Effect of antiandrogen treatment on chemical hepatocarcinogenesis in rats

Matsuura, Bunzo; Taniguchi, Yoshiyasu; Ohta, Yasuyuki

doi:10.1016/s0168-8278(05)80393-9

Cited by 20 publications

(11 citation statements)

References 19 publications

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“…Nevertheless, clinical trials using various anti-androgens in the attempt to treat HCC have inconsistent conclusions (Groupe d'etude et de traitement du carcinome, H., 2004, Matsuura et al, 1994, Chao et al, 1996). Several hypotheses have been proposed to elucidate this riddle, such as the fact that most of the anti-androgen therapies were developed to reduce/antagonize androgens from binding to AR, but not to target AR itself.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies revealed a male predominance in HCC, which suggested that androgen/AR signals may promote hepatocarcinogenesis (Yeh and Chen, 2010). However, the results from several clinical trials using various anti-androgens to treat HCC remain controversial (Groupe d'etude et de traitement du carcinome, H., 2004, Matsuura et al, 1994, Chao et al, 1996). Interestingly, Ma et al revealed that AR might suppress advanced-stage HCC metastasis using liver-specific deletion of AR (L-ARKO) mice model and in vitro HCC cell lines, and over-expressing AR with Sorafenib treatment could better suppress the HCC progression at late stages (Ma et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals

Lin

et al. 2016

EBioMedicine

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The androgen receptor (AR) was found to suppress hepatocellular carcinoma (HCC) metastasis at late stages. Due to this discovery, we searched for some AR enhancers to increase the efficacy of Sorafenib chemotherapy, and identified the microRNA (miR)-367-3p, whose expression is positively correlated with AR expression in advanced HCC, as an HCC metastasis suppressor. Combining miR-367-3p with Sorafenib showed better efficacy to suppress HCC cell invasion in vitro and in vivo. Mechanism dissection revealed that miR-367-3p could increase AR expression via directly targeting the 3′UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FKBP5 and PHLPP, thus dephosphorylating and inactivating AKT and ERK, to suppress the HCC cell invasion. Interestingly, the suppression of pAKT by miR-367-3p could subsequently attenuate the phosphorylation of AR and MDM2, giving rise to additional enhancement of AR protein expression, effectively forming a positive feedback loop. Together, these results suggest that miR-367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FKBP5/PHLPP/(pAKT and pERK) signals to better suppress HCC metastasis. Successful development of this newly combined chemotherapy in the future may help us to better suppress the HCC metastasis at late stages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals

Lin

et al. 2016

EBioMedicine

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“…HCC occurs much more frequently in men than in women, with a male to female ratio ranging from 2:1 to 11:1 (3). Both animal and human studies support the importance of androgen signaling in determining the male preference of HCC (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). It was also noted that the expression and activation of androgen receptor (AR) is increased in the tumor tissues as well as in the surrounding nontumorous liver tissue of patients with HCC (14)(15)(16).…”

mentioning

confidence: 87%

Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Chiu

Yeh

Chen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

130

120

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Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBVrelated HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.androgen-responsive element H epatocellular carcinoma (HCC) is one of the leading cancers in the world, with more than half a million deaths per year (1). Chronic hepatitis, caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, is a major risk factor for the development of HCC (2). Another risk factor is the male gender. HCC occurs much more frequently in men than in women, with a male to female ratio ranging from 2:1 to 11:1 (3). Both animal and human studies support the importance of androgen signaling in determining the male preference of HCC (4-13). It was also noted that the expression and activation of androgen receptor (AR) is increased in the tumor tissues as well as in the surrounding nontumorous liver tissue of patients with HCC (14-16). Intriguingly, the gender preference of HCC differs between HBV-and HCV-related cases. The male predominance in HBV-related HCC is significantly higher than that of HCVrelated HCC, with a ratio of 5-7:1 vs. 2-3:1 (17, 18). Among male HBV carriers, those with a higher level of serum androgen and more active AR gene alleles have a significantly increased risk of HCC (19,20). However, these two factors have not been reported to contribute to the increased risk of HCV-related HCC. Thus, HBV infection might uniquely cooperate with androgen signaling to accelerate hepatocarcinogenesis, raising the possibility that certain HBV gene(s) could modulate AR signaling activity and HCC development.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (21,22). It consists of several functional domains individually responsible for the activities ...

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“…Animal studies demonstrated that the expression of both AR and ER increases during preneoplastic stages and that progression towards cancer development can suppress ER and maintain AR expression levels [94,100] . Interestingly, anti-androgen treatment has been shown to reduce AR levels in liver as well as the size and number of tumors in male Spargue Dawley rat model of hepatocarcinogenesis [101] . It has been shown that inhibition of AR positive HCC with anti-androgen cypertone acetate in male mice involves cell cycle arrest and to some extent induction of apoptosis due to increased synthesis of transforming growth factor-β 1 (TGF-β1) [102] .…”

Section: Androgen Receptor Studiesmentioning

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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Effect of antiandrogen treatment on chemical hepatocarcinogenesis in rats

Cited by 20 publications

References 19 publications

The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals

The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals

Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

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