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Chang TJ, Hsia CY, Chau GY, Hsiao LT, Huang KT, King KL, Lui WY, Li AFY, Wang CL, Tsai PH, Chien Y, Lin TH. Characterization of Androgen Receptor Complex Associated Protein (ARCAP) in hepatocellular carcinoma and liver. J Chin Med Assoc 2021; 84:1100-1108. [PMID: 34596084 DOI: 10.1097/jcma.0000000000000628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks many tasks in clinical oncology due to possibly developing a general tumor in men and, usually lead to malignant to death within years. Researches had reported about major factors for being HCC was male sex and HCC associated with cirrhosis in childhood was found more common in males than females. In certain mouse strains as studied, breeding with testosterone significantly increases the development of HCC. Furthermore, castration of male mice diminished the frequency of the development of liver tumors. Meanwhile male hepatitis B virus transgenic mice have a greater occurrence of HCC than females. METHODS We apply degenerate priming PCR to observe the expression of various steroid receptors in livers. Yeast-two hybrid screening to search a novel RNA fragment helps to find a new full-length gene by RACE experiment. RT-PCR is applied to detect various expressions in tissues and cell lines. In situ hybridization detects DNA in Chromosome mapping. GFP-constructs transfection proves the gene localization in cells. Immunoprecipitation pulldown assay verifies protein interaction. Gene transfection followed with luciferase assay demonstrates the interaction of genes within cellular signaling. Genomic alignment analysis for observing sequences data perform from NCBI database website (http://www.ncbi.nim.nih.gov/genebank/). RESULTS The androgen receptor (AR) expression level is found at the highest level among the steroid receptors families detected in liver tumors. By yeast-two hybrid screening, we cloned an Androgen Receptor Complex Associated Protein (ARCAP), of 95 Kd in molecular weight and its cDNA. ARCAP locates at Chromosome 1. Our findings indicate ARCAP is highly expressed in hepatoma cell lines and liver tumors and their adjacent tumors as observed. Yeast two-hybrid assay and in vitro immunoprecipitation assays demonstrated an interaction between AR and ARCAP. CONCLUSION We aim to search for different types and levels of steroid receptors expressed within human HCCs and in the adjacent liver tissues. To verify possible molecular mechanisms by which AR might affect hepatoma cells, we had characterized a novel protein ARCAP which functions as a coregulator to interact with AR within liver. The ligand-dependent AR with its cofactor, ARCAP, can induce a signal cascade by transactivation.
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Affiliation(s)
- Tai-Jay Chang
- Department of Medical Research, Basic Research Division, Laboratory of Genome Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Cheng-Yuan Hsia
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Gar-Yang Chau
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Liang-Tsai Hsiao
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Kuang-Tzu Huang
- Department of Medical Research, Basic Research Division, Laboratory of Genome Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Kung-Liang King
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Wing-Yiu Lui
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Anna F-Y Li
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chia-Lin Wang
- Laboratory of Nuclear Magnetic Resonance, Basic Research Division, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-Hsing Tsai
- Department of Medical Research, Basic Research Division, Laboratory of Genome Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yueh Chien
- Department of Medical Research, Basic Research Division, Laboratory of Genome Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ta-Hsien Lin
- Laboratory of Nuclear Magnetic Resonance, Basic Research Division, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks. Sci Rep 2021; 11:3646. [PMID: 33574348 PMCID: PMC7878907 DOI: 10.1038/s41598-021-82252-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 01/11/2021] [Indexed: 12/13/2022] Open
Abstract
A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.
