Effect of androgens and their manipulation on cell growth and androgen receptor (AR) levels in AR-positive and -negative human hepatocellular carcinomas

Yu, Ling; Nagasue, Naofumi; Makino, Yoshinari; Nakamura, Teruhisa

doi:10.1016/0168-8278(95)80282-7

Cited by 20 publications

(7 citation statements)

References 28 publications

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“…Androgens can both up-regulate and down-regulate AR in a cell or tissue-specific manner [74,75]. Our data on correlation analyses showed an inverse relationship between AR mRNA and serum/tissue testosterone levels in both males and females with PTC, FTC and FTA.…”

Section: Discussionmentioning

confidence: 46%

Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers

Stanley

Aruldhas

Chandrasekaran

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionmentioning

confidence: 46%

Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers

Stanley

Aruldhas

Chandrasekaran

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…HCC has a higher incidence in males than females ( 45 , 46 ), and both serum and intracellular DHT to testosterone ratios are increased in patients with HCC compared with those with cirrhosis alone or normal controls ( 47 ). DHT enhances HCC cell proliferation in an AR-dependent manner ( 48 ), and the regression of HCC in response to AR antagonism is related to the reduction in circulating DHT levels ( 49 ). AR expression was observed in all of the mouse livers affected by HCC in our study (data not shown), although this is not a universal finding in the published literature ( 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice

et al. 2013

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Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.

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“…Therefore, in terms of tumorigenesis, DHT (a more active T metabolite and AR ligand) cannot be omitted. According to Yu et al DHT reinforces hepatocellular carcinoma cell division depending on AR activation [123], and the decline in HCC malignancy after AR antagonism treatment is linked with a decrease in blood DHT [124]. This data confirms the observations of Dowman et al [12], where more than half of the mice after one year of the ALIOS diet revealed hepatocellular lesions similar to those observed in HCC, compared to one-fifth of 5αR2 −/− and zero of 5αR1 −/− (isoform 5α-reductase knockout) mice.…”

Section: Hcc Malignancy and Sex Hormonesmentioning

confidence: 99%

Sex Hormone-Dependent Physiology and Diseases of Liver

Kur

Kolasa

Misiakiewicz-Has

et al. 2020

IJERPH

111

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Sexual dimorphism is associated not only with somatic and behavioral differences between men and women, but also with physiological differences reflected in organ metabolism. Genes regulated by sex hormones differ in expression in various tissues, which is especially important in the case of liver metabolism, with the liver being a target organ for sex hormones as its cells express estrogen receptors (ERs: ERα, also known as ESR1 or NR3A; ERβ; GPER (G protein-coupled ER, also known as GPR 30)) and the androgen receptor (AR) in both men and women. Differences in sex hormone levels and sex hormone-specific gene expression are mentioned as some of the main variations in causes of the incidence of hepatic diseases; for example, hepatocellular carcinoma (HCC) is more common in men, while women have an increased risk of autoimmune liver disease and show more acute liver failure symptoms in alcoholic liver disease. In non-alcoholic fatty liver disease (NAFLD), the distinction is less pronounced, but increased incidences are suggested among men and postmenopausal women, probably due to an increased tendency towards visceral fat accumulation.

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Effect of androgens and their manipulation on cell growth and androgen receptor (AR) levels in AR-positive and -negative human hepatocellular carcinomas

Cited by 20 publications

References 28 publications

Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers

Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers

Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice

Sex Hormone-Dependent Physiology and Diseases of Liver

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