37), and the OR for three putative high-risk genotypes was 16.67 (1.82, 152.77). These findings strongly suggest that estrogen play a critical role in female hepatocarcinogenesis.
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PMID:Polymorphisms of estrogen-metabolizing genes and risk of hepatocellular carcinoma in Taiwan females. 1534 Oct 23

Estrogen is an important steroid hormone that mediates most of its effects on regulation of gene expression by binding to intracellular receptors. The consensus estrogen response element (ERE) is a 13bp palindromic inverted repeat with a three nucleotide spacer. However, several reports suggest that many estrogen target genes are regulated by diverse elements, such as imperfect EREs and ERE half sites (ERE 1/2), which are either the proximal or the distal half of the palindrome. To gain more insight into ERE half site-mediated gene regulation, we used a region from the estrogen-regulated chicken riboflavin carrier protein (RCP) gene promoter that contains ERE half sites. Using moxestrol, an analogue of estrogen and transient transfection of deletion and mutation containing RCP promoter/reporter constructs in chicken hepatoma (LMH2A) cells, we identified an estrogen response unit (ERU) composed of two consensus ERE 1/2 sites and one non-consensus ERE 1/2 site. Mutation of any of these sites within this ERU abolishes moxestrol response. Further, the ERU is able to confer moxestrol responsiveness to a heterologous promoter. Interestingly, RCP promoter is regulated by moxestrol in estrogen responsive human MCF-7 cells, but not in other cell lines such as NIH3T3 and HepG2 despite estrogen receptor-alpha (ER-alpha) co transfection. Electrophoretic mobility shift assays (EMSAs) with promoter regions encompassing the half sites and nuclear extracts from LMH2A cells show the presence of a moxestrol-induced complex that is abolished by a polyclonal anti-ERalpha antibody. Surprisingly, estrogen receptor cannot bind to these promoter elements in isolation. Thus, there appears to be a definite requirement for some other factor(s) in addition to estrogen receptor, for the generation of a suitable response of this promoter to estrogen. Our studies therefore suggest a novel mechanism of gene regulation by estrogen, involving ERE half sites without direct binding of ER to the cognate elements.
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PMID:Estrogen regulation of chicken riboflavin carrier protein gene is mediated by ERE half sites without direct binding of estrogen receptor. 1571 31

Hepatocellular carcinoma (HCC), the major manifestation of primary liver cancer, is one of the most frequent and malignant cancers worldwide, especially in Taiwan. Estrogen receptors (ERs) have been reported to play either a proliferation- or apoptosis-enhancing role in the differentiation of cancers, including HCC. In a previous experiment, we showed that transient overexpressed estrogen receptor-alpha induced early stage HCC cell line Hep 3B cell apoptosis by increasing the hTNF-alpha gene expression in a ligand-independent manner. To further clarify if the apoptotic effect occurs in poorly differentiated HCC cell line, HA22T, and elucidate the roles of ERs and TNF-alpha, DNA fragmentation and caspase activity were measured in late stage HCC cell line, HA22T, by measuring the expression of hER-alpha and hER-beta using a Tetracycline-inducible system (Tet-on). Increased DNA fragmentation and caspase-3 activity were found in hERbeta-overexpressed HA22T cells treated with estrogen (10(-8) M) but not in hERalpha-overexpressed HA22T cells. Using RT-PCR/PCR and western blotting in HA22T cells, overexpressed hER-beta was also found to increase the expression of hTNF-alpha mRNA and induce hTNF-alpha-dependent luciferase activity in a ligand-dependent manner. Additionally, LPS treatment and hER-beta overexpression both enhance caspase-8 activities, whereas neither hER-beta nor E2 treatment affected caspase-9 activities. In addition, the overexpressed hER-beta plus E2 enhanced DNA fragmentation and caspase-8 activities were only partially reduced by anti-hTNF-alpha (0.1 ng/ml), which was possibly due to the involvement of P53 and TGF-beta. Taken together, our data indicates that overexpressed hER-beta but not hER-alpha may induce caspase-8-mediated apoptosis by increasing the hTNF-alpha gene expression in a ligand-dependent manner in poorly differentiated HA22T cells.
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PMID:Opposing action of estrogen receptors alpha and beta on tumor necrosis factor-alpha gene expression and caspase-8-mediated apoptotic effects in HA22T cells. 1663 37

Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 microg/pup/day) or tamoxifen (TAM; 10 microg/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-alpha, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.
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PMID:Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen. 1671 94

Hepatitis B virus (HBV) X protein (HBx) is considered to play a role in the development of hepatocellular carcinoma (HCC) during HBV infection. HCC was shown to be more prevalent in men than in women. Estrogen, which exerts its biological function through estrogen receptor (ER), can inhibit HBV replication. ERDelta5, an ERalpha variant lacking exon 5, was found to be preferentially expressed in patients with HCC compared with patients with normal livers. Here, we report the biological role of ERDelta5 and a novel link between HBx and ERalpha signaling in hepatoma cells. ERDelta5 interacts with ERalpha in vitro and in vivo and functions as a dominant negative receptor. Both ERalpha and ERDelta5 associate with HBx. HBx decreases ERalpha-dependent transcriptional activity, and HBx and ERDelta5 have additive effect on suppression of ERalpha transactivation. The HBx deletion mutant that lacks the ERalpha-binding site abolishes the HBx repression of ERalpha. HBx, ERalpha and histone deacetylase 1 (HDAC1) form a ternary complex. Trichostatin A, a specific inhibitor of HDAC enzyme, can restore the transcriptional activity of ERalpha inhibited by HBx. Our data suggest that HBx and ERDelta5 may play a negative role in ERalpha signaling and that ERalpha agonists may be developed for HCC therapy.
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PMID:Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. 1675 75

Hepatocellular carcinoma is the fifth most common malignant neoplasm worldwide. Most patients are not candidates to surgical treatment. The prognosis of this neoplasm is poor, with an overall survival rate of 8 weeks in unresectable tumors. Estrogen receptors have been found in up to 33% of this tumors, reason why treatment with tamoxifen or progesterone compounds have been tried to diminish this neoplasm's progression but its use remains controversial. In our institution, thirteen patients were treated with tamoxifen (20- 40 mg/day) and 26 received supportive measures only. The clinical and tumoral characteristics were similar in both groups. Survival in the Tamoxifen group was of 5.5 +/- 1.7 months while in the supportive measures group was of 2.1 +/- 0.5 months (p = 0.018). Other factors related to an increased survival were: female gender and the Okuda score; age, TNM and alphaFP were not related to survival. The multivariate analysis showed that treatment with tamoxifen duplicates survival independently of the tumoral stage and functional hepatic reserve. It seems that the benefit of treatment with tamoxifen is limited and is not associated to the presence of estrogen receptors. In our study a 69 year-old man with diagnosis of non-resectable hepatocellular carcinoma and negative estrogen receptors, was treated with tamoxifen with a partial response and an overall survival of 4 years until November 2005. Despite some case reports that have shown tumoral regression, while other studies do not report any survival benefits. It is important to identify patients that would benefit from treatment with tamoxifen.
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PMID:Response of negative estrogen-receptor hepatocarcinoma to tamoxifen, and survival of non-resectable patients. 1715 78

Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.
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PMID:Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. 1735 61

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.
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PMID:Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. 1803 65


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