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Liver-specific androgen receptor knockout attenuates early liver tumor development in zebrafish. Sci Rep 2019; 9:10645. [PMID: 31337771 PMCID: PMC6650507 DOI: 10.1038/s41598-019-46378-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most severe cancer types and many genetic and environmental factors contribute to the development of HCC. Androgen receptor (AR) signaling is increasingly recognized as one of the important factors associated with HCC. Previously, we have developed an inducible HCC model in kras transgenic zebrafish. In the present study, to investigate the role of AR in liver tumor development, we specifically knocked out ar gene in the liver of zebrafish via the CRISPR/Cas9 system and the knockout zebrafish was named L-ARKO for liver-specific ar knockout. We observed that liver-specific knockout of ar attenuated liver tumor development in kras transgenic zebrafish at the early stage (one week of tumor induction). However, at the late stage (two weeks of tumor induction), essentially all kras transgenic fish continue to develop HCC irrespective of the absence or presence of ar gene, indicating an overwhelming role of the driver oncogene kras over ar knockout. Consistently, cell proliferation was reduced at the early stage, but not the late stage, of liver tumor induction in the kras/L-ARKO fish, indicating that the attenuant effect of ar knockout was at least in part via cell proliferation. Furthermore, androgen treatment showed acceleration of HCC progression in kras fish but not in kras/L-ARKO fish, further indicating the abolishment of ar signalling. Therefore, we have established a tissue-specific ar knockout zebrafish and it should be a valuable tool to investigate AR signalling in the liver in future.
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Ali MA, Lacin S, Abdel-Wahab R, Uemura M, Hassan M, Rashid A, Duda DG, Kaseb AO. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway? Onco Targets Ther 2017; 10:1403-1412. [PMID: 28424556 PMCID: PMC5344425 DOI: 10.2147/ott.s111681] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.
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Affiliation(s)
- Mahmoud A Ali
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sahin Lacin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Reham Abdel-Wahab
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Clinical Oncology, Assiut University, Assiut, Egypt
| | - Mark Uemura
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dan G Duda
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:285-300. [PMID: 25241227 DOI: 10.1007/s12016-014-8449-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.
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Affiliation(s)
- Ying Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
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Ahmed HH, Shousha WG, Shalby AB, El-Mezayen HA, Ismaiel NN, Mahmoud NS. Implications of Sex Hormone Receptor Gene Expression in the Predominance of Hepatocellular Carcinoma in Males: Role of Natural Products. Asian Pac J Cancer Prev 2015; 16:4949-4954. [PMID: 26163620 DOI: 10.7314/apjcp.2015.16.12.4949] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025] Open
Abstract
The present study was planned to investigate the role of sex hormone receptor gene expression in the pathogenesis of hepatocellular carcinoma (HCC). Adult male Wistar rats were divided into seven groups. Group (1) was negative control. Groups (2), (5), (6), and (7) were orally administered with N-nitrosodiethylamine for the induction of HCC, then group (2) was left untreated, group (5) was orally treated with curcumin, group (6) was orally treated with carvacrol, and group (7) was intraperitoneally injected with doxorubicin, whereas groups (3) and (4) were orally administered only curcumin and carvacrol, respectively. The HCC group showed significant upregulation in the androgen receptor (AR) and the estrogen receptor-alpha (ERα) gene expression levels in the liver tissue. On the contrary, HCC groups treated with either curcumin or carvacrol showed significant downregulation in AR and ERα gene expression levels in the liver tissue. In conclusion, the obtained data highlight that both AR and ERα but not estrogen receptor-beta (ERβ) gene expression may contribute to the male prevalence of HCC induced in male rats. Interestingly, both curcumin and carvacrol were found to have a promising potency in alleviating the male predominating HCC.
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Affiliation(s)
- Hanaa H Ahmed
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt E-mail :
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Al Sayed AA, Al Sulaiman MH, Mishriky A, Anil S. The role of androgen receptor gene in cyclosporine induced gingival overgrowth. J Periodontal Res 2014; 49:609-614. [PMID: 24206119 DOI: 10.1111/jre.12141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Gingival overgrowth is a prominent side effect of cyclosporine (CsA) therapy in renal transplant patients. Although the exact mechanism by which this drug induces gingival overgrowth is uncertain, marked variations in individual susceptibility to this drug suggest a genetic predisposition. Studies have shown that genetic variation (polymorphism) in the trinucleotide cytosine-adenine- guanine (CAG) sequence in exon 1 of the androgen receptor (AR) gene is related to altered activity of the AR as a transcription factor. However, the relationship between the length of the CAG repeat and gingival overgrowth has not yet been studied. The present study was carried out to determine whether there is an association between CsA-induced gingival overgrowth and the length of the CAG repeats in the AR gene. MATERIAL AND METHODS Genomic DNA samples were prepared from the blood of 50 renal transplant patients with CsA-induced gingival overgrowth and from the blood of 100 renal transplant patients on CsA with no gingival overgrowth. RESULTS The difference in allele distribution among the subjects with gingival overgrowth and control samples was statistically significant (p = 0.001). CONCLUSION The findings suggest a link between CsA7induced gingival overgrowth and a smaller size of CAG repeat in the AR gene.
