Sex steroid receptor proteins in foetal, adult and malignant human liver tissue

Iqbal, Mohammad Perwaiz; Wilkinson, Mark; Pj, Johnson; Williams, Roger

doi:10.1038/bjc.1983.268

Cited by 91 publications

(31 citation statements)

References 29 publications

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“…In 1978, Duffy and Duffy first reported the presence of ER in normal human liver [28] . Subsequently, the presence of ERs in human HCC was demonstrated by Molteni et al [29] followed by Friedman et al [30] and Iqbal et al [31] . Since then, a number of studies have been reported addressing the expression of ERs in normal as well as neoplastic liver tissues.…”

Section: Estrogen Receptormentioning

confidence: 99%

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Kalra¹,

Mayes²,

Assefa³

et al. 2008

WJG

133

116

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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 ERα alone until 1996 when ERβ 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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Section: Estrogen Receptormentioning

confidence: 99%

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Kalra¹,

Mayes²,

Assefa³

et al. 2008

WJG

133

116

View full text Add to dashboard Cite

show abstract

“…Regardless of the etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more common in men than in women (16,54). The significance of androgen receptor (AR) expression in HCC and the surrounding liver has been studied extensively (18,31,33). With this background, we decided to investigate the relationship between AR and HCC after HCV infection, knowing that human liver expresses both estrogen receptors and ARs.…”

mentioning

confidence: 99%

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Kanda

Steele²,

Ray

2008

J Virol

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Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male-dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross talk with the androgen receptor (AR) signaling pathway for promotion of carcinogenesis. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of the Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of AR in liver and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. Together, our results suggest that HCV core protein acts as a positive regulator in AR signaling, providing further insight into oncogenic potential in the development of HCC in HCV-infected individuals.Hepatitis C virus (HCV) infection affects nearly 4 million people and is the most common cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (23). The current approved therapy for treatment for HCV is pegylated interferon in combination with ribavirin (43). Although several advances have shown promise for improving the management of HCV infection, it nevertheless remains as a major health problem (2, 7, 60). Regardless of the etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more common in men than in women (16,54). The significance of androgen receptor (AR) expression in HCC and the surrounding liver has been studied extensively (18,31,33). With this background, we decided to investigate the relationship between AR and HCC after HCV infection, knowing that human liver expresses both estrogen receptors and ARs.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (14, 17). The transcriptional activation function of AR is not only essential for normal sexual development in men but is also implicated in the progression of cancer (9). AR has a modular structure containing the N terminus harboring transcriptional activation domain(s), a central DNA-binding domain, and a C-terminal ligand-binding domain. Binding of androgen to the ligand-binding domain induces conformational change in AR and leads to the shuttling of receptor from the cytoplasm to the nucleus, where it forms a homodimer and is recruited to the AR element (ARE). ARE is present in the regulatory elements on the target genes such as vascular endothelial growth factor (VEGF) and transforming growt...

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“…The stimulatory effect on fetal hepatocyte proliferation may be due to the direct action of estrogen receptors present in fetal hepatocytes (PASQUALINI, SUMIDA and GELLY, 1976;IQBAL et al, 1983;LAX et al, 1983). An increase in RNA polymerase activity by estrogens may be a possible trigger for hepatocyte proliferation, as has been reported for the uterus (CLARK and PECK, 1979).…”

Section: Discussionmentioning

confidence: 99%

“…E3 is the most potent stimulant of hepatocyte proliferation among these three natural estogens (FUJII, HAYAMA and KOTANI,1985). Estrogen receptors are known to exist in the fetal liver cells of various species (PASQUALINI, SUMIDA and GELLY, 1976;IQBAL et al, 1983;LAX et al, 1983). Therefore, in the present study, fetal mouse livers were transplanted beneath the kidney capsule of adult hosts and E3 was administered to ascertain its possible physiological role in the growth of the fetal liver.…”

mentioning

confidence: 99%

Promotion by Estriol of the Development of Grafted Fetal Livers in Mice.

Terao

Kotani

1995

Archives of Histology and Cytology

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Summary. Mouse fetal livers of 12 days gestation were transplanted beneath the kidney capsule of syngeneic castrated male hosts. Recipients received a single intraperitoneal injection of 5 mg estriol (E3) immediately after transplantation and were sacrificed 4, 7 and 14 days later. Control mice received injections of solvent only. The fetal liver grafts of the E3 groups showed remarkable growth compared with the control grafts at each corresponding time. In the grafted fetal livers of the E3 groups, many more basophilic hepatocytes appeared for much longer periods, and the early formation of wide sinusoids was noted. Although hemopoietic activity had almost ceased a short time after transplantation in the control grafts, many prominent extra. sinusoidal erythroid, granulocytic and megakaryocytic hemopoietic foci developed and persisted to the end of the experiments in the grafted fetal livers of the E3 groups. In the next experiment, the recipients received three injections of 0.5-5 mg E3 at 5-day intervals, and were sacrificed 21 days after transplantation. Control animals received solvent only in the same manner. The fetal liver grafts of the E3 groups also showed remarkable, dose dependent growth. The growth was particularly striking at doses of 3-5 mg E3. In the grafts of these groups, basophilic hepatocytes were predominant, and hepatic cords and sinusoids were well formed. Moreover, sinusoidal erythropoiesis was intense. These results provide evidence for the possible role of E3, secreted from the placenta into the fetal circulation, in the development of the fetal liver.

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Sex steroid receptor proteins in foetal, adult and malignant human liver tissue

Cited by 91 publications

References 29 publications

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Promotion by Estriol of the Development of Grafted Fetal Livers in Mice.

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