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Affiliation(s)
- A A Al Sayed
- Prince Sultan Military Medical City, Ministry of Defense, Riyadh, Saudi Arabia
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8
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Luisier R, Unterberger EB, Goodman JI, Schwarz M, Moggs J, Terranova R, van Nimwegen E. Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion. Nucleic Acids Res 2014; 42:4180-95. [PMID: 24464994 PMCID: PMC3985636 DOI: 10.1093/nar/gkt1415] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well-characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and β-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis.
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Affiliation(s)
- Raphaëlle Luisier
- Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, 4057 Basel, Switzerland, Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, 72074 Tübingen, Germany, Department of Pharmacology and Toxicology, Michigan State University, MI 48824, USA and Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland
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Fujimoto N, Inoue K, Yoshida M, Nishikawa A, Ozawa S, Gamou T, Nemoto K, Degawa M. Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats. J Toxicol Sci 2012; 37:281-6. [PMID: 22467018 DOI: 10.2131/jts.37.281] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The present study examined hepatic estrogen receptor (ER) and androgen receptor (AR) levels as well as estrogen-signaling status in a model of rat hepatic hypertrophy induced by phenobarbital (PB), chlofibrate (CF), or piperonyl butoxide (PBO). Male F344 rats were fed with PB at 2,500 ppm, CF at 2,500 ppm, and PBO at 20,000 ppm for 3 days, 4 weeks, and 13 weeks. CF and PBO induced diffuse hypertrophy, while centrilobular hypertrophy was observed with PB administration. The levels of mRNA for ERα, AR and leukemia inhibitory factor receptor (LIFR) which was found to be estrogen responsive in the present study, were determined by quantitative RT-PCR. In the CF and PBO groups, ERα mRNA expression was reduced, and consequently, the expression of a responsive gene, LIFR, was also decreased, while PB had no effect on ER mRNA levels. AR mRNA expression decreased in all the treated groups, but reduction was persistent only in PB group. Recently, LIFR was identified as a tumor suppressor gene in human HCC. Thus, LIFR may be one of the key mediators of hepatic carcinogenesis induced by CF and PBO, but PB appears to act via different mechanisms.
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Affiliation(s)
- Nariaki Fujimoto
- Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
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Kennedy GL, Butenhoff JL, Olsen GW, O'Connor JC, Seacat AM, Perkins RG, Biegel LB, Murphy SR, Farrar DG. The Toxicology of Perfluorooctanoate. Crit Rev Toxicol 2010; 34:351-84. [PMID: 15328768 DOI: 10.1080/10408440490464705] [Citation(s) in RCA: 565] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.
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Ruggieri A, Barbati C, Malorni W. Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. Int J Cancer 2010; 127:499-504. [PMID: 20201099 DOI: 10.1002/ijc.25298] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and one of the most fatal human cancers. Besides alcoholic liver disease as well as genetic and environmental factors, hepatitis B and C viral infections also represent the most important risk factors for onset and development of the disease. In fact, HCC worldwide prevalence varies widely and mirrors the geographical distribution of chronic viral hepatitis. Interestingly, a gender difference was described for this disease: in almost all populations, a male/female ratio averaging between 2:1 and 4:1 was reported. Here, we analyze the implication of cytokines and sex hormones in this issue. Exploiting the emerging knowledge on the possible differential role of hepatitis viruses B and C, we discuss the role of reactive oxygen species and apoptosis dysregulation in the characterization of the molecular mechanisms of gender disparity in the development of HCC.
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Affiliation(s)
- Anna Ruggieri
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita', Rome, Italy
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Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World J Gastroenterol 2008; 14:5945-5961. [PMID: 18932272 PMCID: PMC2760195 DOI: 10.3748/wjg.14.5945] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2008] [Revised: 09/16/2008] [Accepted: 09/23/2008] [Indexed: 02/06/2023] Open
Abstract
The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERalpha alone until 1996 when ERbeta isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.
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Ma WL, Hsu CL, Wu MH, Wu CT, Wu CC, Lai JJ, Jou YS, Chen CW, Yeh S, Chang C. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology 2008; 135:947-55, 955.e1-5. [PMID: 18639551 PMCID: PMC2753209 DOI: 10.1053/j.gastro.2008.05.046] [Citation(s) in RCA: 188] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Revised: 04/01/2008] [Accepted: 05/15/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes. METHODS By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC. RESULTS We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models. CONCLUSIONS Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.
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MESH Headings
- Androgen Receptor Antagonists
- Animals
- Apoptosis
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation
- Curcumin/analogs & derivatives
- Curcumin/therapeutic use
- DNA Damage
- DNA Repair
- Female
- Genes, p53
- Humans
- Liver/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Male
- Mice
- Mice, Knockout
- Mice, Nude
- Oxidative Stress
- RNA, Small Interfering/therapeutic use
- Reactive Oxygen Species/metabolism
- Receptors, Androgen/metabolism
- Testosterone/blood
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Affiliation(s)
- Wen-Lung Ma
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Cheng-Lung Hsu
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung University/Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Heng Wu
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Chun-Te Wu
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung University/Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Chia Wu
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Jiann-Jyh Lai
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Yuh-Shan Jou
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chun-Wei Chen
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Shuyuan Yeh
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
| | - Chawnshang Chang
- George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology and the Cancer Center, University of Rochester Medical Center, Rochester, NY
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14
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Vizoso FJ, Rodriguez M, Altadill A, González-Diéguez ML, Linares A, González LO, Junquera S, Fresno-Forcelledo F, Corte MD, Rodrigo L. Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma. World J Gastroenterol 2007; 13:3221-3227. [PMID: 17589901 PMCID: PMC4436608 DOI: 10.3748/wjg.v13.i23.3221] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2007] [Revised: 03/05/2007] [Accepted: 03/15/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis. METHODS We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls) to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitative score based on their intensity, and the percentage of immunostained cells was measured. RESULTS A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However, the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis. CONCLUSION Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.
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Affiliation(s)
- F J Vizoso
- Unidad de Investigación, Fundación Hospital de Jove, Gijón, and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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15
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Yoon G, Kim JY, Choi YK, Won YS, Lim IK. Direct activation of TGF-beta1 transcription by androgen and androgen receptor complex in Huh7 human hepatoma cells and its tumor in nude mice. J Cell Biochem 2006; 97:393-411. [PMID: 16187311 DOI: 10.1002/jcb.20638] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Importance of androgen for promotion of hepatocelullar carcinoma (HCC) has long been supported by clinical and experimental evidences. However, mechanisms involved in the carcinogenesis have not yet been fully elucidated. Moreover, unbalanced expression of TGF-beta1 during tumor progression results in prooncogenic rather than growth inhibition. To investigate the effect of androgen on transcriptional regulation of TGF-beta1, we isolated rat TGF-beta1 promoter, based on our previous report (GenBank AF249327), and examined regulation of its promoter activity by dihydrotestosterone in Huh7, LNCaP, and PC3 cells. Several putative transcription factor-binding sites were found, but no TATA box. When the full-length (-4784 to +68) and variously deleted promoter DNAs were evaluated, the promoter region spanning from -2732 to -1203 showed the highest activity towards dihydrotestosterone in a dose-dependent manner in both Huh7 and PC3 cells with androgen receptor (AR) expression. Putative androgen response sequence half site (5'-TGTCCT-3') was identified to be located within -1932 to -1927, proved by mutant (5'-AGACCT-3') analysis and chromatin immunoprecipitation (ChIP) assay. AR mediated upregulation of TGF-beta1 expression was confirmed by HCC developed in nude mice with AR-overexpressed Huh7-cells. This work presents in vivo and in vitro evidences of activation of TGF-beta1 expression by androgen and AR, and implicates the modulation of hepatocarcinogenesis by AR through the regulation of TGF-beta1 expression.
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Affiliation(s)
- Gyesoon Yoon
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721, Korea
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16
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Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004; 40:1361-9. [PMID: 15565568 DOI: 10.1002/hep.20474] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The growth of hepatocellular carcinoma (HCC) is thought to be dependent on androgens, as androgen receptors are present in most of these tumors. The aim of this multicenter trial was to assess the effect of antiandrogens in patients who have advanced HCC. Male patients with advanced HCC were randomized into 2 groups treated with (1) leuprorelin (3.75 mg/mo subcutaneously), flutamide (750 mg/d orally), and tamoxifen (30 mg/d orally) or (2) tamoxifen alone (30 mg/d orally) administered until death. Survival was the main end point (log-rank test). The required sample size was 375 patients (alpha, 5%; beta, 10%; 1-year survival, 45% in treated group and 30% in controls). Between February 1994 and January 1998, 376 male patients (mean age, 66 years; treated group, n = 192; control group, n = 184) were included. No baseline imbalance was found between the groups. At the reference date (January 1, 2003), 183 deaths (95.3%) were observed in the treated group and 177 deaths (96.2%) were observed in controls. Thirteen patients were lost to follow-up. Median survival time was estimated to be 135.5 days (95% CI, 112-189) and 176 days (95% CI, 141-227) in treated and control groups, respectively (P = .21). Crude and adjusted relative risks of death in the treated group were estimated at 1.14 (95% CI, 0.93-1.40) and 1.08 (95% CI, 0.87-1.33; P = .48) respectively. Premature interruption of treatment was more frequent in the treated group (n = 45) than in controls (n = 22; P = .0045), mainly because of digestive side effects. In conclusion, no benefit in survival was found with antiandrogenic treatment in male patients with advanced HCC.
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17
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Tadic SD, Elm MS, Li HS, Van Londen GJ, Subbotin VM, Whitcomb DC, Eagon PK. Sex differences in hepatic gene expression in a rat model of ethanol-induced liver injury. J Appl Physiol (1985) 2002; 93:1057-68. [PMID: 12183503 DOI: 10.1152/japplphysiol.00568.2001] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Sex differences in susceptibility to alcohol-induced liver injury have been observed in both humans and experimental animal models. Using a standard model of alcohol-induced fatty liver injury and microarray analysis, we have identified differential expression of hepatic genes in both sexes. The genes that exhibit differential expression are of three types: those that are changed only in male rats fed alcohol, those that change in only female rats fed alcohol, and those that change in both sexes, although not always in the same manner. Certain of the differentially expressed genes have previously been identified as participants in the induction of alcohol-induced liver injury. However, this analysis has identified a number of genes that heretofore have not been implicated in alcoholic liver injury; such genes may provide new areas of investigation into the pathogenesis of this disease.
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Affiliation(s)
- Stasa D Tadic
- Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15240, USA
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18
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Harada H, Pavlick KP, Hines IN, Hoffman JM, Bharwani S, Gray L, Wolf RE, Grisham MB. Selected contribution: Effects of gender on reduced-size liver ischemia and reperfusion injury. J Appl Physiol (1985) 2001; 91:2816-22. [PMID: 11717250 DOI: 10.1152/jappl.2001.91.6.2816] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is a common occurrence in resectional surgery as well as reduced-size liver transplantation (e.g., split liver or living donor transplantation). However, the I/R induced by these types of surgical manipulations may impair liver regeneration, ultimately leading to liver failure. The objectives of the study were to develop a murine model of reduced-size liver I/R and assess the role of gender in this model of hepatocellular injury. We found that 100% of female mice survived the surgery indefinitely, whereas all male mice had greater initial liver injury and died within 5 days after surgery. The protective effect observed in females appeared to be due to ovarian 17beta-estradiol, as ovariectomy of females or administration of a selective estrogen antagonist to female mice resulted in enhanced liver injury and greater mortality following reduced-size liver I/R. Conversely, 17beta-estradiol-treated male mice exhibited less hepatocellular damage and survived indefinitely. Taken together, these data demonstrate an estrogen-mediated protective pathway(s) that limits or attenuates hepatocellular injury induced by reduced-size liver I/R.
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Affiliation(s)
- H Harada
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
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19
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Eagon PK, Elm MS, Tadic SD, Nanji AA. Downregulation of nuclear sex steroid receptor activity correlates with severity of alcoholic liver injury. Am J Physiol Gastrointest Liver Physiol 2001; 281:G342-9. [PMID: 11447013 DOI: 10.1152/ajpgi.2001.281.2.g342] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic ethanol ingestion in rats and humans results in significant alterations in sex steroid levels and expression of sex hormone-dependent phenotype. In this study, we used the intragastric feeding model in male rats to determine hepatic sex hormone receptor activity under circumstances of chronic ethanol exposure and differing degrees of liver injury induced by type of dietary fat. Pathological analysis and quantitation of hepatic androgen receptor (AR) and estrogen receptor (ER) activity, serum sex hormones, and sex hormone-responsive protein and mRNA expression were performed. The activity of the physiologically relevant nuclear form of both AR and ER was significantly decreased with ethanol and correlated inversely with the severity of liver injury. Serum testosterone levels, as well as expression of an androgen-dependent hepatic mRNA, were decreased by ethanol and progressive liver injury. Serum estradiol increased with liver injury. We postulate that these changes in receptor activity may be due to the oxidative stress, reduced cellular energy, and/or altered cytokine milieu known to occur in this model.
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Affiliation(s)
- P K Eagon
- Veterans Affairs Medical Center, and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
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20
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Nakatani T, Roy G, Fujimoto N, Asahara T, Ito A. Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin. Jpn J Cancer Res 2001; 92:249-56. [PMID: 11267934 PMCID: PMC5926710 DOI: 10.1111/j.1349-7006.2001.tb01089.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The prevalence of liver tumors throughout the world makes it imperative to seek chemopreventive agents. This tumor appears to be hormone-responsive and hormonal manipulations may therefore be beneficial. On this basis, both sexes of 12-day-old B6C3F(1) mice were injected i.p. with diethylnitrosamine (DEN) at the dose of 2.5 mg / g body weight and observed for 32 weeks (males) or 36 weeks (females). In 100% of male mice, liver tumors were observed with an average diameter of 2.72 mm and multiplicity of 60.8. Orchidectomy at 6 weeks of age in these mice inhibited the incidence, multiplicity and size to 63%, 5.6 and 1.54 mm, respectively. By further implantation with an E(2) pellet at monthly intervals, these parameters were reduced to 26%, 0.6 and 0.61 mm, respectively. Administration of a gonadotropin-blocking chemical, leuprorelin, to DEN-treated male mice significantly reduced the multiplicity and size of tumors to 18.3 and 2.54 mm (P < 0.01 compared to those of DEN only). In female mice, the incidence of liver tumor was significantly smaller than that of males. However, ovariectomy and / or testosterone supplement significantly increased the occurrence of liver tumor. An anti-estrogen, toremifene, caused a marked further decrease of liver tumors. Mitotic indices with bromodeoxyuridine in tumor tissues paralleled the occurrence of liver tumors. Serum testosterone levels were significantly reduced by orchidectomy or by leuprorelin administration. These results further confirm that liver tumor is testosterone-responsive and hormonal manipulation by surgical orchidectomy or by chemical orchidectomy i.e. by leuprorelin, could substantially prevent the appearance of liver tumors.
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Affiliation(s)
- T Nakatani
- Department of Cancer Research, Research Institute for Radiation Biology, Hiroshima University School of Medicine, Minami-ku, Hiroshima 734-8553, Japan
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21
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Alvaro D, Alpini G, Onori P, Perego L, Svegliata Baroni G, Franchitto A, Baiocchi L, Glaser SS, Le Sage G, Folli F, Gaudio E. Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats. Gastroenterology 2000; 119:1681-1691. [PMID: 11113090 DOI: 10.1053/gast.2000.20184] [Citation(s) in RCA: 144] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS We investigated the expression of estrogen receptor (ER) alpha and beta subtypes in cholangiocytes of normal and bile duct-ligated (BDL) rats and evaluated the role and mechanisms of estrogens in the modulation of cholangiocyte proliferation. METHODS ER-alpha and ER-beta were analyzed by immunohistochemistry, reverse-transcription polymerase chain reaction, and Western blotting in normal and BDL rats. The effects of the ER antagonists tamoxifen and ICI 182,780 on cholangiocyte proliferation were evaluated. RESULTS Cholangiocytes expressed both ER-alpha and ER-beta subtypes, whereas hepatocytes expressed only ER-alpha. In association with a marked cholangiocyte proliferation and with enhanced estradiol serum levels, the immunoreactivity for ER-alpha involved a 3-fold higher percentage of cholangiocytes in 3-week BDL than in normal rats; immunoreactivity for ER-beta showed a 30-fold increase. Western blot analysis showed that during BDL, the total amount of ER-beta in cholangiocytes was markedly increased (5-fold), whereas that of ER-alpha decreased slightly (-25%). Treatment with tamoxifen or ICI 182,780 of 3-week BDL rats inhibited cholangiocyte proliferation and induced overexpression of Fas antigen and apoptosis in cholangiocytes. In vitro, 17 beta estradiol stimulated proliferation of cholangiocyte, an effect blocked to the same extent by tamoxifen or ICI 182,780. CONCLUSIONS This study suggests that estrogens and their receptors play a role in the modulation of cholangiocyte proliferation.
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Affiliation(s)
- D Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University La Sapienza, Rome, Italy
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22
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Mitry RR, Mansour MR, Havlík R, Habib NA. Gene therapy for liver tumours. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2000; 465:193-205. [PMID: 10810627 DOI: 10.1007/0-306-46817-4_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Affiliation(s)
- R R Mitry
- Liver Surgery Section, Imperial College School of Medicine, London, United Kingdom
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23
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Tadic SD, Elm MS, Subbotin VM, Eagon PK. Hypogonadism precedes liver feminization in chronic alcohol-fed male rats. Hepatology 2000; 31:1135-40. [PMID: 10796890 DOI: 10.1053/he.2000.6960] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Men who chronically abuse alcohol may display a spectrum of endocrine abnormalities including hypogonadism and feminization, with elevated serum estradiol and low serum testosterone. We examined factors that may result in disruption of hepatic sex hormone homeostasis in alcohol-fed male rats and possible consequences of such changes. Rats were fed alcohol-containing or isocaloric diets for 30, 60, and 90 days. In alcohol-fed rats, serum testosterone levels and hepatic activity of 2 androgen-dependent estrogen metabolizing enzymes were reduced (P <.05) at all times, as was activity of androgen receptor. There was also a significant early and progressive decrease in testes/body ratio in alcohol-fed rats. Compared with this early decrease in testosterone-related parameters, there was a significant increase in serum estrogen levels (at 30 and 90 days, 132% and 168% of control values, respectively). An increase in serum ceruloplasmin, an estrogen-responsive liver protein, was apparent at 60 and 90 days, but not at 30 days of alcohol exposure, suggesting that hypogonadism precedes liver feminization. Hepatic estrogen receptor activity was decreased in alcohol-fed rats at 60 and 90 days, the latter despite elevated serum estrogen levels. Hepatic aromatase was slightly increased in alcohol-fed rats, an elevation probably not sufficient to account for observed increases in serum estrogen. Taken together, these data suggest that (1) alcohol induces profound reduction of serum testosterone, resulting in loss of androgen-regulated hepatic functions such as estrogen-metabolizing enzyme activity and activity of androgen receptors; and (2) such alcohol-induced hypogonadism precedes changes in hepatic sex hormone homeostasis and subsequent feminization.
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Affiliation(s)
- S D Tadic
- Veterans Affairs Medical Center, Pittsburgh, PA 15261, USA
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24
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Villa E, Dugani A, Moles A, Camellini L, Grottola A, Buttafoco P, Merighi A, Ferretti I, Esposito P, Miglioli L, Bagni A, Troisi R, De Hemptinne B, Praet M, Callea F, Manenti F. Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease. Hepatology 1998; 27:983-8. [PMID: 9537437 DOI: 10.1002/hep.510270413] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Variant estrogen receptors may be found in hepatocellular carcinoma and may influence its natural history. Because it is not known whether their occurrence is an early or a late event during the course of chronic liver disease or whether they cluster in some subgroups of patients, we investigated a series of patients in different stages of chronic liver disease. One hundred eleven consecutive patients were studied for variant estrogen receptor transcripts by reverse-transcription polymerase chain reaction of RNA extracted from liver biopsy specimens. In chronic active hepatitis, variant estrogen receptor transcripts were coexpressed with wild-type significantly more often in men than in women (P = .029) and in hepatitis B surface antigen (HBsAg)-positive subjects than in subjects positive for antibody to hepatitis C virus (P = .0006). In hepatocellular carcinoma, again in men (P = .004) and in HBsAg-positive patients (P = .0015), the variant estrogen receptor transcript was overexpressed or remained the only one expressed. Patients with liver cell dysplasia presented with the same estrogen receptor pattern than patients with hepatocellular carcinoma. This further reinforces the significance of liver cell dysplasia as a preneoplastic condition. The significantly higher occurrence of variant estrogen receptor in men (especially in HBsAg-positive men) already at an early stage of disease, like chronic active hepatitis, suggests that the alteration of estrogen receptors, favoring uncontrolled proliferation and development of hyperplasia, might constitute a prominent mechanism facilitating neoplastic transformation especially in men.
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Affiliation(s)
- E Villa
- Department of Internal Medicine, University of Modena, Italy
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25
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Pignata S, Daniele B, Gallo C, De Vivo R, Monfardini S, Perrone F. Endocrine treatment of hepatocellular carcinoma. Any evidence of benefit? Eur J Cancer 1998; 34:25-32. [PMID: 9624234 DOI: 10.1016/s0959-8049(97)00317-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the past 20 years, a number of studies have investigated the relationship between sex hormones and liver cancer. Experimental studies indicate that a dynamic process, with sequential modifications in the pattern of sex hormones in the serum and of sex hormone receptors in the liver, occurs progressively during hepatocarcinogenesis. Overall, it seems that both androgens and oestrogens may enhance liver carcinogenesis, while androgens may also support the growth of established liver tumours. Unfortunately, clinical studies of endocrine treatment of hepatocellular carcinoma (HCC) have not adequately tested the suggestions from biological studies. So far, no clinical trial has been performed to test the efficacy of endocrine manipulation for the chemoprevention of HCC in cirrhotic patients nor in preventing relapse after radical resection of primary HCC. Anti-oestrogens have been the most studied agents for the endocrine treatment of established HCC, although the rationale that supports their use is weaker than for anti-androgens. Studies with anti-androgens have produced prevalently negative results, due to either a lack of activity or excessive toxicity. The use of chemical castration, which theoretically could enhance the activity of antihormonal compounds, yielded no benefit at all. In summary, there is, as yet, no definitive evidence that endocrine treatment favourably affects the outcome of patients with HCC.
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Affiliation(s)
- S Pignata
- Istituto Nazionale dei Tumori, Napoli, Italy
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